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FLUOROURACIL
Evaluaciones de DRUGDEX®

OVERVIEW
1) Class
a) This drug is a member of the following class(es):
Antimetabolite
Antineoplastic, Dermatological
Antineoplastic Agent
2) Dosing Information
a) Adult
1) use patient's actual weight for dosage calculation; use the estimated lean body mass (dry weight)
if the patient is obese or had spurious weight gain due to edema, ascites or other forms of abnormal
fluid retention [1]
a) Actinic keratosis
1) cover lesions TOPICALLY with 2 or 5% solution or cream twice daily for 2 to 6 weeks [80], or
with 0.5% microsphere formulation once daily for up to 4 weeks [81]
b) Breast cancer, Palliative
1) 12 mg/kg IV daily for 4 days, if tolerated then 6 mg/kg IV daily on days 6, 8, 10, 12 (MAX dose
800 mg/day); if tolerated maintenance therapy may be given by repeating the first course every 30
days, after the last day of the previous treatment cycle or 10 to 15 mg/kg/week after toxic signs
resulting from the initial course of therapy have subsided; MAX dose 1 g/week [1]
c) Carcinoma of pancreas, Palliative
1) 12 mg/kg IV daily for 4 days, if tolerated then 6 mg/kg IV daily on days 6, 8, 10, 12 (MAX dose
800 mg/day); if tolerated maintenance therapy may be given by repeating the first course every 30
days, after the last day of the previous treatment cycle or 10 to 15 mg/kg/week after toxic signs
resulting from the initial course of therapy have subsided; MAX dose 1 g/week [1]
d) Colorectal cancer, Adjuvant
1) Oxaliplatin 85 mg/m(2) IV on weeks 1,3, 5 for three 8-week cycles with an IV bolus of fluorouracil
500 mg/m(2) and leucovorin 500 mg/m(2) IV weekly for 6 weeks of an 8-week cycle for 3 cycles
[33]
e) Colorectal cancer, Palliative
1) 12 mg/kg IV daily for 4 days, if tolerated then 6 mg/kg IV daily on days 6, 8, 10, 12 (MAX dose
800 mg/day); if tolerated maintenance therapy may be given by repeating the first course every 30
days, after the last day of the previous treatment cycle or 10 to 15 mg/kg/week after toxic signs
resulting from the initial course of therapy have subsided; MAX dose 1 g/week [1]
f) Gastric cancer, Palliative
1) 12 mg/kg IV daily for 4 days, if tolerated then 6 mg/kg IV daily on days 6, 8, 10, 12 (MAX dose
800 mg/day); if tolerated maintenance therapy may be given by repeating the first course every 30
days, after the last day of the previous treatment cycle or 10 to 15 mg/kg/week after toxic signs
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resulting from the initial course of therapy have subsided; MAX

dose 1 g/week [1]

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resulting from the initial course of therapy have subsided; MAX dose 1 g/week [1]
g) Superficial basal cell carcinoma
1) cover lesions TOPICALLY with 5% cream or solution twice daily for 3 to 6 weeks up to 10 to 12
weeks
b) Pediatric
1) safety and effectiveness in children has not been established [1]
3) Contraindications
a) Bone marrow depression
b) Dihydropyrimidine dehydrogenase enzyme deficiency (topical route) [205]
c) Hypersensitivity to fluorouracil or capecitabine
d) Poor nutritional state
e) Pregnancy, existing or potential (topical)
f) Serious infection
4) Serious Adverse Effects
a) Anaphylaxis
b) Angina
c) Bleeding
d) Cardiotoxicity
e) Cerebellar syndrome, acute
f) Coronary arteriosclerosis
g) EKG finding
h) Eye / vision finding
i) Finding of lacrimation
j) Gastrointestinal ulcer
k) Immune hypersensitivity reaction
l) Myelosuppression, Anemia, leukopenia, thrombocytopenia
m) Nystagmus
n) Photophobia
o) Stenosis of lacrimal system
p) Thrombophlebitis
5) Clinical Applications
a) FDA Approved Indications
1) Actinic keratosis
2) Breast cancer, Palliative
3) Carcinoma of pancreas, Palliative
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4) Colorectal cancer, Palliative
5) Gastric cancer, Palliative
6) Superficial basal cell carcinoma
b) Non-FDA Approved Indications
1) Colorectal cancer, Adjuvant

DOSING INFORMATION
Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the
Tradename List (Product Index)
B) Synonyms
5-Fluorouracil
5-FU - 5-Fluorouracil
Fluorouracil
C) Orphan Drug Status
1) Fluorouracil has been designated an orphan drug product for use in the treatment of
esophageal carcinoma, colorectal carcinoma, and colorectal adenocarcinoma in conjunction with
other agents.
D) Physicochemical Properties
1) Molecular Weight
a) 130.08 [368][360]
2) pH
a) Injection: approximately 9.2 [368]; topical cream: approximately 8.5 [549]
3) pKa
a) 8, 13 [550]
4) Solubility
a) Sparingly soluble in water; slightly soluble in alcohol; 1 g is soluble in 100 mL of propylene
glycol [360][549].

Storage and Stability
A) Preparation
1) General Information
a) Use proper procedures for the handling and disposal of chemotherapy [203].
b) Fluorouracil injection is for IV use only [203].
2) Intravenous route
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a) Dilution is not required before fluorouracil IV administration [203].
b) When transferring the fluorouracil solution from a pharmacy bulk vial, the contents must be
transferred within 4 hours after puncturing the vial. The vial should only be punctured one time.
Additionally, the transferred drug solution should be administered within 4 hours [203].
3) Topical application route
a) Apply Efudex(R) with a non-metallic applicator or suitable glove. If Efudex(R) is applied with
fingers, wash hands immediately after application [82].
b) Apply a thin film of Carac(R) cream 10 minutes after thoroughly washing, rinsing, and drying
the area; may apply with fingertips; wash hands immediately after application [81].
B) Parenteral route
1) Fluorouracil solutions should be stored at 15 to 30 degrees Celsius (C) (59 to 86 degrees
Fahrenheit (F)) and protected from light. Solutions may discolor slightly but potency and safety
are not adversely affected. Any precipitate which forms may be resolubilized by heating to 140
degrees F and agitating; allow to cool to body temperature before using [207].
2) Fluorouracil solution (Roche) maintained 98% to 100% potency over 48 hours after dilution
and storage in syringes or ethylene vinyl acetate infusion-pump reservoirs. Fluorouracil was
diluted to 12 and 40 mg/mL with normal saline or 5% dextrose injection and stored in 60-mL
polypropylene syringes for 72 hours. It was also diluted to 15 and 45 mg/mL with normal saline
and stored in ethylene vinyl acetate infusion-pump reservoirs. High-performance liquid
chromatography and thin-layer chromatography were used to measure fluorouracil concentrations
and urea, a product of fluorouracil degradation [405].
3) Fluorouracil in 5% dextrose injection showed a biphasic decrease in potency in both glass and
plastic containers. In glass, however, the initial decrease was greater and more rapid. The
decrease of fluorouracil content in glass was 10% by seven hours; however, a 10% decrease was
not observed until 43 hours in plastic [406].
4) The stability of fluorouracil prepared for infusion in plastic containers used in IV administration
systems intended for home use was investigated. Fluorouracil 500 mg was diluted in 5% dextrose
to a total volume of 50 mL in a plasticized polyvinylchloride container (MVP drug reservoir) or 60
mL in an elastomeric balloon used in a disposable drug pump (Infusor). Storage without
protection from light at room temperature and at 5 degrees C was continued for 4 months with
periodic sampling. High performance liquid chromatography (HPLC) assays revealed no significant
loss of potency and no degradation over 16 weeks in the MVP drug reservoir and change in
concentrations in Infusor bags was less than 10% over this time period at room temperature. In
MVP reservoirs, a progressive increase in fluorouracil concentration was observed (presumably
due to water loss due to evaporation through the container) with a predicted change of 10% in
concentration occurring at 55 days. Infusor bags were not studied at room temperature. The
investigators concluded that fluorouracil is stable in 5% dextrose in these containers for at least
16 weeks when stored at 5 degrees C [407].
5) The stability of aqueous fluorouracil 50 mg/mL was studied in portable infusion pumps under
simulated infusion conditions. The drug was found to be stable for 7 days at 37 degrees C.
However, at 25 degrees C a fine white precipitate was reported after 48 to 96 hours in the
extension tubing of the devices containing Roche brand fluorouracil. Precipitate formation was
also reported in all solutions adjusted to below pH 8.7 [408].
6) Fluorouracil 50 mg/mL was stable in polypropylene infusion-pump syringes at 30 degrees C for
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21 days [409].
C) Latex/Polyvinylchloride Gloves
1) Using a radiotracer method, the permeability of latex and polyvinylchloride gloves to
fluorouracil and methotrexate were determined. Both types of gloves demonstrated timedependent permeability to both agents. Intra-lot variability was seen, suggesting exposure of
personnel could be variable [410].
D) Microwave Thawing
1) Precipitate in fluorouracil injection can be redissolved by heating to 60 degrees C in a
microwave oven without significantly affecting the drug's stability [411].

Adult Dosage
Normal Dosage
Intra-arterial route
1) Intra-arterial administration of fluorouracil 800 to 1200 milligrams/m(2) as a
continuous infusion on days 1 to 4, followed by 600 milligrams/m(2) as a continuous
infusion on days 5 to 21 has been used for hepatic tumor involvement [4]. Also,
hepatic artery infusion of fluorouracil in doses of 10 to 30 milligrams/kilogram/day and
15 milligrams/kilogram/week as maintenance/adjuvant therapy have been used in
hepatic carcinoma and hepatic metastases [194][155][195][196]. Adjuvant hepatic
arterial bolus infusions (over 10 minutes) of fluorouracil 15 milligrams/kilogram/week
(duration of 6 months) were administered to 20 patients undergoing curative
resection of colorectal liver metastases [194].
Intralesional route
1) In one study, intradermal fluorouracil (15 to 150 milligrams twice weekly by
infiltration of tumor sites) was useful in infiltrating basal cell carcinoma [197]. In
another study, patients were treated with 1 to 3 milliliters of fluorouracil for
keratoacanthomas. Each treatment included injections to the periphery and the center
of the lesions. Injections were given at 1- to 4-week intervals. Lesions were
successfully cleared [151].
Intravenous route
Breast cancer, Palliative
a) The recommended intravenous dose of fluorouracil is 12 milligrams/kilogram
(mg/kg) once daily for 4 successive days. In the absence of toxicity, 6 mg/kg
may be given on the 6th, 8th, 10th and 12th days unless toxicity occurs, with
therapy being discontinued after the 12th day. No therapy is given on the 5th,
7th, 9th or 11th days; total daily dose should not exceed 800 mg [1].
b) Maintenance therapy may be considered in patients tolerating fluorouracil
toxicity by repeating the first course every 30 days, after the last day of the
previous treatment cycle. Alternatively, a single maintenance dose of 10 to 15
mg/kg/week may be given after toxic signs resulting from the initial course of
therapy have subsided; a dose of 1 gram weekly should not be exceeded [1].
Carcinoma of pancreas, Palliative
a) The recommended intravenous dose of fluorouracil is 12 milligrams/kilogram
(mg/kg) once daily for 4 successive days. In the absence of toxicity, 6 mg/kg
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may be given on the 6th, 8th, 10th and 12th days unless toxicity occurs, with
therapy being discontinued after the 12th day. No therapy is given on the 5th,
7th, 9th or 11th days; total daily dose should not exceed 800 mg [1].
b) Maintenance therapy may be considered in patients tolerating fluorouracil
toxicity by repeating the first course every 30 days, after the last day of the
previous treatment cycle. Alternatively, a single maintenance dose of 10 to 15
mg/kg/week may be given after toxic signs resulting from the initial course of
therapy have subsided; a dose of 1 gram weekly should not be exceeded [1].
Cervical cancer
a) HIGH-RISK CERVICAL CANCER
1) The study group in this trial was administered cisplatin 75 milligrams/square
meter (mg/m(2)) infused over 4 hours followed by fluorouracil (5-FU) 4000
mg/m(2) infused over 96 hours plus a total of 85 Gy radiation. Chemotherapy
was given every 3 weeks for a total of 3 cycles. Again, when compared to
radiation alone, this regimen achieved significantly better survival [545].
b) In a trial by the Radiation Therapy Oncology group (RTOG), CISPLATIN (75
milligrams/square meter on day 1 of weeks 1, 5, 8, and 11) in combination with
FLUOROURACIL (1 gram/square meter continuous infusion on days 1 through 4
of weeks 1, 5, 8, and 11), and RADIATION (50 Gy delivered in 25 fractions) was
administered to patients with nondisseminated squamous or adenocarcinoma of
the thoracic esophagus. This combination achieved significantly greater survival
than radiation alone [546].
1) LOCALLY ADVANCED CERVICAL CANCER
a) This trial was divided into 3 groups. The first group received cisplatin 40
milligrams/square meter (mg/m(2)) over 4 hours at weeks 1 through 6. The
second group received cisplatin 50 mg/m(2) on days 1 and 29,
FLUOROURACIL 4 grams/square meter as a 96 hour infusion on days 1 and 29,
and HYDROXYUREA 2 grams/square meter orally twice a week at weeks 1
through 6. The CONTROL group was administered only hydroxyurea 3
grams/square meter orally twice weekly on weeks 1 through 6. All groups
received RADIATION at varying doses depending on stage of disease. Actual
survival rates among the first, second, and the control groups were 66%,
67%, and 49.7%, respectively [547].
Colorectal cancer, Adjuvant
a) Based upon studies using the combination of oxaliplatin, fluorouracil and
leucovorin the following regimens have been used. The FLOX regimen consists
of oxaliplatin 85 milligrams per square meter (mg/m(2)) intravenously (IV) on
weeks 1,3 and 5 for three 8-week cycles added to leucovorin 500 mg/m(2) IV
and IV bolus fluorouracil 500 mg/m(2) weekly for 6 weeks of an 8-week cycle
for 3 cycles [33]
Colorectal cancer, Palliative
a) The recommended intravenous dose of fluorouracil is 12 milligrams/kilogram
(mg/kg) once daily for 4 successive days. In the absence of toxicity, 6 mg/kg
may be given on the 6th, 8th, 10th and 12th days unless toxicity occurs, with
therapy being discontinued after the 12th day. No therapy is given on the 5th,
7th, 9th or 11th days; total daily dose should not exceed 800 mg [1].
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and 5 Repeat all doses every 3 weeks mg/m(2) = milligrams/square meter thomsonhc. a single maintenance dose of 10 to 15 mg/kg/week may be given after toxic signs resulting from the initial course of therapy have subsided. and 11). Alternatively. starting 1 day prior to docetaxel (day 0) Docetaxel 75 mg/m(2) intravenously over 1 hour on day 1. this regimen achieved significantly better survival [545]. Cisplatin. and 11) in combination with FLUOROURACIL (1 gram/square meter continuous infusion on days 1 through 4 of weeks 1.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Esophageal cancer a) HIGH-RISK CERVICAL CANCER 1) The study group in this trial was administered cisplatin 75 milligrams/square meter (mg/m(2)) infused over 4 hours followed by fluorouracil (5-FU) 4000 mg/m(2) infused over 96 hours plus a total of 85 Gy radiation. and RADIATION (50 Gy delivered in 25 fractions) was administered to patients with nondisseminated squamous or adenocarcinoma of the thoracic esophagus. Administer sequentially in the following order: Premedicate docetaxel with dexamethasone 8 mg orally twice daily for 3 days. when compared to radiation alone.25/10/12 Drug details . 3. b) In a trial by the Radiation Therapy Oncology group (RTOG).IntermediateToDocumentPrintLink 7/317 . cisplatin. Again.MICROMEDEX® 2. 5. 8. and fluorouracil improved overall survival compared to cisplatin and fluorouracil in patients with advanced gastric adenocarcinoma (n=445). a dose of 1 gram weekly should not be exceeded [1]. Chemotherapy was given every 3 weeks for a total of 3 cycles. 8. 2. after the last day of the previous treatment cycle. This combination achieved significantly greater survival than radiation alone [546]. followed by: Cisplatin 75 mg/m(2) intravenously over 1 to 3 hours on day 1. Fluorouracil (TCF) 1) A regimen consisting of docetaxel. 5. followed by: Fluorouracil 750 mg/m(2)/day intravenously over 24 hours on days 1. CISPLATIN (75 milligrams/square meter on day 1 of weeks 1. Gastric cancer a) Advanced Gastric Adenocarcinoma: Docetaxel.0 b) Maintenance therapy may be considered in patients tolerating fluorouracil toxicity by repeating the first course every 30 days. 4. including adenocarcinoma of the gastroesophageal junction [60].

10th and 12th days unless toxicity occurs. thomsonhc. lean body weight is used if the patient is obese or if there is weight gain secondary to edema or ascites [1]. Gastric cancer. or neutropenia lasting more than 7 days [60]. Three cycles were administered (every 28 days). However. mitoguazone has been given in doses of 400 milligrams/square meter over 90 minutes on days 1 and 8. however. This regimen enabled organ preservation without an apparent compromise of survival. resectable carcinoma of the head and neck. then repeated at 5 weeks in patients with colorectal carcinoma. No therapy is given on the 5th. each given twice daily. An oral dose of fluorouracil 15 milligrams/kilogram/week was used in patients with hepatoma [200]. granulocyte-colony stimulating factor (G-CSF) was recommended during the second and/or subsequent cycles in case of febrile neutropenia.0 2) In the clinical trial.25/10/12 Drug details . complete responders or those with tumor downstaging to T1N1 were given radiation therapy (total doses of approximately 70 Gy) [544]. 8th. Head and neck cancer a) In untreated good-risk patients with advanced.MICROMEDEX® 2. respectively. Palliative a) The recommended intravenous dose of fluorouracil is 12 milligrams/kilogram (mg/kg) once daily for 4 successive days. In the absence of toxicity. 6 mg/kg may be given on the 6th. with therapy being discontinued after the 12th day. after the last day of the previous treatment cycle. documented infection with neutropenia. Continuous ambulatory infusions of fluorouracil produced better response rates than traditional bolus infusions in patients with advanced colorectal cancer [66]. further study is warranted [65]. Alternatively. 7th. Oral route Breast cancer a) A 28-day regimen (5-week courses) has been administered to previously treated advanced BREAST CANCER patients [548]. The fluorouracil dosage is based on actual body weight. combined with continuous infusions of cisplatin 30 milligrams/square meter plus 5-fluorouracil on days 8 to 12. 9th or 11th days. then once weekly to 20 patients with advanced colorectal cancer on an outpatient basis [198][199]. c) Continuous 5-day infusions may provide greater efficacy than 5-day intermittent bolus injections in gastrointestinal carcinoma. total daily dose should not exceed 800 mg [1]. Fluorouracil 15 milligrams/kilogram/day was administered orally for 6 days. Doses of eniluracil and 5fluorouracil were 10 milligrams/square meter (mg/m(2)) and 1 mg/m(2). a dose of 1 gram weekly should not be exceeded [1]. Fluorouracil 20 milligrams/kilogram/day was administered orally for 5 days. a single maintenance dose of 10 to 15 mg/kg/week may be given after toxic signs resulting from the initial course of therapy have subsided. b) Maintenance therapy may be considered in patients tolerating fluorouracil toxicity by repeating the first course every 30 days.IntermediateToDocumentPrintLink 8/317 .com/micromedex2/librarian/PFDefaultActionId/evidencexpert.

Ten minutes before applying the cream. The treatment period is usually 2 to 6 weeks. A sufficient amount should be used to cover entire affected areas. Normal response to therapy is erythema. especially when treating areas other than the head and neck [85]. usually followed by vesiculation. erosion. Therapy should be continued until the inflammatory response reaches the erosion. c) In the treatment of multiple actinic (solar) keratoses. 5%)) recommends a twice daily application with a sufficient amount to cover the lesion.IntermediateToDocumentPrintLink 9/317 . The average duration of therapy was 6.25/10/12 Drug details . The mouthwash was administered for 10 days and repeated for 2 to 10 courses (Umsawasdi et al. use a nonmetallic applicator or fingertips to apply. Topical application route Actinic keratosis a) Fluorouracil cream 0. but may be longer. Superficial basal cell carcinoma a) Apply the 5% cream or solution (only the 5% strength is recommended) twice daily in an amount sufficient to cover lesions and continue for at least 3 to 6 weeks. 1975). Intraoral Mouthwash a) Fluorouracil 1 gram was used intraorally as a mouthwash for inducing remission in patients with residual or localized relapsing cancer of the lip. Dosage in Other Disease States A) Obesity 1) The American Society of Clinical Oncology guidelines on appropriate chemotherapy dosing for obese adult patients with cancer include the following highlights [202]: 1). rinsed. usually 2 to 4 weeks (complete healing may not occur for 1 to 2 months after cessation of therapy). only a thin layer of cream is needed. Treatment should be continued for up to 4 weeks (Prod Info fluorouracil Microsponge(R).0 Oral and intravenous administration of fluorouracil 15 milligrams/kilogram/week was compared in patients with pancreatic cancer.5% incorporated into a microsphere (Microsponge(R)) should be applied once daily to actinic keratosis lesions and the surrounding skin. Therapy may be required for as long as 10 to 12 weeks for obliteration of lesions [80]. If the lesions were not flattening and desquamating. and dried.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Oral administration was associated with a greater incidence of toxicity than the intravenous route [201]. Ten patients applied the solution to affected areas morning and evening 1 day a week.MICROMEDEX® 2. b) The manufacturer of Efudex(R) (fluorouracil cream (5%). solution (2%. necrosis and ulceration stage. the skin should be thoroughly washed. necrosis and epithelialization [80]. obese. the manufacturer of Fluoroplex(R) (fluorouracil 1%) recommends a twice daily application to affected areas. Toxicity is no greater for thomsonhc. ulceration. buccal mucosa or soft palate. the weekly pulse was increased to two consecutive days of treatment a week. Chemotherapy doses should be calculated using actual body weight in overweight. d) Weekly pulse dosing with topical fluorouracil 5% solution was reported effective and acceptable in patients with actinic keratosis. and morbidly obese adult patients (BMI greater than 25). 2000) [81].7 weeks with a recovery period of 2 to 4 weeks [86].

or impaired hepatic or renal function). Dubois and Dubois.0 obese patients with appropriate dosing. regardless of obesity. carboplatin and bleomycin. especially when the goal of treatment is cure. or widespread involvement of bone marrow by metastatic tumors. 5). should be followed. Depending on the type and severity of a toxicity.25/10/12 Drug details . curative or palliative). Gehan and George. comorbidities must be considered. if no toxicity occurs. and the intent of the treatment (ie. PHARMACOKINETICS Drug Concentration Levels A) Therapeutic Drug Concentration 1) Colorectal cancer. the same guidelines for dose reductions. and 9. B) Poor Risk . The total daily dose in these patients should not exceed 400 milligrams [1]. previous use of alkylating agents.IntermediateToDocumentPrintLink 10/317 . history of high-dose pelvic irradiation. Pediatric Dosage Normal Dosage Intravenous route 1) The safety and effectiveness of fluorouracil in pediatric patients has not been established [1]. 4). 2000 to 3000 mcg/L [374]. acute toxicity was linked to a plasma concentration greater than 3000 mcg/L [374]. continuing with 3 milligrams/kilogram on days 5. It provided a high survival rate and was well tolerated. 3). and closely monitor. 6. BSA can be calculated using any of the standard formulas such as Mosteller. Initial intravenous doses for these patients should be 6 milligrams/kilogram/day for 3 days. No therapy is administered on days 4. however. If a dose reduction is needed. 7. Fixed dosing is only recommended for select cytotoxic agents which can safely be dosed independently of weight or body surface area (eg.MICROMEDEX® 2. Haycock.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. thomsonhc. 2). or Boyd. or when vincristine is capped at a maximum dose of 2 mg when used in the CHOP and CVP regimens). or 8. a) This therapeutic range was used for determining the dose of a weekly 8-hour infusion.Inadequate Nutritional Status 1) Lower doses of fluorouracil should be used in poor risk patients (poor nutritional state. consider returning to the appropriate weight-based dose upon resolution. Full weight-based dosing (IV or oral) should be administered to obese patients. comorbid conditions.

5% fluorouracil cream 1 gram (g) daily and 5% fluorouracil cream 1 g twice daily for up to 28 days. B) Time to Peak Concentration 1) Intrapericardial.996 hours.001). 14.999 to 1.492 ng/ml (range. the mean 5-FU Css was 94 ng/mL with 27% interpatient and 20% intrapatient coefficients of variation. the peak concentration was 1.075 hours. parallel group study involving 21 patients (mean age. Patients were administered interferon alfa-2a (5 million units subcutaneously on days 1-7).25/10/12 Drug details . The median thomsonhc. were 3. respectively.803 ng x h/ml and in 6 patients receiving 5% fluorouracil cream was 22. 5-fluoro-5. Intravenous.507 to 37.4 ng x h/mL [376]. the concentration decreased to 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 0. open label. Intrapericardial. 5fluoro-5. b) The mean AUC's of the parent drug 5-FU were 3.2 ng/ml) and a mean Tmax of 1.6 and 5. the median AUC on day four was 2018 microM x min compared with 1721 microM x min on day one (p less than 0.26 mcg/mL appearing at mean Tmax of 0.390 ng x h/ml (range. respectively. a) The mean peak concentrations (Cmax) of the parent drug 5-FU were 18.5% fluorouracil cream was 2. 5-FU Css did not correlate with response or toxicity [380].74 mg/mL.113 mg/mL at 5 hours [377].61 mcg/mL x h [375]. in 20 patients with colorectal cancer. patients received topical 0. 16 to 24 mg x h/L [374]. and fluorouracil 370 mg/square meter IV over one hour on days 2-6. were 5.5% fluorouracil group demonstrated a maximum observed drug concentration (Cmax) value of 0. respectively [375].739 mg x hr/mL [377]. 5-fluoro-5. a) After intrapericardial administration to 1 patient. [376].41 mcg/mL after IV bolus doses of 250 and 370 mg/m(2).0 2) Colorectal cancer.77 to 13.MICROMEDEX® 2. 3.IntermediateToDocumentPrintLink Cmax value for the fluorouracil 370 11/317 . 22. respectively.6-dihydrouracil.39 and 8. In a randomized. 2) Oral: 35 minutes [379] 3) Intravenous bolus: 0.025 hours (range.45 and 0. infusion: 45 minutes [377]. d) In a study evaluating fluorouracil as a one-hour infusion in 22 patients with gastrointestinal tract cancers. a) One patient in the 0.45 and 0.15 and 48. Only.518 ng x h/ml). Topical.050 to 27. 64 years) with actinic keratosis. c) The AUC in one patient receiving 0. A randomized. a) This was determined from 0 to 8 hours during a continuous 8-hour infusion. after 5-FU doses of 250 and 370 mg/m(2).61 mcg/mL x h after IV bolus doses of 250 and 370 mg/m(2). 4) Topical: 1 hour [376]. 5. Corresponding average Cmax values for the catabolite. C) Area Under the Curve 1) Intravenous.69 hour. Corresponding average AUC's for the catabolite.77 and 13.69 hour for the catabolite. 64 years) with actinic keratosis.6-dihydrouracil (5-FDHU).75 mcg/mL x hr [375].768 nanograms (ng)/milliliter (ml) and time to maximum drug concentration (Tmax) of 0. respectively [375].5% fluorouracil cream 1 gram (g) daily (n=11) and 5% fluorouracil cream 1 g twice daily (n=11) for up to 28 days. patients received TOPICAL 0.6-dihydrouracil. mean steady state concentration (Css): 94 ng/mL [380]. parallel group study involving 21 patients (mean age. open label. 7 patient's data were evaluable [376]. acute toxicity was linked to an AUC from 0 to 8 hours greater than 24 mg x h/L [374]. Six patients receiving 5% fluorouracil demonstrated a mean Cmax of 11. followed immediately by leucovorin 500 milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6. 4. a) In a study of 61 patients with colorectal cancer receiving 5-FU 300 mg/m(2)/day via protracted venous infusion for up to 26 weeks.

parallel group study involving 21 patients with actinic keratosis [376]. a) The systemic absorption of TOPICAL 0. draining lymph nodes.5% and 5% fluorouracil cream was 0. b) Bioavailability of oral dose was 50% to 80% that of intravenous administration [379].55% and 2.IntermediateToDocumentPrintLink 12/317 . respectively. and neoplastic tissue [385][381][386].1 microM. cerebral spinal fluid. liver. tumor. liver. The Cmax and AUC following fluorouracil 370 mg/square meter as a five-minute injection were 7. The average Cmax and median Tmax values were 1092 mcg/L and 0. of 5-FU absorption in patients receiving oral eniluracil (50 mg). e) The AUC was estimated after intrapericardial administration of fluorouracil 200 mg to 1 patient [377]. but not the extent.4-fold increase in the time to peak plasma concentration (Tmax) compared to when they fasted before receiving a dose of 5-FU.006). brain. respectively [383].3-fold and 2. One-hour fluorouracil infusion data was compared retrospectively with five-minute fluorouracil injection data from a study utilizing an identical dose schedule and modification guidelines. in an open label. than following the one-hour infusion.4%. Distribution A) Distribution Sites 1) Tissues and Fluids a) TISSUES 1) FLUOROURACIL distributes in tissue and extracellular fluid. and bowel wall following intramural injection. 1999)[381] a) Oral FLUOROURACIL is incompletely absorbed from the gastrointestinal tract (Bruckner & Cresey.95 hours for the fed group. including intestinal mucosa.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. portal blood. B) Effects of Food 1) Consumption of food 20 minutes before oral administration of 5-FU 20 mg/m(3) decreased the rate. Best overall concentrations are in blood.MICROMEDEX® 2. respectively. 1974)[382].0 mg/square meter IV over one hour on days 2-6. 2) Topical: Systemic absorption is minimal [376][381]. bone marrow. In this randomized.4-fold higher. The lower decreased systemic exposure with the one-hour infusion was associated with a lower apparent clinical toxicity [378].8 hours for the fasting group and 822 mcg/L and 1. When patients consumed meal before 5-FU administration. Poorest distribution followed intraluminal administration [387]. they showed a 25% decrease in maximal plasma concentration (Cmax) and a 2. p=0. respectively. ADME Absorption A) Bioavailability 1) Oral: 0% to 80% (Iyer & Ratain. pharmacokinetic data was obtained for a group of 12 patients who either ate a full meal 20 minutes before 5-FU administration or fasted for 2 hours before 5-FU administration. two-way crossover study. The median Cmax value for the fluorouracil 370 mg/square meter dose cycle was significantly higher on day four compared with day one (32.25/10/12 Drug details .2 microM versus 22. thomsonhc.

inactive metabolites [385] Excretion A) Kidney 1) Renal Clearance (rate) a) 170 to 180 mL/min [386] 1) Based upon urinary excretion data in a open label. Individuals with genetic DPD deficiency have altered 5. parallel group study involving 21 patients with actinic keratosis. 2) Renal Excretion (%) a) 7% to 20% [385][381] . 0 to 15 mcg).B) Distribution Kinetics 1) Distribution Half-Life a) Distribution phase half-life (t1/2-alpha) was 3. potentially active [381] 2) Carbon monoxide urea and alpha-fluoro-beta-alanine. in a study of 20 patients with colorectal cancer [375]. undetectable to 330 mcg) and 40 mcg/hour.FU pharmacokinetic profiles and have experienced severe 5-FU-related toxicity (Iyer & Ratain.6 and 1. respectively [376]. Michaelis-Menten) elimination. B) Metabolites 1) Dihyro-5-fluorouracil. 2) Volume of Distribution a) Volume of distribution ranged from 13 to 27 L in five studies of intravenous bolus administration (Iyer & Ratain. respectively [375]. respectively.14 and 4.57 mg/L (mean).39 mcg/hour in patients treated with topical 0. no such correlations existed for Km [388]. The mean steady-state Vd after IV bolus doses of 250 and 370 mg/m(2) were 9. respectively. 1999). The interpatient variabilities in these parameters were 20% to 22%. Body surface area and the degree of metastatic liver involvement were positively correlated with Vmax. while the half-saturating plasma concentration (Km) was 5. The corresponding average maximum rate of elimination (Vmax) was 1390 mg/h. Metabolism A) Metabolism Sites and Kinetics 1) LIVER. b) In a study of 21 patients with colorectal carcinoma who received folinic acid 200 mg/m(2) over 2 hours. then 5-FU 400 mg/m(2) over 10 minutes followed by a continuous infusion of 600 g/m(2) over 22 hours. 5-fluoro-5. The corresponding values in patients treated with topical 5% fluorouracil cream were 120 mcg over 24 hours (range.8 and 8. the cumulative fluorouracil excreted over 24 hours was 3 micrograms (mcg) (range. in 20 patients with colorectal cancer.6. were 7. Corresponding mean t1/2-alpha for the catabolite. primary site [385][386] a) The rate-limiting step in the metabolism of 5-fluorouracil (5-FU) is conversion to 5-6dihydrofluorouracil by the enzyme dihydropyrimidine dehydrogenase (DPD).dihydrouracil. investigators determined that the pharmacokinetics of 5-FU are consistent with the two-compartment model with nonlinear (saturable. with a mean maximum excretion rate of 0. 1999).15 L/m(2).4 minutes.5% fluorouracil cream.2 minutes for parent drug 5-FU after IV bolus doses of 250 and 370 mg/m(2).

Continuous intravenous infusion. followed immediately by leucovorin 500 milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6.003).0 B) Total Body Clearance 1) Intravenous bolus. 1999)[381] 1) After intrapericardial administration of fluorouracil 200 mg to 1 patient. the median day one clearance of all fluorouracil doses was significantly higher than on day four (1764 versus 1297 ml/min/square meter. expired as carbon dioxide [386] Elimination Half-life A) Parent Compound 1) ELIMINATION HALF-LIFE a) 6 to 22 minutes [385][375].64 and 25. range of 777 to 1410 mL/min. b) These instructions should be thoroughly reviewed before administration of fluorouracil [204].2 and 48 minutes after IV 5-FU bolus doses of 250 and 370 mg/m(2). p=0. range of 3097 to 7000 mL/min in four studies of continuous intravenous infusion (Iyer & Ratain. One-hour infusion.MICROMEDEX® 2. 2001).43 L/h/m(2).64 and 25. trace amounts [381] b) Lung. 1999). Following IV bolus doses of 250 and 370 mg/m(2) in 20 patients with colorectal cancer. Because of the possibility of severe toxic reactions. 14/317 . C) Other 1) OTHER EXCRETION a) Bile. the elimination half-life was 169 minutes [377]. it is recommended that patients be hospitalized at least during the initial course of therapy. the mean total body clearances of the parent drug 5-FU were 54. b) In a study evaluating fluorouracil as a ONE-HOUR INFUSION in 22 patients with gastrointestinal tract cancers. respectively. 1999). 54. range of 3097 to 7000 mL/min(Iyer & Ratain. and fluorouracil 370 mg/square meter IV over one hour on days 2-6 [378]. B) Metabolites 1) 52. respectively. respectively [375]. (Iyer & Ratain. Patients were administered interferon alfa-2a (5 million units subcutaneously on days 1-7). 1297 to 1764 mL/min/sq meter (Green et al. a) Range of 777 to 1410 mL/min in five studies of intravenous bolus administration.43 L/h/m(2)[375]. in 20 patients with colorectal cancer [375]. Intravenous Bolus. CAUTIONS Black Box Warning 1) Intravenous (Solution) a) It is recommended that fluorouracil be given only by or under the supervision of a qualified physician who is experienced in cancer chemotherapy and who is well versed in the use of potent antimetabolites.25/10/12 Drug details .

impaired fertility D) Metastases involving bone marrow E) Previous high dose pelvic irradiation F) Previous treatment with alkylating agents G) Renal or hepatic impairment H) Use proper procedures for handling and disposal of chemotherapy Adverse Reactions Cardiovascular Effects Acute coronary syndrome 1) A 48-year-old male developed acute coronary syndrome. Ramipril 10 mg/day and bisoprolol 5 mg/day (later changed to diltiazem 240 mg/day) was prescribed and the patient was discharged. the patient developed convulsive status epilepticus.IntermediateToDocumentPrintLink 15/317 . diarrhea.25/10/12 Drug details .5 nanograms/mL). vomiting. The patient was stabilized following dobutamine administration and placement of an intraaortic balloon pump. the patient presented to the emergency room with chest pain radiating toward both arms. Chemotherapy was initiated with a FOLFOX regimen consisting of 5-fluorouracil 400 mg/m(2) (followed by slow infusion of 2400 mg/m(2) over 46 hours). following a chemotherapy regimen including 5-fluorouracil for the adjunctive treatment of colic adenocarcinoma. ECG results showed severe hypokinesia in all apical and median segments and a left ventricular ejection fraction (LVEF) of 15%. Twenty-four hours later. Two weeks later. and was transferred to the cardiology intensive care unit.0 Contraindications A) Bone marrow depression B) Dihydropyrimidine dehydrogenase enzyme deficiency (topical route) [205] C) Hypersensitivity to fluorouracil or capecitabine D) Poor nutritional state E) Pregnancy. Blood pressure and heart rate were stable and there were no signs of cardiac failure. similar to Tako-Tsubo cardiomyopathy. Clinical examination found no signs of cardiac failure.MICROMEDEX® 2. thomsonhc. and a mildly increased troponin T level (0. existing or potential (topical) F) Serious infection Precautions A) Dihydropyrimidine dehydrogenase enzyme deficiency (intravenous route) [204] B) Avoid application of topical FLUOROURACIL to mucous membranes or irritated skin. The cycle was well tolerated and diltiazem was discontinued. oxaliplatin 85 mg/m(2) and calcium folinate 200 mg/m(2). and do not use occlusive dressing C) Carcinogenic. received cardiopulmonary resuscitation for cardiac arrest. mutagenic. A few hours following the end of the 5-fluorouracil infusion. Total recovery of left ventricular dysfunction was confirmed 1 month later by MRI and a second cycle of chemotherapy was administered at half of the initial dose.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. a third cycle was administered using a full dose regimen and on the second day of therapy the patient complained of chest pain radiating to the upper limbs.

the patient had chest pain with nausea and diaphoresis. 2000).0 however. an LVEF of 35%.75 mg/day.IntermediateToDocumentPrintLink 16/317 . 2) Ischemic chest pain was described in a 67-year-old man on the third day of a 5-day continuous infusion of fluorouracil (1500 mg/day). the LVEF was 62% and no rhythm disturbances occurred during the rest of the hospitalization.MICROMEDEX® 2. Angina 1) ISCHEMIC CHEST PAIN and myocardial ischemia may occur with intravenous fluorouracil administration [207]. within 58 hours he developed hypotension that required dopamine and norepinephrine. The Naranjo adverse drug reaction probability scale revealed a probable relationship (score of 8) between the development of Tako-Tsubo-like syndrome and 5-flurouracil in this case [216]. It is speculated that fluorouracil can induce CORONARY ARTERY SPASM. although studies must confirm this [222]. but may or may not be prevented with vasodilators such as nitrates or calcium channel blockers [220][219]. This was the first course of combined chemotherapy and radiation therapy for a Duke's B colorectal cancer. The FOLFOX regimen was discontinued. the onset of pain at rest and within 3 days of the start of fluorouracil infusion suggested that fluorouracil was the precipitating cause of the chest pain. Angina at rest occurred in a 70-year-old man on two different occasions at 72 and 24 hours after the initiation of continuous fluorouracil (1000 mg/square meter/day). Cardiogenic shock 1) Cardiogenic shock. and low cardiac output indexes. and diaphoresis or signs of electrocardiogram changes may occur [217][218]. The patient experienced crushing central chest pain at rest and transient electrocardiogram changes. hypokinetic left ventricle with an ejection fraction of 7%. After several days. occurred in a 72-year-old woman on the 4th day of the 5th monthly 5-day treatment with 5-FU (425 milligrams (mg)/square meter (m(2)) per day) and folinic acid (20 mg/m(2)/day) for resected rectal adenocarcinoma.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. which improved after discontinuation of the fluorouracil infusion. The coronary artery spasm recurred upon rechallenge with fluorouracil [223]. Further fluorouracil therapy was discontinued and the patient proceeded with radiation therapy alone for his colorectal cancer [221]. Although a subsequent cardiac catheterization revealed severe triple-vessel disease. angiography revealed a dilated. vomiting.25/10/12 Drug details . and bisoprolol was restarted at 3. unresponsive to inotropic and vasopressor treatment. transthoracic echocardiography showed an abnormal left ventricle with diffuse hypokinesia. After 50 hours (3750 milligrams). After fluorouracil discontinuation. 2) A case of reversible cardiogenic shock was associated with continuous fluorouracil infusion in a 48-year-old male with no cardiac history. An intra-aortic balloon pump (IABP) maintained systemic perfusion with dramatic improvement within 48 hours. 3) VARIANT ANGINA during weekly intravenous fluorouracil therapy in a 63-year-old male with no history of angina pectoris was reported. ejection fraction improved from 20% with severe global hypokinesia to 50% with septoapical hypokinesia (10 days after IABP) and finally to normal (30th day) (David et al. Diltiazem given for 24 hours prior to subsequent fluorouracil courses prevented further episodes. Associated symptoms of nausea. 4) A bolus dose of fluorouracil 250 mg induced coronary artery spasm. hemodynamic parameters also indicated cardiogenic thomsonhc. Onset of pain in many cases occurs within hours of receiving a second or third dose but may be associated with the first dose [219][220]. ANGINAL ATTACKS often recur upon rechallenge. ramipril was continued.

on day 5. ECG showed ST segment elevation in leads. Death has occurred secondary to cardiogenic shock [233][234]. Clinical status improved with dobutamine and furosemide [225]. hypokinetic left ventricle. II. Serum levels of cardiac enzymes and echocardiography were normal. On day 4. Fluorouracil was discontinued and sublingual nitroglycerin provided immediate. but temporary relief. however. cardiomyopathy.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. She had no cardiac symptoms on follow-up. Echocardiography and right heart catheterization confirmed alteration of the myocardial contractility. Most commonly. anginal attacks. The patient recovered uneventfully after a period of 2 weeks. sudden death [228][229][226][230][231][232]. myocardial infarction. aVF. and very rarely. Cardiotoxicity 1) Summary a) Although uncommon. hemodynamic parameters also indicated cardiogenic shock.IntermediateToDocumentPrintLink 17/317 .25/10/12 Drug details . The first patient was a 40-year-old woman with no prior history of heart disease being treated for adenocarcinoma of the cecum and who developed cardiotoxicity on the third day of the first cycle of fluorouracil. tachycardiac. The patient developed cardiac and renal failure approximately 1 day after a 5-day course of 5fluorouracil and cisplatin for laryngeal neoplasm. most reported cases are in those with no previous history of CAD [230][231]. The patient was discharged on oral diltiazem 90 mg/day and different chemotherapy agents were started. these effects occur when the drug is administered as a continuous infusion and within several hours from the start of the infusion. Patients with pre-existing coronary artery disease (CAD) appear to be at greater risk. Chest radiograph revealed right pleural effusion and infiltrate. Symptoms from a massive aortic embolism began 16 hours after the end of the infusion. the patient had no previous cardiac symptoms or ECG/chest radiogram abnormalities [227]. and hypotensive. Despite. Cardiomyopathy 1) Acute DILATED CARDIOMYOPATHY was described in a 41-year-old male with heart failure and renal failure following fluorouracil therapy [226]. The patient was admitted to the cardiac care unit and given heparin and a nitroglycerin infusion. This appears to be the first case report of acute dilated myocardiopathy secondary to 5-fluorouracil. moderate ethanol consumption. Dopamine administration was required to control blood pressure. 2) Two patients undergoing chemotherapy with IV fluorouracil (425 mg/m(2)/day) and folinic acid (25 mg/m(2)/day) developed cardiotoxicity (chest pain and ECG changes) requiring discontinuation of fluorouracil. Clinical status improved over the next day [224].0 with an ejection fraction of 7%. III. Coronary angiography revealed normal cardiac physiology.MICROMEDEX® 2. fluorouracil has been associated with chest pain. the patient was dyspneic. ischemic electrocardiographic changes. fluorouracil was discontinued. 3) Another case describes reversible cardiogenic shock related to continuous fluorouracil infusion intravenously (750 mg/m(2)/day) and intraperitoneally (1000 mg/m(2)/day) each for 5 days in a 38-year-old male with no cardiac history. V5. The second patient was a 63-year-old man with a thomsonhc. Diagnostic testing showed no signs of coronary artery stenosis. 2) A case of fatal acute dilated cardiomyopathy associated with continuous infusion of fluorouracil (1 gram/square meter(m(2)/day for 120 hours) pretreated with cisplatin 100 mg/m(2) on day 1 has been reported. and V6. electrocardiogram indicated a dilated.

Other treatments consisted of topical or sublingual nitroglycerin and an increased oxygen rate. autoimmune phenomena.MICROMEDEX® 2. were present. This compound may be metabolized to fluoroacetate (FAC).Drug details .6% to 68%).9%) cases of suspected cardiotoxicity during high-dose. cohort study identified 9 (1. four major impurities including fluoracetaldehyde-acetal. Based upon retrospective and anecdotal reports it appears that the incidence of fluorouracilinduced toxicity has increased from 1. V4. Although several hypotheses regarding the mechanism of this adverse effect are under investigation. increased myocardial oxygen demand. The patient was discharged on an oral nitrate and diltiazem and fluorouracil was discontinued [232]. investigators estimated the overall incidence as varying from 1. a highly cardiotoxic substance [239]. and may be due to the administration of high-dose fluorouracil [236][237].5 mol% of the total contents. most cases are fully reversible within a few days.2% to 13. The mechanism of fluorouracil-induced cardiotoxicity is the topic of much speculation. V5. The predominant symptom was chest pain but dysrhythmia and marked hypotension were also noted. III. and V6. only 1 had a recurrence of symptoms.6% incidence of cardiotoxicity associated with high-dose continuous infusion fluorouracil in a prospective study of 367 patients was reported. due to acetalisation by tris. (de Forni et al. Nuclear magnetic resonance (NMR) spectroscopic analysis of Roche fluorouracil vials.3% of cases. concomitant medications. Seven of 9 cases required termination of the infusion. Results of this study were similar to others except high-dose. Atherosclerotic plaques were identified in the left anterior descending and circumflex arteries. endothelial cell damage with thrombus formation. The right coronary artery was totally occluded proximally. Experimentation with animal models has 18/317 . The patient had ST segment elevation in leads II. Patients with pre-existing ischemic heart disease or myocardial infarction showed a higher risk for cardiotoxicity than patients without these conditions. 1992). The typical onset is within hours of the initial 5-FU dose.2% to 18% with resultant mortality in 2. 5) A 7. dose and route of administration. thrombogenic effect.6% to approximately 10% during the 1980 to 1990 period. coronary vasospasm. displayed 6 fluorinated compounds accounting for 1 to 1. Five of the 9 patients were rechallenged with 5-FU. 1992). 3) In a review of fluorouracil (5-FU)-associated cardiotoxicity. IV nitroglycerin and diltiazem were initiated in the cardiac care unit and his chest pain resolved within 30 minutes. however. such as coronary vasospasm. France distribution). and fluoroacetate formation [235][238]. 5-FU should be discontinued when cardiotoxicity arises and should not be reinstituted due to a high incidence of recurrence [228]. age and gender do not consistently correlate with 5-FU-associated cardiotoxicity. 4) A prospective. as pre-existing cardiac disease or chest irradiation. continuous infusion of fluorouracil (5-FU) which was lower than reported in other studies (7. Available data do not permit clinicians to predict which patients are at risk.0 history significant for coronary artery disease with adenocarcinoma of the duodenum who developed cardiotoxicity on the third day of fluorouracil. Proposed mechanisms include: direct myocardial toxicity. 6) Fluoroacetaldehyde has been found in fluorouracil vials (manufactured by Roche Pharmaceuticals. (de Forni et al. aVF. results are inconclusive. interference with myocardial cell metabolism and dihydropyrimidine dehydrogenase deficiency. continuous infusion resulted in a low incidence of cardiotoxicity compared to earlier studies [235]. There were no elevations in cardiac enzymes and echocardiography was normal. FAC was not present.

episodes of "ischemia" recorded during therapy and baseline were 356 and 28. One review very briefly summarizes 10 cases of sudden death associated with high-dose fluorouracil infusions in a retrospective review of 244 patients [230].com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details . The patient had interventricular septal defect since childhood and was receiving digoxin for atrial flutter. EKG finding 1) Twenty-five patients with carcinomas of the head and neck were monitored for electrocardiogram (ECG) changes from baseline during fluorouracil infusion (4 to 5 grams/square meter over 96 to 120 hours). respectively. Only one patient experienced angina. and FAC has been detected in urine in patients receiving Roche fluorouracil. suggestive of ischemia. respectively. others have hypothesized the occurrence of sudden death in association with fluorouracil exposure. Of the patients with ST elevations or depressions. after the administration/monitoring period. Premature ventricular depolarizations were also more common during therapy. Upon rechallenge with fluorouracil 1 month later. Cardiac enzymes were also elevated (creatine phosphokinase and aspartate transaminase) and chest thomsonhc. a) Two patients died suddenly 4 and 12 hours. Coronary arteriosclerosis 1) Myocardial ischemia has been reported in patients receiving intravenous fluorouracil [207]. but not all of whom experienced cardiotoxicity [239]. two others died suddenly 4 and 12 hours. 3) Thirty-five cases of fluorouracil-associated myocardial ischemia were summarized by 2 investigators [220]. but only these 4 out of 140 total patients treated similarly developed chest pain [242]. after the administration/monitoring period in a prospective study of electrocardiogram (ECG) changes from baseline during fluorouracil infusion (4 to 5 grams/square meter over 96 to 120 hours) in 25 patients with carcinoma of the head and neck [231].0 demonstrated that the conversion of fluoracetaldehyde to FAC does occur in vivo. some. c) Raised ST segment and inverted T-waves were reported in a 33-year-old male who developed cardiotoxic effects secondary to 5-fluorouracil [233]. 2) Two cases of 5-FU cardiotoxicity manifested by ECG or cardiac enzyme changes while they were receiving 5-FU by prolonged infusion were reported (Sanani. All patients had received left ventricular irradiation prior to drug treatment. both patients had ST segment changes (with no ischemic evidence at baseline) and increased incidence of premature ventricular depolarizations. Continuous ambulatory Holter monitoring revealed 17 of 25 patients with ST segment changes. respectively. which continued for 1 month after discontinuation of fluorouracil [240]. 1981). In addition. There were EKG abnormalities in 3 of the patients which included T-wave inversion. Two of the 4 patients had normal predose EKGs and none had a history of myocardial ischemia or hypertension. The authors cautioned that patients with preexisting coronary artery disease may be at greater risk for these changes [231]. During infusion. the patient redeveloped conduction abnormalities.MICROMEDEX® 2. Four cases of chest pain occurring after fluorouracil treatment were reported. during therapy as compared to 6 of 25 at baseline. 1992). b) Conduction disorders were reported in a 45-year-old male following fluorouracil 500 mg/m(2)/day therapy. (De Forni et al. Each patient developed ISCHEMIC CHEST PAIN within 18 hours of the second or third dose of 5-fluorouracil and a rechallenge was positive in 3 of the 4 patients. S-T elevation and peaked T-waves.IntermediateToDocumentPrintLink 19/317 .

com/micromedex2/librarian/PFDefaultActionId/evidencexpert. a 61year-old man developed severe contact sensitivity at application sites and later had a similar reaction to the first intravenous dose of 5-FU. Neither patient had a history of angina or of hypertension. the patient developed acute dermatitis. Some ST depression was evidenced on EKG. Rectal adenocarcinoma was later diagnosed. unstable angina. The patient responded to diltiazem and isosorbide therapy. areas of blistering and exudation developed.IntermediateToDocumentPrintLink 20/317 . dosage 10 mg/kg 4 days later [234]. she rapidly developed cardiogenic shock and died. Serial cardiac enzymes in the this patient revealed no evidence of myocardial infarction. after 1 intravenous bolus of 5-fluorouracil. or documented coronary artery spasm. It was recommended that fluorouracil be used cautiously in individuals with previous heart disease. vomiting and dyspnea. localized dermatitis soon after application of 5-FU cream should raise the suspicion of an allergic contact dermatitis reaction. but no reaction to propylene glycol occurred. which responded to diamorphine. Patch testing demonstrated a strong reaction to 5-FU in 1% petrolatum on days 2 and 4. during a continuous infusion of 5-fluorouracil (third day of the third treatment cycle which consisted of 1.84 g daily for 4 days). Thrombophlebitis 1) Thrombophlebitis has been reported in patients receiving intravenous fluorouracil [207]. If 5-fluorouracil infusions are administered to these patients. with no prior history of heart disease. After the first dose of intravenous 5-FU. ST elevations and ANTEROLATERAL ISCHEMIA with inverted T-waves has also been reported elsewhere [217]. The reaction was more severe on the right arm where the 5-FU was administered. 2) Cardiac arrest was described in a 61-year-old male. and an erythematous. nausea. it is recommended that concurrent use of calcium channel-blocking agents be considered [241]. The authors caution that rapid development of acute. 5-FU could not be used in this patient. head and neck edema. A 65-year-old female developed severe central chest pains several hours after the sixth bolus of 20 mg/kg 5-FU with concomitant features of sweating. The second case. and 5-FU 1 g/week administered intravenously. scalp. Both patients were on single-agent therapy for adenocarcinoma of the colon.MICROMEDEX® 2. Glyceryl trinitrate failed to relieve pain. Dermatologic Effects Contact dermatitis 1) After using topical fluorouracil (5-FU) 5% cream intermittently for 4 years. Acute transmural anterolateral MYOCARDIAL INFARCTION was evidenced by the EKG. Due to the severity of this reaction. and both hands.25/10/12 Drug details . Myocardial infarction 1) There are reports of 2 cases of cardiotoxicity secondary to 5-fluorouracil (5-FU). developed severe central chest pain that radiated into the left arm 7 hours after a second bolus dose of 5-FU (15 mg/kg).0 x-ray revealed pulmonary edema. Chest pains again occurred. radiotherapy. vesicular rash on the face. a 43-year-old male. with cardiac enzyme activities remaining within normal limits. but not as severe. The reaction to topical 5-FU began within 2 to 3 hours after application. treatment consisted of surgery. 2) Topical 5-fluorouracil has been associated with allergic contact DERMATITIS in thomsonhc. neck. especially in patients with a history of recent myocardial infarction. Electrocardiogram (EKG) monitoring suggested coronary artery spasm as the underlying event in this patient.

Non-itchy.IntermediateToDocumentPrintLink of neutropenia and hand-foot 21/317 . and desquamation may also occur. necrotic keratinocytes. FISSURING. Onset of the reaction has ranged from 3 days to 10 months [296][294]. pigment incontinence. Many irregular dark streaks were noted which extended from the hand to the shoulder. The linear erythematous streaks followed the superficial linearity of the veins. Drug-induced erythema 1) A causal relationship between infusion of 5-fluorouracil (5-FU) and the development of bilateral persistent supravenous erythematous eruption in a 47-yearold-male with squamous cell carcinoma was described (Rujol et al. however. (Prod Info fluorouracil injection. DRY SKIN. erythematous. PHOTOSENSITIVITY. Severity appeared dose related in one case [297]. symmetric swollen palms of hands and soles of feet [207][294]. Tingling. with the exception thomsonhc. The cutaneous eruption remitted over several weeks. Hair finding 1) ALOPECIA is also a commonly occurring effect following systemic fluorouracil therapy [208]. Topical 5fluorouracil ointment (5%) was reported to exacerbate dermatitis when it was mistakenly given instead of fluocinonide ointment [293]. however. This is the first case of its kind reported in the literature to date [303].4 to 5 cm in diameter also were observed on the trunk. and VEIN PIGMENTATION have been reported in patients receiving intravenous fluorouracil [207]. via continuous or intermittent infusions or bolus doses) has been associated with a syndrome characterized by varying degrees of painful. rash. erythematous macules and plaques of 0. These streaks were 1 to 1. The condition gradually subsides over 5 to 7 days when the drug is discontinued. and thighs. a linear eruption developed on both upper extremities and later extended to the trunk and legs. PALMAR-PLANTAR ERYTHRODYSESTHESIA. 1997). 1998). pyroxidine has been reported to ameliorate symptoms [207]. The patient developed nasal mucosal friability. nail changes.25/10/12 patients with actinic keratosis and basal cell epitheliomas [291][292]. ACRAL ERYTHEMA.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5 cm wide and serpignous in their course. The reaction has been described as PAINFUL RED HANDS. or hand-foot syndrome [295]. and perivascular lymphocytic infiltrates. Hand-foot syndrome due to cytotoxic therapy 1) The administration of fluorouracil (alone or in combination regimens. Dermatological finding 1) Alopecia. The patient received intravenous 5-FU in both forearms. No apparent extravasation or phlebitis was detected. diffuse hyperpigmentation of the face and hands and markedly increased pigmentation of skin immediately overlying the veins used for multiple fluorouracil infusion. hand-foot syndrome. lumbosacral area. 2) A meta-analysis of 6 randomized trials comparing intravenous fluorouracil by continuous infusion or bolus injection found that toxicities associated with the 2 methods were similar in frequency. Four days following therapy. Discoloration of skin 1) Serpentine supravenous fluorouracil HYPERPIGMENTATION was reported in a 56year-old black male following IV 5-fluorouracil 750 mg/m(2)/week over 24 weeks for stage D prostatic carcinoma. tenderness. recurrence may occur upon rechallenge [296]. Biopsy results showed prominent vacuolar alteration of basal cells. residual serpentine supravenous pigmentation became apparent. This cleared within a 3-month period.

MICROMEDEX® 2. and the patient was treated with steroids and saline compresses with a subsidence of symptoms [302]. Telangiectasia 1) Four patients receiving topical 1% 5-fluorouracil in propylene glycol applied TID for 7 to 28 days. the most common being a pruritic MACULOPAPULAR RASH appearing on the extremities and most frequently the trunk. Two patients developed herpes labialis 7 to 10 days after initiation of therapy and 2 patients developed persistent telangiectasia at the application site [304]. loss of nail.0 methods were similar in frequency.IntermediateToDocumentPrintLink 22/317 . was nearly doubled when fluorouracil was administered by continuous infusion (34% versus 13%. with the exception of neutropenia and hand-foot syndrome. Bullous lesions were pruritic and sore and some contained hemorrhagic fluid. half and half nail changes.0001). This is usually reversible upon withdrawal of 5-fluorouracil [207]. and a good performance status significantly increased the risk for nonhematologic toxicities. All treated lesions became bullous with development of a few bullae on untreated areas of normal skin. Leukocytosis (11.96). Nail damage 1) Diffuse blue superficial pigment. RR 0. nausea and vomiting. p less than 0. paronychial inflammation.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The lesions resolved following a 6-week course of topical 5-FU followed by topical triamcinolone for 10 days (Nabai et al. dystrophy. Anemia and thrombocytopenia occurred in less than 5% of all patients. In hand-foot syndrome. Blister fluid contained predominantly eosinophils and immunofluorescent studies of the serum and blister fluid revealed basement-membrane antibody titers of 1:640 and 1:160. Hematologic toxicity. 1999). respectively. Pemphigus 1) A case of BULLOUS PEMPHIGOID was reported in an 84-year-old male following topical therapy with 5-fluorouracil 1% solution daily over several days for actinic keratosis. which investigators described as a selective inflammatory reaction. a 72. while increased age.219 patients with colorectal cancer. Fluorouracil was discontinued. occurred significantly more often in patients receiving bolus injections (31% versus 4%. and hyperpigmentation have been reported with 5-fluorouracil therapy [207][298][299][300][301]. Rash 1) 5-Fluorouracil is associated with many types of skin reactions. The incidence of hand-foot syndrome. RR 1.year-old male developed pruritic rash evolving into lichenified plaques of the forearms in areas of preexisting actinic keratoses. transverse striations. mucositis was similar between groups (13% versus 14%. Topical midpotency corticosteroids were initially ineffective. Factors increasing the risk for hematologic toxicity included a poor performance status and fluorouracil administration by bolus injection.25/10/12 Drug details . p less than 0. primarily neutropenia. 2) Following a course of systemic 5-fluorouracil for colon cancer. the incidence of grade 3 to 4 diarrhea.14.001). however. RR 0. pain and thickening of the nail bed.87. It has further been reported that the blue pigment may be scraped off [299]. Endocrine/Metabolic Effects Hypercalcemia thomsonhc. In 1. female gender. continuous administration of fluorouracil was an additional prognostic factor [259]. ONYCHOLYSIS.700) was present.

2) Oral glutamine supplementation attenuated fluorouracil/folinic acid (5-FU/FA)induced changes in intestinal absorption and permeability in a placebo-controlled. bowel rest. The latter 4 patients were treated with calcium supplementation which led to resolution of symptoms. administered with dexamethasone 36 mg daily IV.02).05)[211]. with recurrent toxicity observed in 2 patients. Chemotherapy dosing included FA 100 milligrams/square meter (mg/m(2))/day plus 5-FU 450 mg/m(2)/day. The authors suggest that calcium levels should be monitored in patients receiving this regimen. resulted in rapid response [256]. urinary recovery of mannitol and the cellobiose/mannitol ratio also favored glutamine recipients. 15 (65%) developed hypocalcemia.4 mg% with leukopenia. each given for 5 days. and two each had tetany or hiccups. Parathyroid levels were within the normal range. Symptoms improved with supportive care. the active metabolite of irinotecan.4 tablet) thomsonhc.0 1) A case of malignant hypercalcemia was reported in a 36-year-old female with metastatic carcinoma of the breast following 5-fluorouracil 6 mg/kg IV daily for 5 days. and calcium supplementation should be provided if calcium levels are low [257]. Intravenous sodium sulfate. Gastrointestinal Effects Abdominal pain 1) A series of 6 adults. weakness. Average loperamide dosage requirements were significantly lower with glutamine (0. Grade 3/4 toxicity with the irinotecan/5-FU/LV regimen compared with the 5-FU/LV/irinotecan regimen included DIARRHEA (4% versus 17%). developed severe abdominal pain and diarrhea associated with intravenous fluorouracil and leucovorin administration for adenocarcinoma of the colon. was 40% lower when irinotecan was administered prior to 5-FU/LV versus after 5FU/LV (p less than 0. and a semi-comatose state.8%. aged 40 to 70 years. double-blind. Parathyroid and vitamin D levels were measured in 12 patients at the end of a single course of chemotherapy. Rechallenge during subsequent chemotherapy courses was generally well tolerated.IntermediateToDocumentPrintLink 23/317 . Serum calcium level was 9. Starting 5 days prior to the first 5-FU/FA cycle. Intestinal absorption of D-xylose decreased significantly more in the placebo group than in the glutamine group (7. and dosage reduction in most instances. randomized trial of 70 chemotherapy-naive patients with colorectal cancer.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Diarrhea 1) Toxicity was reduced with the administration of irinotecan prior to a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) compared with administration of irinotecan after 5-FU/LV in 23 chemotherapy-naive metastatic colorectal cancer patients. nausea and vomiting. The area under the curve (AUC) of SN-38. Hypocalcemia 1) Of 25 patients receiving low-dose leucovorin (20 mg/m(2)) and fluorouracil (425 to 600 mg/m(2)). and febrile neutropenia (4% versus 17%). The mechanisms for this toxicity may include direct vascular injury and increased thrombus formation which result in impaired gastric mucosal blood flow and injury [261][262]. tachycardia. As measures of intestinal integrity.1% versus 3. neutropenia (22% versus 39%). All patients underwent prior surgical resection. SMALL BOWEL PERFORATION accompanied by severe ulceration and inflammation was documented laparoscopically in 2 patients and required resection. but vitamin D levels were low in 4 patients.25/10/12 Drug details . patients consumed 6-gram sachets of either glutamine or placebo dissolved in water 3 times daily for a total of 15 days.MICROMEDEX® 2. p=0.

and the patient remains in complete remission. Cultures did NOT grow Clostridium difficile. Differences in the extent and duration of diarrhea between groups failed to reach statistical significance [263]. Treatment consisted of antibiotics including ticarcillin. The mechanism by which 5-FU causes PMC is potentially related to its antimitotic effect on intestinal crypt and its antibacterial activity which may alter the intestinal flora [267]. he had persistent abdominal pain. he was admitted to the hospital with fever. p=0. the leukocyte count and absolute neutrophil count were 1700/microliter and 270/microliter.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. intravenous fluids. 3) A 64-year-old man developed NEUTROPENIC ENTEROCOLITIS after receiving 3 courses of 5-fluorouracil 370 mg/m(2)/day and leucovorin 200 mg/m(2)/day administered as a bolus infusion for 5 consecutive days and repeated every 4 weeks. Subsequent computed tomography showed a normal bowel. and metronidazole and furosemide and spironolactone for bowel wall edema and ascites. This patient had an unusual course in that enterocolitis failed to resolve despite an increase in neutrophil count and appropriate therapy. treatment with oral vancomycin 500 mg 4 times daily resulted in a decrease of symptoms by 48 hours and complete resolution by 7 days. Treatment was for liver metastases associated with colon adenocarcinoma. this complication usually occurs in patients with hematologic malignancies [264]. retrospective review. Although this was a small. VOMITING. NAUSEA. Gastrointestinal tract finding 1) Commonly occurring symptoms during IV fluorouracil therapy are stomatitis. colitis suggestive of pseudomembranous colitis (PMC) developed in a 67year-old man with metastatic colon cancer. thomsonhc. jaundice.MICROMEDEX® 2. pain medications. abdominal cramps. and liquid stools with blood. it appears that the increased risk of toxicity should NOT preclude use of this therapy in patients with potentially curative disease. Additional diagnostic tests were consistent with enterocolitis. fever. However. the increased risk of toxicity should be carefully weighed in patients with incurable gastrointestinal cancer.25/10/12 Drug details .5 tablets. and ranitidine.IntermediateToDocumentPrintLink ANOREXIA and DIARRHEA 24/317 . however. 5) Diarrhea followed by neutropenia and life-threatening or fatal sepsis occurred in two of 55 patients with advanced colorectal carcinoma in a pilot study of continuous infusion fluorouracil (750 mg/m(2)/day for 5 days) plus subcutaneous recombinant interferon alfa-2a (6 to 18 million units/day) [266]. About 2 weeks after the third course. After discharge. 6) After 36 treatments with intravenous 5-fluorouracil (5-FU) 700 mg and folinic acid 150 mg. No further chemotherapy was administered. Presenting symptoms included fever. and diarrhea which required readmission. Endoscopy showed yellowish white plaques surrounded by hyperemic mucosa suggestive of PMC. it addresses a clinically important question since patients with IBD have an increased risk of developing gastrointestinal cancer [265]. The dosage or method of administering 5-FU or concurrent use of radiation therapy did NOT appear to influence development of severe diarrhea.002). both cases responded to oral vancomycin [268]. Two other cases of 5-FU-induced diarrhea and colitis associated with Clostridium difficile have been reported. The incidence of diarrhea reported in this small series of patients is higher than that reported in previous clinical trials.0 than with placebo (2. ESOPHAGOPHARYNGITIS. Based on data obtained in this small group of patients with IBD. diarrhea. Treatment comprised bowel rest. nine (53%) developed grade III/IV diarrhea during treatment with fluorouracil (5-FU) for gastrointestinal cancer. gentamicin. 4) Of 17 patients with previously diagnosed inflammatory bowel disease (IBD). right lower quadrant pain.

A significantly higher number of patients receiving fluorouracil over five minutes experienced grade 2 or greater mucositis (p=0. p less than 0.25/10/12 Drug details . and VOMITING). severe diarrhea. Nine (41%) patients receiving fluorouracil as a one. the incidence of grade 3 to 4 diarrhea. NEUTROPENIA. Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease included: dehydration (from DIARRHEA. however. leucovorin.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. nausea and vomiting. It has been suggested that the early deaths reported by Sargent et al may be due to the bolus administration of fluorouracil. was nearly doubled when fluorouracil was administered by continuous infusion (34% versus 13%.0001) and diarrhea (p=0. an adjuvant study of patients with resected stage III colon cancer. p less than 0. and leucovorin and a regimen of oxaliplatin and irinotecan. with the exception of neutropenia and hand-foot syndrome. The other trial. fluorouracil. Fluorouracil should be withdrawn at the first signs of stomatitis or esophagopharyngitis. Three large ongoing European trials have not reported an increased incidence of early deaths with infusional fluorouracil. The fluorouracil maximum observed drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) following a dose of 370 mg/square meter as a five-minute injection were 7. The incidence of hand-foot syndrome. respectively.0 ESOPHAGOPHARYNGITIS. Patients were administered interferon alfa-2a (5 million units subcutaneously on days 1-7). occurred significantly more often in patients receiving bolus injections (31% versus 4%. 3) An unexpectedly HIGH DEATH RATE occurring within 60 days after the initiation of treatment in patients receiving a regimen of IRINOTECAN.14. RR 0. intractable vomiting.001).0001). followed immediately by leucovorin 500 milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6. mucositis was similar between groups (13% versus 14%.219 patients with colorectal cancer.96). 4) A meta-analysis of 6 randomized trials comparing intravenous fluorouracil by continuous infusion or bolus injection found that toxicities associated with the 2 methods were similar in frequency. Hematologic toxicity.IntermediateToDocumentPrintLink toxicity included a poor 25/317 . and LEUCOVORIN for colorectal cancer was revealed in an interim analysis of data from two separate cooperative-group clinical trials sponsored by the National Cancer Institute and conducted throughout out the United States and Canada. FLUOROURACIL. compared fluorouracil and leucovorin with the irinotecan. One trial of patients with metastatic colon cancer compared the regimen of irinotecan. Factors increasing the risk for hematologic thomsonhc.3fold and 2. and SEPSIS [212]. ANOREXIA and DIARRHEA [207][258][208]. fluorouracil. and leucovorin (described by Saltz et al. than following the one-hour infusion [210]. and leucovorin regimen. Anemia and thrombocytopenia occurred in less than 5% of all patients. or GASTROINTESTINAL ULCERATION and BLEEDING [207]. and irinotecan [213]. NAUSEA. NAUSEA. 2) The clinical toxicity observed in a study involving 22 patients with gastrointestinal tract cancers was substantially lower in a trial utilizing a combination chemotherapy regimen with fluorouracil given as a ONE-HOUR INFUSION compared retrospectively with those observed in a study using the same regimen except fluorouracil was administered as a five-minute injection.009) compared with patients receiving fluorouracil as a one-hour infusion. primarily neutropenia.4-fold higher. and fluorouracil 370 mg/square meter IV on days 2-6. Dose modifications were made in both trials in an attempt to ameliorate the toxicity of the regimen. Enrollment in both trials has been suspended. while seven (32%) required a dose reduction.hour infusion tolerated a dose escalation to 425 mg/square meter or above.87. VOMITING. and irinotecan. 2000) with a regimen of oxaliplatin. fluorouracil. In 1. RR 0. leucovorin. RR 1.MICROMEDEX® 2.

5 mg/kg on the 6th and 8th day IV. neutropenia. all cases exhibited remarkable toxicity.IntermediateToDocumentPrintLink 26/317 . Following day 8 of the protocol. and SMALL BOWEL. 5) In patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency administered INTRAVENOUS fluorouracil. BLOODY DIARRHEA. DIARRHEA. STOMACH. and neurotoxicity have been reported. The patient died of bronchopneumonia. neutropenia. She had a leukocyte count of 1. In addition. Autopsy revealed ulcerations from ileocecal valve to the ileocolostomy site. Factors increasing the risk for hematologic toxicity included a poor performance status and fluorouracil administration by bolus injection. however. One case of life-threatening systemic toxicity has been reported with the TOPICAL use of fluorouracil in a patient with DPD enzyme deficiency. The patient developed severe diarrhea and severe ulceration of the bypassed portion of the colon resulting in necrosis of the bypassed portion. and INFLAMMATION OF THE ESOPHAGUS. The authors suggest that monitoring DPD activity may be appropriate in the management of those experiencing severe toxicity from 5-FU [215]. and methotrexate (50 mg/square meter) in combination with 5-FU (600 mg/square meter) on days 1 and 8. Symptoms were thomsonhc. Symptoms included SEVERE ABDOMINAL PAIN. In hand-foot syndrome. accounts for greater than 80% of the drugs catabolism.0 all patients. fever. Enhanced toxicity occurring at normal doses is what usually sets these patients apart. Only a few cases of DPD deficiency have been identified.100. small intestine and colon distal to the colostomy were not involved. she experienced what was classified as mild neurologic toxicity manifest as difficulty with balance. Although this case was observed with 5% fluorouracil cream. the patient experienced severe gastrointestinal (NAUSEA. and a good performance status significantly increased the risk for nonhematologic toxicities. DIARRHEA. 5-fluorouracil was given in doses of 15 mg/kg for 4 days then 7. VOMITING. it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil [205]. prolonged VOMITING.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 6) Severe GI toxicity secondary to 5-fluorouracil was reported in a 53-year-old male following a side to side ileo descending colostomy for disseminated carcinoma [260]. life-threatening toxicities such as STOMATITIS. and hematologic (neutropenia) toxicity that required hospitalization. thrombocytopenia. Gastrointestinal ulcer 1) Gastric ulceration and bleeding have been reported in patients receiving intravenous fluorouracil [207]. female gender. STOMATITIS). Physical examination revealed included STOMATITIS. Dihydropyrimidine dehydrogenase (DPD) as the initial enzyme responsible for the breakdown of 5-FU. The 5-FU doses received by the 35-year-old woman treated with the adjuvant protocol for breast carcinoma were not unusually high. erythematous skin rash. and chills. The mucosa of the stomach. One patient receiving 5-fluorouracil by intrahepatic infusion via percutaneous catheterization in doses of 20 to 30 mg/kg for 4 days followed by 15 mg/kg over 17 days developed gastric ulceration. rare.MICROMEDEX® 2.25/10/12 Drug details . Chemotherapy had been initiated 3 weeks after surgery with a combination of cyclophosphamide (orally 100 mg/day/square meter) for 14 days. while increased age. a) One occurrence of severe fluorouracil (5-FU) toxicity secondary to dihydropyrimidine dehydrogenase deficiency has been reported. with 5% neutrophils (no bands) and fever. continuous administration of fluorouracil was an additional prognostic factor [259]. and spelling simple words which persisted for about 2 weeks.

AGRANULOCYTOSIS. 2) Prevention a) To prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy. Confounders such as fluorouracil regimen and smoking status did not affect the incidence of stomatitis reported.002) with 17% of these reports being severe or very severe (12% male and 22% female. patients older than 65 years of age reported more stomatitis than those younger than 65 [269]. PANCYTOPENIA. stomatitis was reported by 57% of the patients (52% male and 63% female. and fluorouracil 370 mg/square meter IV on days 2-6. p=0. The white blood cell count usually returns to normal by the 30th day. Six clinical trials utilizing 8 different chemotherapeutic regimens were included in the analysis. EPISTAXIS. ANEMIA.IntermediateToDocumentPrintLink 27/317 . p=0. 2) The clinical toxicity observed in a study involving 22 patients with gastrointestinal tract cancers was substantially lower in a trial utilizing a combination chemotherapy regimen with fluorouracil given as a ONE-HOUR INFUSION compared retrospectively with those observed in a study using the same regimen except fluorouracil was administered as a five-minute injection.0 observed from 4 to 20 days after starting therapy [271]. Vomiting See Drug Consult reference: CHEMOTHERAPY AND RADIOTHERAPY TREATMENT GUIDELINES FOR NAUSEA AND VOMITING Hematologic Effects Hematology finding 1) Summary a) LEUKOPENIA is the most common hematologic toxicity associated with fluorouracil (5-FU) with the nadir typically between 9 and 14 days after treatment. Nausea See Drug Consult reference: CHEMOTHERAPY AND RADIOTHERAPY TREATMENT GUIDELINES FOR NAUSEA AND VOMITING Stomatitis 1) Literature Reports a) The results of a meta-analysis of 731 patients (402 men and 329 women) who received fluorouracil-based chemotherapy demonstrated that women are more likely to experience stomatitis than men.MICROMEDEX® 2.0001) compared with patients thomsonhc. maximum depression may be delayed as long as day 20 [207]. A significantly higher number of patients receiving fluorouracil over five minutes experienced grade 2 or greater leukopenia (0.0006). the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend 30 minutes of oral cryotherapy [270].0001) and granulocytopenia (p=0. No regimen was received by more than 40% of the patients included in the analysis and 95% of the patients had colorectal cancer.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Overall. However. Patients were administered interferon alfa-2a (5 million units subcutaneously on days 1-7). 2) GI bleeding occurred in 3 patients and death in 1 patient following intra-arterial 5fluorouracil [272]. and THROMBOCYTOPENIA have also been reported during treatment with intravenous 5-FU [207][208][209].25/10/12 Drug details . followed immediately by leucovorin 500 milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6.

Enrollment in both trials has been suspended. and leucovorin (described by Saltz et al. Anemia and thrombocytopenia occurred in less than 5% of all patients. Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease included: dehydration (from DIARRHEA. continuous administration of fluorouracil was an additional prognostic factor [214]. while increased age. was 40% lower when irinotecan was administered prior to 5-FU/LV versus after 5FU/LV (p less than 0. than following the one-hour infusion [210]. Factors increasing the risk for hematologic toxicity included a poor performance status and fluorouracil administration by bolus injection. the incidence of grade 3 to 4 diarrhea. was nearly doubled when fluorouracil was administered by continuous infusion (34% versus 13%.87. The incidence of hand-foot syndrome. and irinotecan. Dose modifications were made in both trials in an attempt to ameliorate the toxicity of the regimen.4-fold higher. It has been suggested that the early deaths reported by Sargent et al may be due to the bolus administration of fluorouracil. Three large ongoing European trials have not reported an increased incidence of early deaths with infusional fluorouracil. 5) A meta-analysis of 6 randomized trials comparing intravenous fluorouracil by continuous infusion or bolus injection found that toxicities associated with the 2 methods were similar in frequency. RR 0. fluorouracil. NAUSEA.IntermediateToDocumentPrintLink 28/317 . p less than 0.14.MICROMEDEX® 2. In hand-foot syndrome.001). RR 0. 4) An unexpectedly HIGH DEATH RATE occurring within 60 days after the initiation of treatment in patients receiving a regimen of IRINOTECAN. The area under the curve (AUC) of SN-38.05)[211]. Hematologic toxicity.3fold and 2. and leucovorin and a regimen of oxaliplatin and irinoteca. NEUTROPENIA. One trial of patients with metastatic colon cancer compared the regimen of irinotecan. p less than 0. The other trial. an adjuvant study of patients with resected stage III colon cancer.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. leucovorin. Nine (41%) patients receiving fluorouracil as a one-hour infusion tolerated a dose escalation to 425 mg/square meter or above. and leucovorin regimen. FLUOROURACIL. fluorouracil. 3) Toxicity was reduced with the administration of irinotecan prior to a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) compared with administration of irinotecan after 5-FU/LV in 23 chemotherapy-naive metastatic colorectal cancer patients. RR 1. primarily neutropenia. neutropenia (22% versus 39%). fluorouracil. and LEUCOVORIN for colorectal cancer was revealed in an interim analysis of data from two separate cooperative-group clinical trials sponsored by the National Cancer Institute and conducted throughout out the United States and Canada. The fluorouracil maximum observed drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) following a dose of 370 mg/square meter as a five-minute injection were 7.0 receiving fluorouracil as a one-hour infusion. however. In 1. and irinotecan [213].219 patients with colorectal cancer. Grade 3/4 toxicity with the irinotecan/5-FU/LV regimen compared with the 5-FU/LV/irinotecan regimen included diarrhea (4% versus 17%). the active metabolite of irinotecan. and febrile neutropenia (4% versus 17%). while seven (32%) required a dose reduction. 2000) with a regimen of oxaliplatin. nausea and vomiting. and VOMITING). mucositis was similar between groups (13% versus 14%.25/10/12 Drug details . with the exception of neutropenia and hand-foot syndrome. leucovorin. thomsonhc.0001). and SEPSIS [212]. compared fluorouracil and leucovorin with the irinotecan. occurred significantly more often in patients receiving bolus injections (31% versus 4%. female gender.96). respectively. and a good performance status significantly increased the risk for nonhematologic toxicities.

and neurotoxicity have been reported.25/10/12 Drug details . all cases exhibited remarkable toxicity. it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil [205]. vomiting. a) The occurrence of severe fluorouracil (5-FU) toxicity secondary to dihydropyrimidine dehydrogenase deficiency has been reported. Symptoms included severe abdominal pain. she experienced what was classified as mild neurologic toxicity manifest as difficulty with balance and spelling simple words which persisted for about 2 weeks. However. and small bowel. The authors suggest that monitoring DPD activity may be appropriate in the management of those experiencing severe toxicity from 5-FU [215]. fever. 5 of 17 patients with complete or partial response to therapy developed transient ascites (with or without associated hypoalbuminemia) compared to 1 of 27 without such a response [273]. Chemotherapy had been initiated 3 weeks after surgery with a combination of cyclophosphamide (orally 100 mg/day/square meter) for 14 days. Other significant findings in some of the responders included elevated bilirubin and transaminase levels from baseline. Dihydropyrimidine dehydrogenase (DPD) as the initial enzyme responsible for the breakdown of 5-FU. and hematologic NEUTROPENIA toxicity that required hospitalization. and the patient died 2 days later (6 days after starting medication). life-threatening toxicities such as stomatitis. the authors cautioned that the adverse effects observed do not necessarily represent disease progression. The 5-FU doses received by a 35-year-old woman treated with the adjuvant protocol for breast carcinoma were not unusually high. Hepatic Effects Ascites 1) In a retrospective analysis of a phase I-II study of N-phosphonacetyl-L-aspartate (250 mg/square meter) followed by weekly boluses of fluorouracil (600 to 800 mg/square meter) in 44 metastatic colorectal cancer patients. diarrhea. the patient experienced severe gastrointestinal (nausea. erythematous skin rash. and chills. The drug was withdrawn. Enhanced toxicity occurring at normal doses is what usually sets these patients apart. Although 40 of 44 patients had liver metastasis. Only a few cases of DPD deficiency have been identified. the role of 5-fluorouracil in inducing hepatic 29/317 . vomiting. and inflammation of the esophagus. diarrhea.MICROMEDEX® 2. bloody diarrhea. accounts for greater than 80% of the drugs catabolism. Following day 8 of the protocol. One case of life-threatening systemic toxicity has been reported with the TOPICAL use of fluorouracil in a patient with DPD enzyme deficiency. The patient developed nausea. She had a leukocyte count of 1100 with 5% neutrophils (no bands) and fever. stomach. and methotrexate (50 mg/square meter) in combination with 5-FU (600 mg/square meter) on days 1 and 8. rare. diarrhea and massive and diffuse hepatic necrosis. Signs and symptoms included stomatitis. stomatitis). prolonged vomiting. In addition. Hepatotoxicity 1) One report described diffuse hepatic necrosis in a 29-year-old male patient receiving 500 mg daily for 4 days (route of administration unspecified) for adenocarcinoma. however. NEUTROPENIA.0 6) In patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency administered INTRAVENOUS fluorouracil. Although this case was observed with 5% fluorouracil cream. thrombocytopenia. neutropenia.

78 gram/liter) and two non-contrast-enhanced areas on computed brain tomography. cyclophosphamide.MICROMEDEX® 2. 2) Three case reports of HEPATIC INJURY in nurses following years of handling cytostatic drugs (bleomycin. and the fact that all of the cases occurred 2 to 5 days after chemotherapy and during the second (3 patients) and third (2 patients) courses of treatment. and methotrexate) were described [275]. 2) An anaphylactic reaction occurred 4 hours after initiation of 5. diplopia. thomsonhc. the patient presented with confusion. Within 25 minutes. The only abnormalities noted on diagnostic work-up were elevated protein in the cerebrospinal fluid (0. Immunologic Effects Anaphylaxis 1) ALLERGIC REACTIONS and anaphylaxis have been reported in patients receiving intravenous fluorouracil [207]. and collapsed with a rapid thready pulse of 120. doxorubicin.25/10/12 Drug details . It is suggested that HANDLING OF CYTOSTATIC AGENTS may insidiously produce hepatic damage and possibly irreversible fibrosis.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink 30/317 .fluorouracil continuous infusion in a 46-year-old male. Signs and symptoms included skin flushing. vincristine. Epinephrine. 1 mL of 1:1. Cerebrovascular accident 1) A possible association between development of ISCHEMIC STROKE following an infusion of 5-fluorouracil and cisplatin was reported in 5 cancer patients [243].5 grams). His blood pressure was 30/0 mm Hg. Two minutes following his tenth dose of 5FU 900 mg. disorientation. and hypotension (60/40 millimeters of mercury). Neurologic Effects Central nervous system finding 1) Neurological effects reported with the administration of fluorouracil include CONFUSION. insomnia and diminished level of consciousness. and skin color had returned to normal [306]. was administered with immediate and prompt signs of recovery. euphoria.25 grams) and levamisole (cumulative dose: 1. Cerebral 1) Clinicians attributed multifocal cerebral demyelination to a chemotherapy regimen of fluorouracil (5-FU) and levamisole in a 57-year-old male with colon cancer. and ACUTE CEREBELLAR SYNDROME [207]. pulse. which finally remitted after 24 hours of dopamine support [305]. and hepatic fibrosis and fat accumulation in the others.000. All patients had neurological symptoms associated with elevated serum alanine aminotransferase and alkaline phosphatase levels. headache. fluorouracil. nausea. The theory that the stroke may have been drug-induced is based on the inability to identify any other causative factors. Prompt treatment with parenteral hydrocortisone and promethazine reversed the reaction. nystagmus. 3) A case of an anaphylactic reaction with shock following a 10th dose of 900 mg of 5-fluorouracil intravenously was reported in a 60-year-old white male undergoing treatment for colorectal adenocarcinoma. he became cyanotic and diaphoretic. One month after receiving the second cycle of 5-FU (cumulative dose: 8. dacarbazine. and liver biopsy revealed portal hepatitis with piecemeal necrosis in one.0 disease in this patient is unclear [274]. dyspnea. except for hypotension. BP. Demyelinating disease of central nervous system. cyanosis.

most lesions gradually disappeared (Yeo et al. levamisole. dexamethasone 12 mg daily and immunoglobulins have been used. The authors discuss possible mechanisms of 5-FU-induced neurotoxicity. respectively. lactic acidosis (4 to over 12 mg/dL). Encephalopathy 1) Summary a) LEUKOENCEPHALOPATHY associated with fluorouracil (5-FU) has been described in numerous case reports. has been detected. Electroencephalogram (n=8) revealed diffuse cortical dysfunction which suggests metabolic or toxic encephalopathy. confusion. partial or complete deficiency of dihydropyrimidine dehydrogenase (DPD). No further cycles of 5-FU/levamisole were administered. Although the cause of this adverse effect is unknown. and levamisole causes an immune response to the damaged myelin [245][246][247][248][249]. Patients ranged in age from 31 to 65 years and were treated with 5-FU alone or in combination with other agents (eg. The onset of symptoms was a median of 19. MEMORY LOSS. He developed three generalized tonic-clonic seizures. SPEECH DISTURBANCES. (Gottleib & Luce.5 hours after the infusion started.25/10/12 Drug details .IntermediateToDocumentPrintLink 31/317 . and others). confusion. an enzyme necessary for metabolism of fluorouracil. A thorough diagnostic work-up ruled out other possible etiologies.MICROMEDEX® 2. All of the patients recovered except 1 who had bilateral neurosensory hearing impairment. hearing impairment. with no further seizure activity. Metabolic abnormalities were detected at the same time as symptoms and consisted of hyperammonemia (149 to over 500 micromoles/L). SEIZURES. MUSCLE WEAKNESS. 1971). Chemotherapy is usually stopped. it has been suggested that 5-FU has a toxic effect on myelin. stupor. and hypocapnia (pCO2 15 to 30 mmHg). In some patients with encephalopathy. In addition. and COMA. 2) Continuous intravenous infusion of 5-fluorouracil (5-FU) 1500 milligrams/day for 4 days was followed 48 hours later by new-onset confusion. necessitating use of a walker two weeks later. 3) Of 280 patients treated with fluorouracil (5-FU) 24-hour infusion (dose up to 2600 mg/m(2)/week). including Krebs cycle blockade and deficiencies of thiamine or dihydropyrimidine dehydrogenase [251]. in some cases. Over the next 30 months. accompanied by electroencephalographic changes. The patient was treated with phenytoin and thiamine. Follow-up magnetic resonance imaging of the brain at one month indicated demyelination in the form of multifocal hyperintensities. Symptoms were variable and may include ATAXIA. mitomycin.0 Dexamethasone 16 milligrams/day for 28 days then tapered off led to improvement.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. His mental status normalized within 72 hours. however. it has been continued with improvement in symptoms. and coma. breast cancer. agitation. GAIT DISTURBANCES. The course is variable with some patients showing partial and others complete reversal of symptoms with or without treatment. 1999). APHASIA. Careful monitoring is recommended for this adverse effect especially in patients with gastric cancer. cognitive dysfunction and ataxia in a 73-year-old male.7%) developed encephalopathy characterized by disorientation. This adverse effect usually occurs early in therapy between 7 and 19 weeks. However. and median duration was 15 hours. It is estimated that 3% of cancer patients have partial deficiency of DPD and that 1:1000 births may have complete DPD deficiency [250]. seizure. 16 (5. and colorectal cancer who are treated with high-dose 5-FU thomsonhc. Severe nausea and vomiting and Kussmaul's respirations were also noted in 15 and 16 patients. limb ataxia was not completely reversible.

life-threatening toxicities such as stomatitis. however.0 infusions [252]. Enhanced toxicity occurring at normal doses is what usually sets these patients apart. Isolated cases of DPD deficiency have been identified. Twenty of these patients also received tamoxifen for 3 years. Although this case was thomsonhc. fever. and chills. After 1 month in the intensive care unit and several months of rehabilitation.4. and 5-FU. neutropenia. She had a leukocyte count of 1100 with 5% neutrophils (no bands) and fever. mental flexibility. Twenty-eight percent of the CMF patients were classified as impaired in cognitive functioning. the initial enzyme responsible for the breakdown of 5-FU. and hematologic (neutropenia) toxicity that required hospitalization. Impaired cognition 1) There appears to be an association between the administration of adjuvant chemotherapy for BREAST CANCER and the development of cognitive deficits. many of which were statistically significant. erythematous skin rash. methotrexate. and inflammation of the esophagus. Following day 8 of the protocol. Subjective data (self-reported) showed that patients receiving CMF reported having more cognitive problems with respect to memory and concentration when compared to controls. Clinicians determined the cause of this exacerbation of 5-FU toxicity to be dihydropyrimidine dehydrogenase deficiency [253]. bloody diarrhea. visuospatial functioning. all cases exhibited remarkable toxicity. motor function. vomiting. and small bowel. Neuropsychologic tests evaluated attention/concentration. neutropenia. the patient recovered.013). stomatitis). Neurotoxicity 1) In patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency administered INTRAVENOUS fluorouracil. memory. One case of life-threatening systemic toxicity has been reported with the TOPICAL use of fluorouracil in a patient with DPD enzyme deficiency. The patient also experienced severe myelosuppression. thrombocytopenia. Symptoms included severe abdominal pain. p=0. the patient experienced severe gastrointestinal (nausea.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. methotrexate. mucositis and dermatitis. speed of information processing. she experienced what was classified as mild NEUROLOGIC toxicity manifest as difficulty with balance and spelling simple words which persisted for about 2 weeks. The study group consisted of 39 patients who had received 6 cycles of CMF (cyclophosphamide. prolonged vomiting. diarrhea. accounts for greater than 80% of the drugs catabolism. 4) Severe neurotoxicity consisting of encephalopathy. and verbal functioning. The risk for cognitive impairment was greatly increased for patients in the CMF group compared to controls (odds ratio=6. and fluorouracil). and neurotoxicity have been reported. Signs and symptoms included stomatitis. In addition. The study group was compared to a control group (n=34) that was not treated with systemic therapy. The authors suggest that monitoring DPD activity may be appropriate in the management of those experiencing severe toxicity from 5-FU [215]. motor and sensory neuropathy occurred in a 57-year-old male after receiving 3 doses of 5-fluorouracil (5-FU) for treatment of colon cancer. No differences in test performance were found between those treated with CMF plus tamoxifen and CMF alone [244].MICROMEDEX® 2. diarrhea. DPD. rare. stomach. Objective data demonstrated higher depression scores and worse performance on neuropsychologic tests than controls.IntermediateToDocumentPrintLink 32/317 . 5) One investigator reported severe toxicity secondary to dihydropyrimidine dehydrogenase (DPD) deficiency in a 35-year-old woman receiving standard dose 5fluorouracil for breast cancer.25/10/12 Drug details . Chemotherapy had been initiated 3 weeks after surgery with a combination of cyclophosphamide. whereas 12% of controls were.

2) OUTCOME a) Moderate (treatment withdrawal required or requested) [255]. and progressed to COMA within 72 hours of starting the second cycle.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. the patient had mild nausea and confusion. 4) ONSET/DURATION a) After earlier exposure to 5-FU and levamisole (LV). but neurologic complications had completely resolved [254]. An EEG detected metabolic encephalopathy. Twelve hours after initiation of rescue therapy with THYMIDINE 8 grams/square meter/day. Although this case was observed with 5% fluorouracil cream. DISTAL HYPOESTHESIA. Both would result in decreased clearance of 5-FU [255]. stomach.1%) [255]. DECREASED VIBRATORY SENSATION.0 inflammation of the esophagus. and instability in walking [255]. and small bowel.IntermediateToDocumentPrintLink 33/317 . NUMBNESS and WEAKNESS in the lower legs. 5) CLINICAL MANAGEMENT a) In 2 cases. symptoms improved and stabilized in 1 patient each but neurophysiologic studies remained unchanged. symptoms developed with the first course [255]. it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil [205]. 8) DOCUMENTATION a) Good 9) CASE REPORTS thomsonhc. Combination chemotherapy also contained paclitaxel and leucovorin. Gastrointestinal side effects and confusion were mild. but the patient was hospitalized for dehydration. Thymidine was continued for 3 days. Upon rechallenge. symptoms occurred during subsequent courses. Peripheral neuropathy 1) INCIDENCE a) Rare (incidence less than 0. A peroneal splint improved the ability to walk in 1 patient [255]. Although 5-fluorouracil (5-FU) was stopped. After a second course of combination chemotherapy with reduced paclitaxel. 6) DOSE-RELATED a) It is unknown whether dose or duration has any effect on neurotoxicity [255].MICROMEDEX® 2. the patient remained metastatic. elevated liver enzymes. 3) ASSOCIATED SYMPTOMS a) PAIN. a) A 50-year-old patient receiving 5-fluorouracil-based chemotherapy for relapsed metastatic hepatocellular carcinoma developed a severe neurotoxic reaction secondary to dihydropyrimidine dehydrogenase (DPD) deficiency. discontinuation of 5-FU and LV resulted in stabilization or improvement.25/10/12 Drug details . but neurologic studies did NOT improve. and the patient was discharged on day 12. At 19-months followup. the patient rapidly recovered his normal mental status. 7) PROBABLE MECHANISM a) Idiosyncratic (genetically determined abnormal reactivity due to a metabolic or enzymatic deficiency). A link between 5-FU-induced neurotoxicity and hepatic dysfunction or dihydrodipyrimidine dehydrogenase deficiency has been suggested.

and cranial irradiation [276]. and weakness of the legs. or choroidal detachment. lacrimation. or intraocular administration of fluorouracil such as lacrimal duct stenosis. no spontaneous BLEB LEAKAGE was observed. This man presented with rapid worsening of visual acuity and an elevated intraocular pressure. and Dellen corneal erosions occurred when 5-FU injections were used after trabeculectomy [278]. Corneal ectasia may be prevented by instructing patients on the appropriate massage technique and cautioning them not to use vigorous massage. hypotony. It is unclear if use of 5-FU after surgery contributed to this adverse effect or if it was entirely due to vigorous massage of the eye. Eye / vision finding 1) Summary a) Numerous ocular adverse effects may occur following topical. leakage was observed in 10 (32. however. Corneal erosions. Bleb leakage is a potentially serious complication because it may predispose patients to endophthalmitis. Both patients received 5-FU and LV with radiotherapy followed by 5-day courses every 4 weeks. Bilateral cicatricial ECTROPION was reported in a patient who used 5-FU for treating facial actinic keratoses [277]. bleb rupture.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. he admitted to massaging his eye vigorously for a minute or more up to 50 times daily. peripheral anterior synechiae. the patient was instructed to massage his eye three times daily with three 10-second compressions.2%) eyes as determined by the Seidel test. Neurophysiologic studies identified large-fiber demyelinating polyneuropathy which did NOT improve after stopping 5-FU and LV. after applying digital pressure. VISUAL CHANGES. 4) Of 31 eyes exposed to fluorouracil (5-FU) after trabeculectomy. and PHOTOPHOBIA [207]. 2) OPTIC NERVE ATROPHY has been reported after using fluorouracil (5-FU). however. cystic bleb formation. numbness. thomsonhc. Ophthalmic Effects Ankyloblepharon 1) Ankyloblepharon (adherence of eyelids resulting in narrowing of the palpebral aperture) was reported in a 59-year-old male during 5-fluorouracil therapy for metastatic adenocarcinoma of the stomach [288]. Fluorouracil 25 mg/mL was applied to the scleral flap for 5 minutes during the surgical procedure. (KERATECTASIA or protusion of a thinning cornea). hypotony. Following daily injections. and ulcerative blepharitis. neurologic studies showed worsening compared to earlier studies [255].25/10/12 Drug details . It appeared that bilateral conjunctival ulcers secondary to fluorouracil. Other causes of neuropathy were excluded with appropriate clinical and laboratory evaluation.IntermediateToDocumentPrintLink 34/317 . All patients were assessed at least 6 months after surgery [280]. upon questioning. intravenous. and reinitiation of therapy resulted in recurrence of ocular lesions. Withdrawal of chemotherapy resulted in improvement. Rechallenge 3 months later for treatment of metastases resulted in similar symptoms.MICROMEDEX® 2. after a trabeculectomy with injection of 5-fluorouracil (5-FU) 10 mg daily for 14 days [279]. 3) A 38-year-old man developed CORNEAL ECTASIA. early wound leakage. During the 5-day courses. resulted in ankyloblepharon. intrathecal methotrexate. a flat anterior chamber. each patient complained of pain.0 a) Two patients with colorectal cancer treated with 5-FU and LV developed peripheral neuropathy.

Onset of epiphora was within 3 months after commencing chemotherapy. because of potential unwanted effects from 5-FU. Noted in the patient were diffuse keratopathy within 4 days and the whorl-like pattern by 5 weeks postoperatively. LACIMAL CANALICULAR FIBROSIS with permanent EPIPHORA (outflow of tears down cheek) has been reported in 3 breast cancer patients following systemic treatment with 5fluorouracil in combination with cyclophosphamide and methotrexate [283]. pigment-bearing cells invade the central corneal epithelium in a whorl-like pattern. and its ability to cause mucosal inflammation and act on rapidly dividing tear duct cells. and DELLEN CORNEAL EROSIONS (3 of 49) all occurred as late complications [278]. along with 18 previously published cases. 2) TEAR DUCT FIBROSIS has been reported in association with persistent lacrimation. Following trabeculectomy and postoperative 5-FU use. Lacrimation symptoms persisted in 5 patients after withdrawing 5-fluorouracil suggesting an irreversible DACRYOSTENOSIS [286].dacryocystorhinostomy was the only therapeutic option in light of completely stenosed canaliculi. its presence in the tears of patients with epiphora but not in unaffected patients. 5-FU is reserved for those eyes identified to be at high risk for success due to scarring of the conjunctival bleb.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.year-old female presented to the ophthalmologist after 1 year of progressively worsening lacrimation and epiphora. Finding of lacrimation 1) Excessive lacrimation and other OCULAR DISTURBANCES have been reported secondary to IV 5-fluorouracil therapy [283][284][285][276]. A conjunctivo.IntermediateToDocumentPrintLink 35/317 . of lacrimal canalicular stenosis have been attributed to 5-fluorouracil therapy.25/10/12 Drug details . Normalization of pigmentation and visual acuity began over the next 3 months [281]. LACRIMAL DUCT STENOSIS has been reported [207]. 6) One report describes a case of STRIATE MELANOKERATOSIS in a 64-year-old black male who received daily subconjunctival fluorouracil injections of 5 milligrams for 14 days following trabeculectomy. and bleb rupture in 3 of 49 treated. Symptoms usually subside within 2 or 3 weeks after discontinuing the drug but persist throughout therapy. early wound leakage (25%). and 13. HYPOTONY (10 of 49). Indeed. A 56-year-old male was referred in the early stages of epiphora. Early complications included CORNEAL EROSIONS (16%). A review of the literature revealed 5-fluorouracil as the primary agent likely responsible for the epiphora. The SCLEROSING CANALICULITIS ranged from focal stenosis to widespread occlusion. Symptoms can occur within 15 minutes of administration of the drug IV and consist of excessive lacrimation. and usually good success rates for trabeculectomy. 5 mg daily for 7 days.MICROMEDEX® 2. In this condition.0 5) Postoperative subconjunctival injections of fluorouracil (5-FU) following trabeculectomy often improve the success of the procedure. whose punctal stenosis was surgically corrected. One report described persistent lacrimation in 6 patients receiving 5fluorouracil IV weekly for 6 to 10 months. blurring of the vision. Two investigators reported the occurrence of complications after using a total of 50 mg in 49 eyes. A 65. 11. A review of all cases revealed that 5-FU was the likely causative agent due to its temporal relationship to lacrimal symptoms. 3) Two new cases. However. Early recognition and management is important to avoid permanent sequelae [287]. Infectious crystalline keratopathy thomsonhc. reddening of the eyes. then 5 mg on days 9. excessive nasal discharge. CYSTIC BLEB FORMATION (20 of 49).

vincristine. The patient developed severe dyspnea after 12 treatments. and leucovorin (described by Saltz et al.25/10/12 Drug details . Although mitomycin C is most likely the agent responsible for pulmonary toxicity of this patient. Investigators confirmed at necropsy the patient had interstitial fibrosis thought to be a result of therapy with 5-fluorouracil and mitomycin C [290]. The number of chromosome-type breaks was increased significantly among nurses as compared to a control group [307]. Medications administered during this time included topical prednisolone acetate. One trial of patients with metastatic colon cancer compared the regimen of irinotecan. combined use with 5-fluorouracil as a contributing factor cannot be ruled out [289]. The corneal deposits had completely resolved by the next examination 4 days later.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. The patient received 1 g 5-fluorouracil IV weekly for 9 weeks followed 6 months later with 1 g 5-fluorouracil and 10 mg mitomycin C IV every 3 weeks. an adjuvant study of patients with resected stage III colon cancer. doxorubicin. 36/317 . fluorouracil. NEUTROPENIA. and SEPSIS [212]. Dose modifications were made in both trials in an attempt to ameliorate the toxicity of the regimen. and scopolamine. fluorouracil and methotrexate). FLUOROURACIL. intrastromal crystalline material. the time course and the lack of an epithelial defect or ulceration usually seen with fluoroquinolones makes the subconjunctival administration of 5fluorouracil a more likely causative factor [282]. 5-Fluorouracil was given in doses of 750 mg weekly thomsonhc. 2) A case of BACILLUS CEREUS BACTEREMIA possibly associated with 5-fluorouracil was reported in a 66-year-old female receiving the drug for metastatic breast cancer. The other trial. Enrollment in both trials has been suspended. compared fluorouracil and leucovorin with the irinotecan. Although noninfectious crystalline keratopathy has been associated with fluoroquinolones. Slit-lamp examination of the cornea revealed white. Other Anomaly of chromosome pair 1) An increased incidence in the number of chromosomally aberrant lymphocytes was observed in nurses handling cytostatic agents (cyclophosphamide. fluorouracil. ciprofloxacin. NAUSEA. Respiratory Effects Respiratory finding 1) PULMONARY TOXICITY was reported in the form of FIBROSING ALVEOLITIS in a 55-year-old male with gastric adenocarcinoma. 2000) with a regimen of oxaliplatin. Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease included: dehydration (from DIARRHEA. and leucovorin and a regimen of oxaliplatin and irinotecan.0 1) A case of noninfectious crystalline keratopathy is described in a 69-year-old female 5 days following a subconjunctival injection of 5-fluorouracil (5 milligrams) and 6 days following trabeculectomy and sponge application of 5-fluorouracil for uncontrolled exfoliative glaucoma. and LEUCOVORIN for colorectal cancer was revealed in an interim analysis of data from two separate cooperative-group clinical trials sponsored by the National Cancer Institute and conducted throughout out the United States and Canada.IntermediateToDocumentPrintLink by hepatic infusion for 3 weeks. and leucovorin regimen. Sepsis 1) An unexpectedly HIGH DEATH RATE occurring within 60 days after the initiation of treatment in patients receiving a regimen of IRINOTECAN. The patient was asymptomatic. and VOMITING). fluorouracil.

In general. antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations.IntermediateToDocumentPrintLink 37/317 . epirubicin 90 mg/m(2). Teratogenicity/Effects in Pregnancy/Breastfeeding A) Teratogenicity/Effects in Pregnancy 1) U.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.0 5-Fluorouracil was given in doses of 750 mg weekly by hepatic infusion for 3 weeks. and oxaliplatin (FOLFOX) from week 13 of gestation through delivery were born with no evidence of teratogenicity or intrauterine growth retardation and remained developmentally normal at their 2-year follow up. who subsequently delivered a healthy infant at week 35 of gestation. and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The patient developed symptoms of infection (without fever) and leukocytosis. are suspected to have caused. She recovered spontaneously and the authors suggest that the presence of an indwelling cannula. but when given during the second or third trimesters are believed to only increase the risk of growth retardation [369][370]. She was not pregnant when she was diagnosed with locally advanced thomsonhc. leucovorin. A 26-year-old woman diagnosed with metastatic colorectal cancer in week 10 of pregnancy received 10 courses of a full-dose biweekly modified FOLFOX-6 regimen (oxaliplatin 85 mg/m(2) 2-hour infusion with leucovorin 400 mg/m(2). the progression of the disease. These drugs may also have adverse pharmacological effects. The last FOLFOX exposure occurred 15 days before delivery at 33 weeks via cesarean section. or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. The drug is contraindicated in women who are or may become pregnant.25/10/12 Drug details .S. and in some cases earlier-thanterm delivery provides an acceptable compromise between maternal and fetal risk [371][370].MICROMEDEX® 2. b) One case report describes a 33-year old patient treated with 5 courses of FEC regimen (5fluorouracil 600 mg/m(2). and cyclophosphamide 600 mg/m(2) every 3 weeks) during the first 28 weeks of pregnancy. Accompanying texts should be consulted for further details. Depending upon the nature of the malignancy. and how advanced the gestation. Food and Drug Administration's Pregnancy Category: Category X (All Trimesters) a) Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both. the fraternal twins both had birth weights of about 2200 g and had one-minute Apgar scores of 10 [362]. chemotherapy can in some cases be deferred to allow fetal maturation to occur. then 5-FU 400 mg/m(2) bolus and 5-FU 2400 mg/m(2) 46-hour infusion). 5) Literature Reports a) Twin neonates exposed to 5-fluorouracil. 2) Australian Drug Evaluation Committee's (ADEC) Category: D a) Drugs which have caused. See Drug Consult reference: PREGNANCY RISK CATEGORIES 3) Crosses Placenta: Unknown 4) Clinical Management a) Teratogenic effects have been reported with fluorouracil. cytotoxic therapy and the underlying metastasis may have contributed to the infection [308].

25/10/12 Drug details . One birth defect (ventricular septal defect) and cases of miscarriage have been reported when Efudex(R) was applied to mucous membrane areas.IntermediateToDocumentPrintLink 38/317 .5 months for metastatic breast cancer. a 36-year-old breastfeeding female diagnosed with rectal cancer had undetectable levels of 5-fluorouracil in milk samples obtained prior to. bilateral absence of thumbs. Since fluorouracil inhibits DNA. a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. missing fingers (2 on left and 1 on the right hand). The 2070 g infant. during. and up to 10 days following 5-fluorouracil administration. However. RNA. Jerking in all 4 extremities and shallow respirations were noted. Progression of the mediastinal mass was noted. the infant developed cyanosis of the extremities and ash-gray discoloration of the trunk.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. and the patient was admitted for an elective C-section with bilateral partial salpingectomy and bilateral oophorectomy. 4) Literature Reports a) A 36-year-old breastfeeding female diagnosed with rectal cancer had undetectable levels of 5fluorouracil in milk samples obtained prior to. risk to the infant should be considered relative to the inherent toxicity of the drug [360]. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil [360]. f) Topical fluorouracil used during gestation to treat vaginal and vulvar papillomavirus infections and lesions did not cause adverse effects in the infants [366][367]. during. nursing is discouraged with the use of this drug [368].5 hours post delivery. The patient discontinued breastfeeding and continued to pump breast milk twice thomsonhc. maternal use of topical preparations generally carries less risk than systemically administered drug. an ultrasound showed pregnancy of 28 weeks gestation. kidneys. c) One birth defect (cleft lip and palate) has been reported in the newborn of a patient using topical fluorouracil (Efudex(R)) as recommended. and intestines) [365]. and up to 10 days following 5-fluorouracil administration [373]. 3) Clinical Management a) While there is some systemic absorption of fluorouracil after topical administration. The patient received 15 doses of 500 mg IV 5-fluorouracil (7500 mg total) over a period of 2. and visceral defects (lungs. g) The manufacturer's product information for the injectable form of fluorouracil has an FDA pregnancy category D rating [368]. Approximately 1.0 malignant neoplasm of the left breast. delivered by cesarian section and without complications. Abnormalities observed in the abortus included bilateral limb defects. 2) Thomson Lactation Rating: Infant risk cannot be ruled out. After complaining of dilatation of the abdomen and bloating. was developing normally at 1 year of age [363]. e) Multiple congenital anomalies were found in an aborted fetus exposed to 5-fluorouracil during the eleventh and twelfth week of gestation. Chemotherapy was given at a dose of 600 mg five times weekly for 1 month. The infant was placed in an oxygen bed with 34% oxygen and recovered within 24 hours [364]. and protein synthesis. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding. d) Potential neonatal toxicity secondary to 5-fluorouracil therapy during the third trimester of pregnancy was described. B) Breastfeeding 1) World Health Organization Rating: Avoid breastfeeding.

95 micromolar. potentially active [392] Drug Interactions Drug-Drug Combinations Adenovirus Vaccine Type 4. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. 5) Drug Levels in Breastmilk a) Active Metabolites 1) Dihyro-5-fluorouracil. in 33 milk samples evaluated using high performance liquid chromatography (limit of detection 0.5 micromolar).14 and 114. or thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details . who have restored immunocompetence. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. for solid tumors. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Adenovirus Vaccine Type 7. Patients with leukemia. lymphoma. or other malignancies whose disease is in remission. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315].IntermediateToDocumentPrintLink after solid organ transplant should be 39/317 . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. Despite plasma concentrations between 11. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].MICROMEDEX® 2.0 daily during the 5-fluorouracil-based chemoradiotherapy 200 mg/m(2)/day IV. for solid tumors. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. the levels of 5fluorouracil in milk were undetectable at any time during or following 5-fluorouracil administration [373]. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316].

and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. If possible. but a single pretreatment dose of cimetidine 400 mg or daily doses of 1 g for 1 week did not alter 40/317 . An alternative H-2 antagonist could also be substituted for cimetidine. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Cimetidine 1) Interaction Effect: an increased risk of fluorouracil toxicity 2) Summary: Concomitant fluorouracil and cimetidine therapy has resulted in increased peak plasma levels and area under the plasma concentration-time curve (AUC) for fluorouracil[354]. for solid tumors. lymphoma. discontinue the cimetidine prior to the administration of fluorouracil. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. Patients with leukemia. who have restored immunocompetence. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. or other malignancies whose disease is in remission. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. for solid tumors.25/10/12 hematopoietic malignancies. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. lymphoma. These effects were observed after long-term (four weeks) therapy with cimetidine but not after a single dose. 3) Severity: minor 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patients who have received long-term (four or more weeks) therapy with cimetidine for an increased incidence of adverse effects to fluorouracil. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. or other malignancies whose disease is in remission. who have restored immunocompetence. 7) Probable Mechanism: inhibition of fluorouracil metabolism 8) Literature Reports a) Concomitant oral 5-fluorouracil and cimetidine therapy resulted in increased peak plasma levels and area under the plasma concentration-time curve (AUC) for 5fluorouracil in 15 ambulant patients with carcinoma [353]. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. These effects were observed after doses of cimetidine 1 gram daily for 4 weeks. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Bacillus of Calmette and Guerin Vaccine. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. Patients with leukemia.

and volume of distribution.89 (p less than 0.IntermediateToDocumentPrintLink 41/317 . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant use of fluorouracil and fosphenytoin may result in elevated phenytoin (the active metabolite of fosphenytoin) plasma concentrations. Hydrochlorothiazide 1) Interaction Effect: myelosuppression (granulocytopenia) 2) Summary: Thiazide diuretics may enhance the myelosuppressive effects of antineoplastic agents.25/10/12 Drug details .MICROMEDEX® 2. The fluorouracil AUC in patients taking gemcitabine and FUFA was 555 +/. Similarly. Sixteen patients with gastroenteric carcinoma were included in the control group and received FUFA therapy.0 the pharmacokinetics of fluorouracil. 7) Probable Mechanism: unknown 8) Literature Reports a) Gemcitabine enhances systemic exposure to fluorouracil in cancer patients. methotrexate. Twenty patients with advanced gastroenteric carcinoma were included in the experimental group and received gemcitabine and folinic acid (FUFA). Patients in the experimental group had a higher fluorouracil area under the concentration-time curve (AUC). This may be useful in maximizing the antitumor effects and reduce the occurrence of side effects of fluorouracil[348].com/micromedex2/librarian/PFDefaultActionId/evidencexpert.209 mcg/mL/min and in patients taking FUFA 244 +/. 5-fluorouracil combination and a thiazide diuretic thomsonhc. The mechanism of the interaction seems to be related to the combination of drug metabolism inhibition and reduction of liver blood flow induced by cimetidine. lower mean total clearance. 3) Severity: minor 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Synergistic antitumor activity and positive pharmacological interactions can occur between gemcitabine and fluorouracil (and folinic acid) and may also increase the toxicity of fluorouracil in cancer patients. Fosphenytoin 1) Interaction Effect: increased plasma phenytoin (the active metabolite of fosphenytoin) concentrations 2) Summary: The concomitant use of fluorouracil and fosphenytoin may result in elevated phenytoin (the active metabolite of fosphenytoin) plasma concentrations. plasma half-life. Fourteen breast cancer patients treated with a cyclophosphamide.001). the AUC for intravenous 5-fluorouracil was significantly increased following 4 weeks of cimetidine pretreatment. The author suggests that the results of this study should be taken into account when designing clinical trials testing gemcitabine and fluorouracil in combination in order to maximize the antitumor effects and reduce the occurrence of side effects [347]. and monitoring of phenytoin levels may be warranted[349]. 7) Probable Mechanism: unknown Gemcitabine 1) Interaction Effect: enhanced fluorouracil systemic exposure and possible toxicity 2) Summary: A significant increase in systemic fluorouracil exposure occurs when gemicitabine is coadministered. and monitoring of phenytoin levels may be warranted[349].

stomatitis. The treatment used was based on biochemical and cell culture studies which have demonstrated that an excess of intracellular reduced folates is necessary to provide optimal inhibition of thymidylate synthetase and to increase the cytotoxic effect of fluorouracil. for solid tumors. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. or other malignancies whose disease is in remission. 7) Probable Mechanism: unknown 8) Literature Reports a) Thirty patients with advanced colorectal and gastric adenocarcinomas were treated with fluorouracil combined with high-dose folinic acid. GI toxicity).0 experienced significantly higher levels of granulocytes during treatment cycles without the thiazides as compared with cycles that included thiazides[317]. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316].IntermediateToDocumentPrintLink 42/317 . by obtaining periodic CBC's. 7) Probable Mechanism: unknown Influenza Virus Vaccine. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Fluorouracil plus leucovorin is routinely used therapeutically in the treatment of cancer. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. GI toxicity) 2) Summary: The therapeutic efficacy of fluorouracil may be enhanced by leucovorin coadministration[324]. stomatitis. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If concurrent therapy is required. as may fluorouracil toxicity [325][326]. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. Monitor patients. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Leucovorin 1) Interaction Effect: fluorouracil toxicity (myelosuppression. Patients with leukemia.MICROMEDEX® 2. who have restored immunocompetence. lymphoma. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. monitor closely for myelosuppression. for increased toxicity (myelosuppression.25/10/12 Drug details . especially the elderly. It was thomsonhc. A pharmacokinetic study did not find significant differences in fluorouracil pharmacokinetics with this combination [327].

3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Fluorouracil plus levoleucovorin is used therapeutically in the treatment of cancer. However. Levamisole 1) Interaction Effect: hepatotoxicity 2) Summary: A prospective. This hepatotoxicity is usually reversible. The therapeutic efficacy of fluorouracil may be enhanced by levoleucovorin coadministration. or treatment with fluorouracil plus levamisole demonstrated a significantly higher rate of hepatotoxicity with the combination (39. Increases were seen in the time of distribution and volume of distribution of fluorouracil when both drugs were given concurrently. stomatitis. Monitor patients.6%) than with levamisole alone (16.25/10/12 Drug details .0 concluded that folinic acid at high doses (200 mg/m(2)) increases the effectiveness of fluorouracil given simultaneously [322]. for increased toxicity (myelosuppression.025 colon cancer resection patients who received either no treatment. specifically.3%) or no treatment (16. 7) Probable Mechanism: additive hepatotoxic effects Levoleucovorin 1) Interaction Effect: fluorouracil toxicity (myelosuppression.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patients for mild and asymptomatic hepatotoxicity.MICROMEDEX® 2.1%)[346]. although some patients may experience fluorouracil toxicity [359]. treatment with levamisole alone. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. randomized study of 1. gastrointestinal toxicity). Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive thomsonhc. and dehydration have been reported in elderly patients receiving levoleucovorin and fluorouracil[359]. Death from severe enterocolitis. elevated alkaline phosphatase accompanied by increased transaminases or serum bilirubin. High-dose leucovorin (500 mg/m2) was infused over two hours to five patients with metastatic colorectal cancer who were receiving fluorouracil treatment. area under the concentration-time curve (AUC). stomatitis. most commonly taking the form of an elevated alkaline phosphatase. b) Pharmacokinetics of fluorouracil were compared when fluorouracil was administered alone and coadministered with leucovorin. plasma clearance. Hepatotoxicity was described as reversible and characteristically mild and asymptomatic. GI toxicity) 2) Summary: Levoleucovorin increases the concentration of 5-fluorouracil and enhances its toxicity. diarrhea. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. and elimination of fluorouracil were unaltered by leucovorin [323]. especially the elderly. 7) Probable Mechanism: unknown Measles Virus Vaccine. often accompanied by increased transaminases or serum bilirubin.IntermediateToDocumentPrintLink 43/317 .

Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315].0 chemotherapeutic agent. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. and increases of 34% and 38%. or other malignancies whose disease is in remission. thrombocytopenia. Mumps Virus Vaccine. thrombocytopenia (19%).9%. 7) Probable Mechanism: reduced fluorouracil clearance 8) Literature Reports a) A total of 27 patients with metastatic colorectal cancer received daily metronidazole 750 mg/m(2) followed in an hour by fluorouracil 600 mg/m(2). who have restored immunocompetence. if possible. respectively. vomiting) 2) Summary: Coadministered metronidazole significantly reduces fluorouracil clearance resulting in more severe fluorouracil side effects. both drugs given intravenously. in the area under the concentration-time curve (AUC) and half-life of fluorouracil during combined therapy. anemia. severe stomatitis and oral ulceration (34%). The incidence of toxic effects of the metronidazole-fluorouracil regimen included granulocytopenia (74%).25/10/12 Drug details . and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].com/micromedex2/librarian/PFDefaultActionId/evidencexpert. metronidazole combined with fluorouracil did not enhance antitumor activity over 5FU alone [351]. 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Avoid concurrent administration of fluorouracil and metronidazole. The pharmacokinetics of fluorouracil. for solid tumors. Should it become clinically necessary to combine these agents. measured in 10 patients. The occurrence and progression of hematologic and gastrointestinal adverse effects may limit the duration of combined therapy. showed a reduction in fluorouracil clearance of 26. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine thomsonhc. intractable nausea and vomiting (22%). This treatment was repeated every four weeks until prohibitive toxicity or disease progression occurred. lymphoma. stomatitis.MICROMEDEX® 2. for five consecutive days. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. and peripheral neuropathy with paresthesia and weakness (7%). anemia (41%). 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Metronidazole 1) Interaction Effect: increased fluorouracil serum concentrations and fluorouracil toxicity (granulocytopenia. without enhanced therapeutic results[352].IntermediateToDocumentPrintLink 44/317 . At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. monitor patients for fluorouracil toxicity. In vitro. Patients with leukemia.

3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. drowsiness. nystagmus. phenytoin was restarted at a reduced dose of 230 mg daily. The chemotherapy was stopped after two cycles due to progression of the disease [320]. dysarthric. He was unable to stand unsupported. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].MICROMEDEX® 2. lymphoma. Patients with leukemia. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent.25/10/12 Drug details .0 while on concomitant methotrexate therapy [316]. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. who have restored immunocompetence. had bilateral gaze evoked nystagmus and marked limb ataxia on examination. and fatigue preventing him from walking. for solid tumors. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. His epilepsy was controlled with phenytoin 300 mg and phenobarbital 90 mg daily. He was diagnosed with Dukes' C adenocarcinoma of the thomsonhc. b) A 60-year-old man with a history of post-traumatic generalized tonic clonic epilepsy was being treated with phenytoin 430 mg daily with stable phenytoin serum levels (75 mcmol/L). He was drowsy. Seven weeks after starting chemotherapy he was admitted with a 10-day history of progressive confusion. Phenytoin was withheld for 5 days until his serum level was less than 80 mcmol/L. His serum phenytoin level increased to 75 mcmol/L on this dose before dropping to 22 mcmol/L 5 weeks after stopping chemotherapy. 7) Probable Mechanism: unknown 8) Literature Reports a) A 65-year-old Asian male with a 10-year history of generalized tonic clonic epilepsy. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Phenytoin 1) Interaction Effect: an increase in serum phenytoin levels and phenytoin toxicity (ataxia. or other malignancies whose disease is in remission. His serum phenytoin level was 162 mcmol/L (40-80).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. generalized weakness. When his serum level was 67 mcmol/L. tremor) 2) Summary: An increased risk of phenytoin toxicity exists with the concomitant use of fluorouracil[321]. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Phenytoin levels should be frequently measured in all patients receiving phenytoin and fluorouracil. Monitoring should continue after chemotherapy has been completed to ensure that the phenytoin level is sufficient to prevent seizures. hyperreflexia. as well as Dukes' B adenocarcinoma of the colon. His phenobarbitone level was 89 mcmol/L (65-170).IntermediateToDocumentPrintLink 45/317 . experienced an increase in serum phenytoin following palliative 5FU/FA at doses of 370 and 20 mg/m2 weekly. His symptoms and signs resolved with the decreasing serum phenytoin level.

25/10/12 Drug details . the patient presented with a 6-day history of progressive light-headedness and inability to stand unsupported. and limb ataxia. Since his discharge from the hospital he has had a seizure associated with a subtherapeutic serum phenytoin level of 24 mcmol/L and his phenytoin dose has been increased to 200 mg daily [320]. Her phenytoin was withheld for 5 days until her serum phenytoin level was under 80 mcmol/L and the dose was reduced to 300 mg daily. clobazam 10 mg and sodium valproate 1 gm twice daily. After developing breast cancer she underwent adjuvant treatment with intravenous cyclophosphamide. His phenytoin level was 213 mcmol/L. and twice daily capecitabine. The mechanism of this interaction is postulated to be at the level of the CYP2C9 isoenzyme system. Six weeks after starting therapy she was admitted with a 2-day history of an unsteady gate. Serum phenytoin levels at this time were 141 mcmol/L. His phenytoin dose was further reduced and he was discharged on phenytoin 100 mg daily with ongoing chemotherapy. weakness. until phenytoin levels reached 42 mcmol/L. recurrent falls.IntermediateToDocumentPrintLink 46/317 . lymphoma. His serum phenytoin level rose from 42 to 118 mcmol/L at this dose. Her capecitabine was stopped after 2 cycles due to progressive disease. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. followed by docetaxel. Rotavirus Vaccine. c) A 45-year-old female with a greater than 10-year history of poorly controlled generalized tonic clonic epilepsy was taking phenytoin 400 mg daily. 5-FU 600 mg/m2 days 1 and 8 in a 4 weekly cycle and capecitabine was prescribed at a dose of 1500 mg twice daily for 14 days. completing two cycles) after her cancer progressed. methotrexate 40 mg/m2 days 1 and 8. methotrexate. or other malignancies whose disease is in thomsonhc. Fluorouracil may competitively inhibit the clearance of phenytoin by the CYP2C9 isoenzyme or may reduce its synthesis [320].0 transverse colon and was started on adjuvant 5FU/FA at doses of 370 and 20 mg/m2 weekly. He was restarted on a reduced dose (300 mg daily).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and 5-FU (CMF) chemotherapy. At 4 weeks post chemotherapy initiation. repeating 3 weekly. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. She became lightheaded again and her serum phenytoin level increased on this reduced dose (level of 104 mcmol/L). Her serum phenytoin level fell to 18 mcmol/L after 2 months. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. Her serum phenytoin level was 161 mcmol/L (40-80). Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. She was placed on palliative chemotherapy (doxorubicin. Capecitabine is an orally administered prodrug of fluorouracil. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313].MICROMEDEX® 2. The protocol used for CMF was: cyclophosphamide 100 mg/m2 day 1-14. His phenytoin was withheld for 7 days. poor balance. She was discharged on 260 mg phenytoin daily. Patients with leukemia. for solid tumors. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies.

At least three months should elapse between the thomsonhc. who have restored immunocompetence. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Smallpox Vaccine 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. for solid tumors. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [357]. 3) Severity: contraindicated 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Vaccination with rotavirus vaccine is contraindicated in patients receiving immunosuppressive chemotherapy. Patients with leukemia. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Rotavirus Vaccine.25/10/12 Drug details .MICROMEDEX® 2. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].0 remission. who have restored immunocompetence.IntermediateToDocumentPrintLink 47/317 . lymphoma. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Rubella Virus Vaccine. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. or other malignancies whose disease is in remission. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316].com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The administration of the rotavirus vaccine is contraindicated in patients who are immunosuppressed due to chemotherapeutic agents [358]. Live 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[355][356].

0 discontinuation of chemotherapy and vaccination with a live vaccine [313]. 48 women (13. the risks of adding fluorouracil should be weighed against the potential benefits. if concomitant use is clinically warranted. significantly more serious thromboembolic events (such as deep venous thromboses. Controlled studies are needed to further evaluate whether tamoxifen and fluorouracil alone may cause an increased risk of thromboembolism. 48/317 monitor patients for fluorouracil . or other malignancies whose disease is in remission. Patients with leukemia. who have restored immunocompetence.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. If possible. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].6%) in the tamoxifen-only group. for solid tumors. avoid concomitant use of fluorouracil and tinidazole. 7) Probable Mechanism: unknown 8) Literature Reports a) In a multicenter randomized trial of 705 postmenopausal women undergoing treatment for breast cancer. the incidence of thromboembolism while undergoing therapy with tamoxifen for two years was compared to tamoxifen therapy for two years plus a six-month regimen of intravenous cyclophosphamide. is chemically-related to metronidazole[350]. concurrent administration of tinidazole and fluorouracil may result in fluorouracil toxicity. thrombocytopenia. stomatitis. similar to metronidazole.25/10/12 Drug details . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: In patients undergoing therapy with tamoxifen for breast cancer. Out of 353 women receiving tamoxifen plus CMF. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Tamoxifen 1) Interaction Effect: an increased risk of thromboembolism 2) Summary: The addition of a regimen of cyclophosphamide. and fluorouracil (CMF). and fluorouracil to tamoxifen has been shown to increase the risk of thromboembolic events in postmenopausal women being treated for breast cancer[319]. methotrexate. arterial events. vomiting) 2) Summary: Tinidazole. Tinidazole 1) Interaction Effect: increased fluorouracil serum concentrations and potential fluorouracil toxicity (granulocytopenia. Co-administered metronidazole significantly reduced fluorouracil clearance resulting in more severe fluorouracil side effects. a nitroimidazole. In addition. compared to nine out of 352 women (2. or fatal events) were seen in the tamoxifen plus CMF group compared to the tamoxifen-only group [318]. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine.MICROMEDEX® 2.6%) experienced one or more thromboembolic events. methotrexate. thomsonhc. anemia. without enhanced therapeutic results [352]. lymphoma. Although not specifically studied with tinidazole.IntermediateToDocumentPrintLink However. pulmonary emboli. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies.

thrombocytopenia. and increases of 34% and 38%. respectively.MICROMEDEX® 2. as this may result in fluorouracil toxicity without additional therapeutic benefits.9%. anemia. anemia (41%). stomatitis. thrombocytopenia (19%). This treatment was repeated every four weeks until prohibitive toxicity or disease progression occurred. thrombocytopenia. intractable nausea and vomiting (22%). if possible. showed a reduction in fluorouracil clearance of 26. 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Avoid concomitant use of fluorouracil and tinidazole.0 However. monitor patients for fluorouracil toxicity (granulocytopenia. and peripheral neuropathy with paresthesia and weakness (7%). both drugs given intravenously.IntermediateToDocumentPrintLink 49/317 . vomiting)[350]. lymphoma. for solid tumors. in AUC and half-life of fluorouracil during combined therapy. for five consecutive days. measured in 10 patients. Typhoid Vaccine 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. who have restored immunocompetence. If concomitant use cannot be avoided. severe stomatitis and oral ulceration (34%). One thomsonhc. anemia. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. In vitro.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The incidence of toxic effects of the metronidazole-fluorouracil regimen included granulocytopenia (74%). 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Varicella Virus Vaccine 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315]. stomatitis. Patients with leukemia. vomiting) [350]. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. The pharmacokinetics of fluorouracil. 7) Probable Mechanism: reduced fluorouracil clearance 8) Literature Reports a) A total of 27 patients with metastatic colorectal cancer received daily metronidazole 750 milligrams per square meter (mg/m(2)) followed in an hour by fluorouracil 600 mg/m(2). metronidazole combined with fluorouracil did not enhance antitumor activity over 5-FU alone [351]. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. monitor patients for fluorouracil toxicity (granulocytopenia. if concomitant use is clinically warranted. or other malignancies whose disease is in remission.25/10/12 Drug details .

who have restored immunocompetence. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. methotrexate.6 sec. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies.0 patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. Patients with leukemia. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. lymphoma. or fluorouracil as drugs that interact with warfarin [343][344][345][203]. The manufacturers do not identify cyclophosphamide. elevated prothrombin times (PT) were experienced within 15 days in 2 patients treated with a fluorouracilchemotherapy regimen and in another patient treated with vinblastine and fluorouracil. An additional 5 case reports of elevated PT with fluorouracil with and without other chemotherapy agents and concomitant warfarin have been identified in the literature [338][339][340][341][342]. PT were not measured with each cycle.IntermediateToDocumentPrintLink 50/317 . He received intravenous vinblastine 2 mg/day and intravenous fluorouracil 800 mg/day for 5 consecutive days at monthly intervals for the treatment of small cell carcinoma of the lung with lymph node and hilar invasion. His PT prior to chemotherapy was 11.25/10/12 Drug details .MICROMEDEX® 2. for solid tumors. however. or other malignancies whose disease is in remission. and should be reassessed periodically during concurrent therapy. the prothrombin time ratio or INR should be closely monitored with the addition and withdrawal of treatment with fluorouracil. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: In patients receiving oral anticoagulant therapy with warfarin. Warfarin dosage may require adjustment to maintain the desired level of anticoagulation. Two of the patients experienced symptoms of epistaxis and either gross hematuria or microscopic hematuria[329][328]. 16 days after the initiation of the last cycle. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Warfarin 1) Interaction Effect: an increased risk of bleeding 2) Summary: In patients on concomitant warfarin. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313]. the PT was thomsonhc. Monitor INR closely and monitor for signs of bleeding when warfarin is used concomitantly with fluorouracil-chemotherapy regimens. 7) Probable Mechanism: decreased synthesis of cytochrome P450 2C9 enzymes which metabolize warfarin 8) Literature Reports a) A 58-year-old male on warfarin 1 mg/day to prevent catheter-associated thrombosis experienced asymptomatic elevated prothrombin times (PT) after initiation of fluorouracil and vinblastine.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation .

3 sec. methotrexate. 39. The PT increased to a range of 24. a 70-year-old woman treated with cyclophosphamide. his INR increased from 3. As an average.5 mg daily on day 2.5 seconds [331]. f) In a study of colon cancer patients administered combined fluorouracil-warfarin. 31. and 29 sec. and fluorouracil for breast cancer experienced elevated prothrombin times (PT) and microscopic hematuria by day 15 of each cycle.5 mg weekly with a mean INR of 2. The PT returned to pretreatment levels within 48 to 72 hours. The patient remained well for several months but subsequently died from brain metastases [328].IntermediateToDocumentPrintLink 51/317 .8 sec. Patients who began the study free of intraluminal lesions did not develop significant bleeding problems.2 to 21 sec with a stable warfarin dose. he discontinued the levamisole-fluorouracil for 5 weeks. With a decline in neutrophil count.5 mg weekly.2 sec over 3 weeks. 3 of 25 patients experienced serious gastrointestinal bleeding even though their PT was within the therapeutic range at the time. his INR dropped below therapeutic levels. His oral warfarin dose was 5 mg daily.MICROMEDEX® 2. at which time his PT was 11.2.66 mg and with fluorouracil the mean was 24 mg. Warfarin was stopped and intravenous phytonadione 10 mg was administered on the next day. e) A case was reported where an elderly man with colon cancer was treated with heparin and warfarin for deep vein thrombosis. Epistaxis and hematuria responded to discontinuation and reduction of warfarin dosage [329]. she experienced gross hematuria on the first occasion and epistaxis on each occasion.43. Five days after cessation of warfarin. b) After starting warfarin.7 seconds on day 2 and 15. After starting fluorouracil 1200 mg daily by continuous infusion. After colon resection for colon cancer.1 seconds from a peak of 22. by day 15 of each subsequent cycle of chemotherapy. When he was restarted on levamisole-fluorouracil. The PT returned to pretreatment levels within 48 hours [329]. the weekly mean dose of warfarin was 40. methotrexate. even though his warfarin dose was decreased to 2.3 seconds. Her PT ranged from 14. The PT increased to 44. a 57-year-old woman treated with cyclophosphamide. Before fluorouracil. furthermore. all patients required a warfarin dose reduction of 44% [333].8 and 14. While these investigators found a lengthening of fluorouracil half-life in rabbits given concomitant fluorouracilwarfarin.04 to 39.8 to 17. that effect was not reproduced in human subjects [332]. he had a rise in PT to 12. his PT came down to 13.25/10/12 Drug details . and fluorouracil for breast cancer experienced elevated prothrombin times (PT) by day 15 on 4 chemotherapy cycles. The following day the PT decreased to 48. c) After starting warfarin. 16. warfarin was discontinued. g) Five patients received warfarin and fluorouracil for a period of 3 years. With a continuing rise in PT.1 sec over a week. The PT continued to decrease to 19.0 elevated at 62.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.6 to 26 sec by day 15 of each subsequent cycle of chemotherapy. d) A case was reported where a 73-year-old man with prosthetic mitral and aortic valve replacement was stabilized on warfarin 22. thereafter. thomsonhc.56. respectively. She also experienced epistaxis on 1 occasion. he again experienced a significant rise in prothrombin time [330]. his warfarin was reduced to 7.8 seconds on day 3. Within 4 weeks of beginning antineoplastic therapy. During this period. he received maintenance doses of levamisole (50 mg every 8 hours for 3 days every other week) and fluorouracil (450 mg/m(2)/week). Her PT ranged from 8. These patients were known to have intracolonic lesions at study entry.6.

The patient was being hospitalized and treated for gastric adenocarcinoma (stage IIIB) with her first cycle of chemotherapy. Bleeding was observed in 8 patients (INR 1. D-dimer. and fibrinogen levels) before heparin infusions were all within normal ranges.2 three weeks after the last cycle and the total weekly warfarin dose was reduced from 9 mg/week to 7 mg/week. A radical total gastrectomy was performed and subsequent administration of the appropriate chemotherapy regimen was initiated. and hematochezia. The INR rose above the targeted INR range of 2 to 3 three to four weeks after the last fluorouracil and leucovorin dose of each chemotherapy cycle. In order to maintain an INR of 2 to 3. Four-hundred eighty eight INR determinations were performed. Of these. Warfarin was subsequently discontinued on day 3 of therapy as the patient's INR reached 5. the weekly warfarin dose needed to be doubled from 7 mg/week to 14 mg/week. cisplatin. hematemesis. The INR dropped to 1. activated partial thromboplastin time.34 to 8. Epistaxis with no gross blood loss was observed in 6 patients. Three days later the patient began to complain about right lower extremity pain. hematuria. Close monitoring of the INR is recommended when warfarin is added to fluorouracil therapy.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Warfarin dosage may need to be reduced by 20 to 70% during concomitant therapy with fluorouracil and then increased within 30 days after discontinuation of fluorouracil to maintain the INR within the desired range [336]. The patient had colon cancer and received an intravenous chemotherapy regimen consisting of 6 cycles of fluorouracil and leucovorin. Her baseline INR was 1. Warfarin was initiated. i) A case report of a 39-year-old female describes an interaction between fluorouracil (5-FU) and warfarin leading to a prolonged prothrombin time (PT). leading to impaired warfarin metabolism [334].8). The patient was diagnosed with deep venous thrombosis in the left leg. Laboratory results showed a prothrombin time of 70.1. The patient was being treated with 5-fluorouracil and warfarin. Ninetyfive cancer patients treated with continuous-infusion FU-based chemotherapy were evaluated. WBC.5 and PT reached 31 seconds. 50 of which (10%) showed an INR of more than 1. Warfarin was added to the existing drug regimen 2 days later.5. PT. Thirty-one patients (33%) had a significant elevation in their INR levels.18 and 1. The proportion distribution of increased INR was the following: the INR became elevated in 12 (57%) of 21 patients treated with the thomsonhc. Previously his INR was maintained between 2 and 3. It is suggested that 5-fluorouracil may inhibit the synthesis of cytochrome P450 2C9. The drugs were given for 5 consecutive days during a month. and hematuria was observed in 2 patients. 6 patients had minimal INR elevations (between 1. The INR peaked at 4. Fluorouracil may inhibit the synthesis of cytochrome P450 2C9 and thus inhibit the metabolism of warfarin. and etoposide. Symptoms were improving and her PT values began to decrease on day 7 after warfarin discontinuation [335].IntermediateToDocumentPrintLink 52/317 . An ultrasound revealed deep venous thrombosis.25/10/12 h) A 59-year-old man with colon cancer experienced epistaxis.7 seconds and an INR of 35. Heparin infusions were initiated during chemotherapy.58 four weeks after the completion of the final cycle of chemotherapy . The chemotherapy regimen consisted of 5-FU.9 four weeks after starting 5-fluorouracil therapy. Laboratory tests (liver function tests. j) Concomitant use of warfarin and fluorouracil resulted in fluctuating INR in a 60year-old female.5). k) Continuous-infusion fluorouracil (FU)-based chemotherapy and minidose warfarin (1 mg/day) has been shown to increase the incidence of INR abnormalities.

9% injection with fluorouracil 16 mg/mL in Sodium chloride 0. immersed in a solution containing fluorouracil 50 mg/mL had no visible reaction after 7 days at 24 degrees C [603] Amifostine 1) Compatible a) Amifostine 10 mg/mL in Dextrose 5% in water with fluorouracil 16 mg/mL in . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients receiving chemotherapy for leukemia and other hematopoietic malignancies. Analysis of 80 patients treated with these regimens showed a statistically significant association between INR elevation and FOLFOX treatment (p = 0. At least three months should elapse between the discontinuation of chemotherapy and vaccination with a live vaccine [313]. 7) Probable Mechanism: decreased immune response allows live vaccine to produce infection Intravenous Admixtures Drugs Allopurinol Sodium 1) Compatible a) Allopurinol sodium 3 mg/mL in Sodium chloride 0. and whose chemotherapy has been discontinued for at least 3 months can receive a live vaccine[313].9% injection. performance status. age. Patients with leukemia. This study demonstrated that coadministration of warfarin and FU resulted in an INR elevation in 33% of patients and that of the 8 patients who developed bleeding problems. Clinicians should regularly monitor the prothrombin time in patients receiving warfarin and FU [337]. number of previous chemotherapy regimens administered or chemotherapy toxicity or INR alteration or bleeding.041).FOLFOX regimen. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine while on concomitant methotrexate therapy [316]. 11 (27%) of 40 patients treated with the de Gramont regimen. who have restored immunocompetence. and 5 (26%) of 19 patients treated with the FOLFIRI regimen. for solid tumors. 7 had an elevated INR. hepatic function. Live virus and bacterial vaccines should not be administered to a patient receiving an immunosuppressive chemotherapeutic agent. lymphoma. No relationship was observed between liver metastasis. or after solid organ transplant should be assumed to have altered immunocompetence and should not be vaccinated with a live vaccine. or other malignancies whose disease is in remission. compatible for up to 4 hours at 22 degrees C [604] Aluminum 1) Compatible a) Aluminum as a component of a chemotherapy-dispensing pin. Yellow Fever Vaccine 1) Interaction Effect: an increased risk of infection by the live vaccine 2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a chemotherapeutic agent has resulted in severe and fatal infections[314][315].

5% Dextrose injection.9% in polyvinylchloride bags at 25 degrees C.5 mg/mL with fluorouracil 1 or 10 mg/mL in Sodium chloride 0. 10% cisplatin loss in 1. fluorouracil activity not tested [564] b) Bleomycin 1. visually compatible in Sodium chloride 0.5 hours whether protected from light or not.2 or 0.5 mL.5 mL visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation. cisplatin 1 mg/mL with fluorouracil 50 mg/mL visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections) [595] Cyclophosphamide . visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [565] c) Bleomycin 3 U/mL with fluorouracil 50 mg/mL.5 mL with fluorouracil 25 mg/0. compatible for up to 4 hours at 23 degrees C [612] Bleomycin Sulfate 1) Compatible a) Bleomycin sulfate 20 or 30 U/L with fluorouracil 1 g/L.5 mg/0.5 U/0. compatible during simulated Y-site administration [597] Aztreonam 1) Compatible a) Aztreonam 40 mg/mL in 5% Dextrose in water with fluorouracil 16 mg/mL in Dextrose 5% in water. greater than 80% cisplatin loss in 24 hours at room temperature in a polyvinylchloride container [593] 2) Cisplatin 0.5 mL with fluorouracil 25 mg/0.9% and greater than 90% bleomycin activity retained for 1 week at 4 degrees C. no loss of fluorouracil potency reported [594] b) Compatible 1) Cisplatin (0.5 mg/mL with fluorouracil 10 mg/mL. visually compatible with no alteration of ultraviolet spectra in 8 hours at 25 degrees C in Dextrose 5% in water [606] Cisplatin 1) Conflicting Data a) Incompatible 1) Cisplatin 0. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [565] Calcium Gluconate 1) Compatible a) Calcium gluconate compatible with fluorouracil (Adrucil(R)). concentrations not specified [601] Cephalothin 1) Compatible a) Cephalothin 1 g/L with fluorouracil 500 mg/L.

b) Cyclophosphamide (10 mg/0. solution reported to change color to deep purple. conditions not specified) thomsonhc. ultraviolet spectrum of cytarabine was altered within 1 hour at room temperature) [554] b) Fluorouracil (250 mg/L with cytarabine 400 mg/L in Dextrose 5% in water.MICROMEDEX® 2. Doxorubicin 1) Conflicting Data a) Incompatible 1) Fluorouracil (250 mg/L with doxorubicin 10 mg/L in Dextrose 5% in water.25/10/12 Drug details . 1988) Doripenem 1) Compatible a) Doripenem 5 mg/mL with fluorouracil 16 mg/mL in either 5% dextrose injection or in 0. ultraviolet spectrum for cytarabine altered with 1 hour at room temperature. analysis by UV/visible spectrometry revealed no alteration in the spectrum of either drug when they were combined in solution. analysis of the ultraviolet/visible spectra did not detect any interaction between the two drugs. precipitate formation reported) (Tech Info Cetus. no change observed in fluorouracil spectrum) [598] Dacarbazine 1) Compatible a) Dacarbazine (with fluorouracil. drug concentrations and test conditions not specified) [581] b) Fluorouracil (with diazepam.5 mL visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation. cyclophosphamide 20 mg/mL with fluorouracil 50 mg/mL visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections) [571].5 mL with fluorouracil 25 mg/0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. drug concentrations and conditions not specified) [609] b) Fluorouracil (with dacarbazine.9% sodium chloride injection is physically compatible for 4 hours at room temperature (approximately 23 degrees C) under fluorescent light during simulated Y-site administration [556]. drug concentrations and conditions not specified) [610] Diazepam 1) Incompatible a) Diazepam (with fluorouracil. concentrations not specified. immediate precipitate formation reported. Cytarabine 1) Incompatible a) Cytarabine (400 mg/L with fluorouracil 250 mg/L in Dextrose 5% in water.0 1) Compatible a) An admixture of fluorouracil 30 milligrams/milliliter (mg/mL) (in normal saline diluent) and cyclophosphamide 5 mg/mL is stable for 7 days at room temperature (25 degrees Celsius) in a PVC reservoir bag [570].IntermediateToDocumentPrintLink 55/317 .

fluorouracil 50 mg/mL with furosemide 10 mg/mL visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections) [586] Gallium Nitrate 1) Incompatible a) Fluorouracil (undiluted) 50 mg/mL admixed in a 1:1 ratio simulating Y-site administration with gallium nitrate (Ganite(R)) 1 mg/mL in Sodium chloride 0. immediate precipitate which cleared after 60 minutes and remained clear for 24-hour study period stored at room temperature under fluorescent light in a glass container.9% from a plastic syringe.5 mg/mL with fluorouracil 50 mg/mL. visually compatible for a 4-hour study period at room temperature under fluorescent light [611] Furosemide 1) Compatible a) Fluorouracil (25 mg/0.5 ml visually compatible in direct admixture in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation. both in Dextrose 5% in water.5 mL with fluorouracil 25 mg/0. doxorubicin 2 mg/mL with fluorouracil 50 mg/mL visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections) [595] Droperidol 1) Incompatible a) Droperidol 1.25 mg/0. visually observed with high-intensity light enhancement [602] Fludarabine 1) Compatible a) Fludarabine 1 mg/mL with fluorouracil 16 mg/mL.Drug details .5 ml with furosemide 5 mg/0.5 mL. particles and long filaments formed in 1 hour.5 mL with fluorouracil 25 mg/0. chemical stability not tested [577] Granisetron Hydrochloride 1) Compatible 56/317 .5 mL visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation. immediate precipitate formation reported when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [605] Filgrastim 1) Incompatible a) Filgrastim 30 mcg/mL in Dextrose 5% in water with fluorouracil 16 mg/mL in Dextrose 5% in water.MICROMEDEX® 2. immediate precipitate formation reported in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [605] b) Droperidol 2.0 [555] b) Compatible 1) Doxorubicin (1 mg/0.

0 a) Fluorouracil 200 mg in 100 mL of 0. stable for 4 hours when mixed in 1:1 ratio during simulated Y-site administration [613] b) Granisetron hydrochloride diluted with 5% dextrose injection to a concentration of 50 mcg/mL is compatible with fluorouracil at a concentration of 16 mg/mL (D5W) during simulated Y-site injection. Turbidity.25/10/12 Drug details .9% Hydrocortisone Sodium Succinate 1) Compatible a) Fluorouracil 50 mg/mL with hydrocortisone sodium succinate 10 mg/L visually compatible.9% Sodium chloride in PVC bag (protected from light) with granisetron hydrochloride 1 mg/mL in Sterile water for injection.5 mL. Heparin 1) Compatible a) Fluorouracil 25 mg/0. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [587] c) Fluorouracil 50 mg/mL with heparin 1000 U/L. visually compatible. macroscopically and microscopically. The mixtures were assessed at 1 and 4 hours (Trissel. visually compatible for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [587] b) Fluorouracil 50 mg/mL with heparin 1000 U/mL. macroscopically and microscopically. for a 4-hour study period at 25 degrees C in the following solutions [608]: Dextrose 5% in lactated Ringer's injection Dextrose 5% in Ringer's injection thomsonhc.MICROMEDEX® 2.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Compatibility was measured using visual examinations in fluorescent light and in high-intensity monodirectional light.IntermediateToDocumentPrintLink 57/317 . particle size and particle counts were completed for certain solutions.5 mL with heparin 500 U/0. 1997). for 4 hour study period at 25 degrees C in the following solutions [588]: Dextrose 5% in lactated Ringer's injection Dextrose 5% in Ringer's injection Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.

23. mixtures were stored in glass containers at 21 to 23 degrees C for 4 hours [585] 58/317 . another source reported conditions under which these drugs were found to be incompatible [553]. color change. or pH changes during simultated Y-site administration. 7 days at 23 degrees C.5 mg/mL admixed with fluorouracil 1 mg/mL in dextrose 5% and NaCl 0. b) Compatible 1) Fluorouracil 25 mg/0.5 mg/mL admixed with fluorouracil 16 mg/mL in dextrose 5% and NaCl 0. gas production.9% Sodium chloride with leucovorin 10 mg/mL and 20 mg/mL.7 mg/mL in 0. mixtures were stored in glass containers at 21 to 23 degrees C for 4 hours [585] 4) Fluorouracil 7 mg/mL and 0. incompatible when mixed in different amounts and stored at 4. 4. visually compatible in direct admixture in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [584] 2) Fluorouracil 50 mg/mL with leucovorin 10 mg/mL. microscopic aggregation.9% Hydromorphone 1) Compatible a) Hydromorphone 0. and 35 days at 4 and -20 degrees C [566]. Leucovorin 1) Conflicting Data a) Incompatible 1) Fluorouracil 50 mg/mL with leucovorin 20 mg/mL (as the calcium salt). microscopic aggregation. gas production. with or without Dextroxe 5% in water.Drug details .9% is physically compatible and chemically stable for 7 days at 32 degrees C and 35 days at 23.MICROMEDEX® 2.5 mL.5 mL with leucovorin 5 mg/0.9% is physically compatible and chemically stable for 3 days at 32 degrees C. or 32 degrees C in polyvinyl chloride containers [552]. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [584] 3) Fluorouracil 50 mg/mL (undiluted) with leucovorin 10 mg/mL and 20 mg/mL. however. color change.0 Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0. no macroscopic precipitation. or pH changes during simultated Ysite administration. b) Hydromorphone 0. no macroscopic precipitation. and -20 degrees C [566].

it has been recommended that these two drugs not be mixed thomsonhc. 0. and Dextrose 5% and 0.25/10/12 Drug details .7 mg/mL in Dextrose 5% in water with leucovorin 10 mg/mL and 20 mg/mL. no macroscopic precipitation.9% Sodium chloride injection.MICROMEDEX® 2.IntermediateToDocumentPrintLink 59/317 . color change. gas production. 23. UV spectra for both drugs were altered within 1 hour at room temperature in Dextrose 5% in water [568] b) Compatible 1) Fluorouracil (25 mg/0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5 mg/0. However. Separate administration of these agents is suggested. concentrations not specified [579] Mannitol 1) Compatible a) Fluorouracil 1 and 2 mg/mL in Dextrose 5% injection. microscopic aggregation.45% Sodium chloride injection with mannitol 20%. mixtures were stored in glass containers at 21 to 23 degrees C for 4 hours [585] Levoleucovorin Calcium 1) Incompatible a) 5-Fluorouracil 50 mg/mL and levoleucovorin calcium 20 mg/mL are incompatible when mixed in various ratios (with or without 5% dextrose injection) in polyvinyl chloride containers at 4.5 mL visually compatible in direct admixture in syringe for 5 minutes at 25 degrees Celsius followed by 8 minutes of centrifugation.5 mL with methotrexate 12. Magnesium Sulfate 1) Compatible a) Fluorouracil (Adrucil(R)) compatible with magnesium sulfate. or pH changes during simulated Y-site administration. or 32 degrees Centigrade.0 degrees C for 4 hours [585] 5) Fluorouracil 0. fluorouracil 50 mg/mL with methotrexate 25 mg/mL visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections) [557]. crystalline particulate formation was observed in some solutions within 24 hours [573]. visually compatible and chemically stable for 24 hour-study (stored at 25 degrees C under constant fluorescent lighting) and during Y-site administration [572] Methotrexate 1) Conflicting Data a) Incompatible 1) Fluorouracil 250 mg/L with methotrexate 200 mg/L. Linezolid 1) Compatible a) Fluorouracil 16 mg/mL (diluted in 5% dextrose injection) with linezolid 2 mg/mL (tested undiluted) is physically compatible for 4 hours at room temperature (approximately 23 degrees C) under fluorescent light during simulated Y-site administration [563].

Metoclopramide 1) Conflicting Data a) Incompatible 1) Fluorouracil 840 mg/16.5 mg/0.0. 1990) b) Compatible 1) Fluorouracil 2.16 mg/mL is 60/317 .1 mg/mL (as the hydrochloride salt) in Dextrose 5% in water. forming an immediate precipitate [574].MICROMEDEX® 2. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Yside arm between injections [562] Mitomycin 1) Compatible a) Fluorouracil 25 mg/0. gellike precipitate [589][590] b) Compatible 1) 5-Fluorouracil up to 0.UK NON-PRESERVED FORMULATION .5 mg/mL and metoclopramide 0.5 mL with mitomycin 0.96 milligram/milliliter (mg/mL) (in normal saline diluent) and fluorouracil 48 mg/mL is stable for 14 days at room temperature (25 degrees Celsius) in a PVC reservoir bag [560]. 2) An admixture of methotrexate 0.0 in the same solution [558][559].8 mg/mL added at 20 mL/hr via a Y-site to ondansetron . visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [569] b) Fluorouracil 50 mg/mL with mitomycin 0. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [569] Morphine Sulfate 1) Incompatible a) Morphine sulfate 1 mg/mL admixed with fluorouracil 1 mg/mL and 16 mg/mL in dextrose 5% and NaCl 0.5 mL.25 mg/0.9% resulted in the formation of a white. stable for 4 hours at 25 degrees C and for 120 hours at 4 degrees C in methyl-methacrylate-butadiene-styrene containers [561] 2) Fluorouracil 25 mg/0. translucent. Ondansetron 1) Conflicting Data a) Incompatible 1) Fluorouracil 16 mg/mL in Dextrose 5% in water with ondansetron 1 mg/mL in Sodium chloride 0.9% is physically incompatible.5 mg/mL.25/10/12 Drug details .016 to 0. precipitate formed upon mixing (Tech Info Reglan(R).8 mL with metoclopramide 10 mg/2 mL incompatible.5 mL with metoclopramide 2.5 mL. visually compatible for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [562] 3) Fluorouracil 50 mg/mL with metoclopramide 5 mg/mL.

for a 4-hour study period at 25 degrees C in the following solutions [551]: Dextrose 5% in lactated Ringer's injection Dextrose 5% in Ringer's injection Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.IntermediateToDocumentPrintLink 61/317 .9% Prednisolone 1) Compatible a) Fluorouracil (250 mg/L with prednisolone 200 mg/L visually compatible in thomsonhc. Oxaliplatin 1) Incompatible a) Oxaliplatin solution is incompatible with alkaline medications such as 5fluorouracil.0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Paclitaxel 1) Compatible a) Fluorouracil 16 mg/mL in Dextrose 5% injection with paclitaxel 1. Do not mix together or administer simultaneously through the same infusion line.016 to 0.16 mg/mL is physically compatible for 24 hours at 25 degrees C under ambient lighting in a polyvinylchloride container [599][600]. visually compatible.25/10/12 Drug details .MICROMEDEX® 2.0 ondansetron . Flush the infusion line with dextrose 5% injection (D5W) prior to administration [592].2 mg/mL in Dextrose 5% injection in glass container. macroscopically and microscopically. However. no visual or turbidimetric evidence of incompatibility in simulated Y-site injection for a 4-hour study period. admixture stored at room temperature under fluorescent light [591]. compatible for 4 hours at 22 degrees C [578] Potassium Chloride 1) Compatible a) Fluorouracil 50 mg/mL with potassium chloride 40 mEq/L.UK NON-PRESERVED FORMULATION . this admixture was not tested for chemical stability. Piperacillin Sodium/Tazobactam Sodium 1) Compatible a) Piperacillin sodium 40 mg/mL plus tazobactam 5 mg/mL in Dextrose 5% in water with fluorouracil 16 mg/mL in Dextrose 5% in water.

both in sodium chloride 0.9%. Sargramostim 1) Compatible a) Fluorouracil 16 mg/mL with sargramostim 10 mcg/mL.5 mL.5 mL with vinblastine 0.MICROMEDEX® 2. visually compatible and no alterations in UV spectra were reported in 8 hours at room temperature in Dextrose 5% in water [582] b) Fluorouracil 25 mg/0.9%.5 mg/0.5 mL. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [583] Vinorelbine Tartrate 1) Incompatible a) Fluorouracil 16 mg/mL in Sodium chloride 0.0 Dextrose 5% in water with no alteration of ultraviolet spectrum of either drug in 8 hours at room temperature) [576] Prednisolone Sodium Phosphate 1) Compatible a) Prednisolone sodium phosphate (200 mg/L with fluorouracil 250 mg/L physically compatible in Dextrose 5% in water with no alteration of the ultraviolet spectra in 8 hours at room temperature) [554] Propofol 1) Compatible a) Propofol 1% injectable emulsion and fluorouracil 16 milligrams/milliliter in a 1:1 volume mixture (simulated Y-site administration) are visually compatible in polycarbonate test tubes at 15 minutes and 1 hour at approximately 23 degrees Celsius as determined by visualization with fluorescent light and a highintensity. visually compatible when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections [596] Vincristine 1) Compatible a) Fluorouracil 10 mg/L with vincristine 4 mg/L. heavy white precipitate formed immediately thomsonhc.5 mL with vincristine 0.IntermediateToDocumentPrintLink 62/317 .com/micromedex2/librarian/PFDefaultActionId/evidencexpert. visually compatible for a 4-hour study period at 22 degrees C under fluorescent light [607] Vinblastine 1) Compatible a) Fluorouracil 25 mg/0. visually compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [596] b) Fluorouracil 50 mg/mL with vinblastine 1 mg/mL.5 mg/0. mono-directional light source (Tyndall beam) [567].25/10/12 Drug details .9% with vinorelbine tartrate 1 mg/mL in Sodium chloride 0. visually compatible in direct admixture in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [583] c) Fluorouracil 50 mg/mL with vincristine 1 mg/mL.

1985) b) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.45% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.9% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.9%.225%. for a 4-hour study period at 25 degrees C in the following solutions) [580]: Dextrose 5% in lactated Ringer's injection Dextrose 5% in Ringer's injection Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.45%.9% Solutions Dextrose 10% in Sodium chloride 0.225% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.0 [575] Vitamin B Complex/Ascorbic Acid 1) Compatible a) Vitamin B complex with C (2 mL/L with fluorouracil 50 mg/mL visually compatible. 1985) b) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers. conditions not specified (Tech Info American McGaw.25/10/12 Drug details . 1985) 63/317 .MICROMEDEX® 2. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers. 1985): Dextrose 10% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.225%. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers.45%. macroscopically and microscopically. conditions not specified (Tech Info American McGaw. 1985): Dextrose 10% in Sodium chloride 0.

5% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.25/10/12 Drug details . 1985): Dextrose 2. conditions not specified (Tech Info American McGaw.5% in water 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 2.5% in Sodium chloride 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.9% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 2. compatible for 24 hours in glass or polyolefin containers.5% in Sodium chloride 0. 1985) b) Fluorouracil 500 mg/L in Dextrose 2.0 b) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers. compatible for 24 hours in glass or polyolefin containers. 1986) Dextrose 5% in Lactated Ringer's injection 1) Compatible a) Dextrose 5% in Lactated Ringer's injection with fluorouracil 500 mg/L.45%. 1985) Dextrose 5% in Ringer's injection 1) Compatible a) Dextrose 5% in Ringer's injection with fluorouracil 500 mg/L. compatible for thomsonhc.5% in Sodium chloride 0.5% in water. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers.5% in Sodium chloride 0.9%.45%. 1985) Dextrose 3.3% with fluorouracil 1. conditions not specified (Tech Info American McGaw. stable for 8 weeks at ambient temperature in glass or polyvinylchloride containers in the dark or under fluorescent light (Biondi & Nairn. conditions not specified (Tech Info American McGaw.IntermediateToDocumentPrintLink 64/317 . 1985): Dextrose 10% in water 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 10% in water.5 g/L.3% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.3% 1) Compatible a) Dextrose 3. conditions not specified (Tech Info American McGaw.45% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 2. compatible for 24 hours in glass or polyolefin containers. 1985): Dextrose 2. conditions not specified (Tech Info American McGaw.9%.5% in Sodium chloride 0.3% in Sodium chloride 0. conditions not specified (Tech Info American McGaw. 1985) b) Fluorouracil 500 mg/L in Dextrose 2. 1985) Dextrose 2. conditions not specified (Tech Info American McGaw.MICROMEDEX® 2. compatible for 24 hours in glass or polyolefin containers.9%.

compatible for 24 hours in glass or polyolefin containers.11%. 1985) b) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers. 1985): Dextrose 5% in Sodium chloride 0. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. compatible for 24 hours in glass or polyolefin containers. conditions not specified (Tech Info American McGaw. compatible for 24 hours in glass or polyolefin containers. compatible for 24 hours in glass or polyolefin containers.45%. 1985): thomsonhc.11%.45% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.9% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.0 24 hours in glass or polyolefin containers. conditions not specified (Tech Info American McGaw.33% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0. 1985) Dextrose 5% in Sodium chloride 0.225%. conditions not specified (Tech Info American McGaw. 1985) b) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.9%. 1985) b) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.25/10/12 Drug details . 1985) b) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0. 1985): Dextrose 5% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers. compatible for 24 hours in glass or polyolefin containers. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw. conditions not specified (Tech Info American McGaw.IntermediateToDocumentPrintLink 65/317 . 1985): Dextrose 5% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.11% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.33%.225%.33%.225% 1) Compatible a) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0. compatible for 24 hours in glass or polyolefin containers.9%. 1985) b) Fluorouracil 500 mg/L in Dextrose 5% in Sodium chloride 0.45%. 1985): Dextrose 5% in Sodium chloride 0.

1984) 4) Dextrose 5% in water with fluorouracil 1. no decrease in fluorouracil concentration reported in 16 weeks at 5 degrees C or in 7 days at 25 degrees C in a plasticized polyvinylchloride container or an elastomeric balloon used in a disposable drug pump (Quebbemen et al.0 Dextrose 5% in water 1) Conflicting Data a) Incompatible 1) Dextrose 5% in water with fluorouracil 8. 1985) Sodium chloride 0. 1986) 5) Dextrose 5% in water with fluorouracil 1 or 2 g/L. however. stable for 8 weeks at ambient temperature in glass or polyvinylchloride containers in the dark or under fluorescent light (Biondi & Nairn. 22. or 35 degrees C protected form light in ethylene vinylacetate portable infusion-pump reservoirs (Rochard et al.3 g/L in a glass container.45% 1) Compatible a) Fluorouracil 500 mg/L in Sodium chloride 0.3 g/L in a polyvinylchloride container.9%.5 g/L. 1992) LACTATED RINGER'S INJECTION 1) Compatible a) Lactated Ringer's injection (with fluorouracil 500 mg/L compatible for 24 hours in glass or polyolefin containers.MICROMEDEX® 2. physically compatible and no fluorouracil decomposition observed by ultraviolet spectroscopy or thin layer chromatography in 48 hours at room temperature [581] 6) Dextrose 5% in water with fluorouracil 10 mg/mL.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details . compatible for 24 hours in glass or polyolefin containers.IntermediateToDocumentPrintLink 66/317 . 10% decrease in fluorouracil concentration in 7 hours at room temperature when tested in glass container. conditions not specified (Tech Info American McGaw. 10% decrease in fluorouracil concentration in 43 hours at room temperature when tested in polyvinyl chloride container [614] b) Compatible 1) Fluorouracil 500 mg/L in Dextrose 5% in water. conditions not specified (Tech Info American McGaw. 1985): Sodium chloride 0.45%. compatible for 24 hours in glass or polyolefin containers. compatible for 24 hours in glass or polyolefin containers. 1985) 2) Dextrose 5% in water with fluorouracil 8. conditions not specified (Tech Info American thomsonhc. conditions not specified) (Tech Info American McGaw.9% 1) Compatible a) Fluorouracil 500 mg/L in Sodium chloride 0. 10% decrease in fluorouracil concentration in 43 hours at room temperature [406] 3) Dextrose 5% in water with fluorouracil 10 g/L. stable for up to 28 days at 4.

9%.8 mL 3.25/10/12 Drug details . immediate formation of turbidity reported. physically compatible and no fluorouracil decomposition observed by ultraviolet spectroscopy or thin layer chromatography in 48 hours at room temperature [616] TOTAL PARENTERAL NUTRITION 1) Conflicting Data a) Incompatible 1) Fluorouracil 16 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution in simulated Y-site administration.5 mM 25 mEq 35 mEq 8 mEq 10 mL 1 mL 9. stable for 8 weeks at ambient temperature in glass or polyvinylchloride containers in the dark or under fluorescent light [615] c) Fluorouracil 1 or 2 g/L in Sodium chloride 0. 1985): b) Fluorouracil 1.5 g/L in Sodium chloride 0.9%. specific composition of total parenteral nutrition solution listed below [620]: Amino acids 10% (FreAmine(R) III) Dextrose Sterile water for injection Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate 3.0 McGaw. specific composition of total parenteral nutrition solution listed below [620]: Amino acids 10% (Aminosyn(R) II) Dextrose Sterile water for injection Potassium phosphates Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate 3.5% 5% 516.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. small crystals (both visible only in high-intensity light) and amber discoloration were reported in 1 to 4 hours at 23 degrees C. formation of a slight haze. small crystals (both visible only in high-intensity light) and amber discoloration were reported in 1 to 4 hours at 23 degrees C.5% 5% 516.5 mEq 40 mEq 8 mEq 10 mL 1 mL 5 mEq 3) Fluorouracil 16 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution in simulated Y-site administration.IntermediateToDocumentPrintLink 67/317 .75 mL 37. formation of a slight haze.3 mEq 2) Fluorouracil 16 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution in simulated Y-site administration. specific composition of total parenteral nutrition solution thomsonhc.

25% 25% 158.6 mL 5.15 mEq 4) Fluorouracil 16 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution in simulated Y-site administration.MICROMEDEX® 2.5% with electrolytes 500 mL Dextrose 50% 500 mL thomsonhc.75 mM 40 mEq 25 mEq 8 mEq 10 mL 1 mL 7.25% 25% 161 mL 15 mM 25 mEq 18 mEq 8 mEq 10 mL 1 mL 9. but compatibility is questionable because HPLC results were erratic.25/10/12 Drug details .5 mEq 5) Fluorouracil (1 or 4 g/L in a total parenteral nutrition solution physically compatible for 42 hours at room temperature. particulate matter levels or pH in 24 hours at 5 degrees C) [617] 2) Total parenteral nutrition (with fluorouracil 1 g/L visually compatible and fluorouracil chemically stable for 48 hours at room temperature in ambient light.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink 68/317 . specific composition of total parenteral nutrition solution listed below [620]: Amino acids 10% (FreAmine(R) III) Dextrose Sterile water for injection Potassium phosphates Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate 4. specific composition of total parenteral nutrition solution described below) [621]: Amino acids 8.5% with electrolytes 500 mL/L Dextrose 50% 500 mL/L Calcium gluconate 1 g/L Multivitamins 5 mL/L b) Compatible 1) Total parenteral nutrition (amino acids 4.0 listed below [620]: Amino acids 10% (Aminosyn(R) II) Dextrose Sterile water for injection Potassium phosphates Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate 4. with fluorouracil 500 mg/L exhibited no significant change in appearance. specific composition of total parenteral nutrition solution described below) [618]: Amino acids 8. immediate formation of turbidity reported.25% in dextrose 25%.

thomsonhc. Patients with hyperglycemia are at risk of developing severe life-threatening toxicity with 5-fluorouracil [404]. B) Toxic 1) Laboratory Parameters a) Intravenous 1) Monitor white blood count with differential prior to each dose of the drug [402].com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5% with electrolytes 500 mL/L Dextrose 50% 500 mL/L Calcium gluconate 1 g/L Multivitamins 5 mL/L 4) Total parenteral nutrition (ProcalAmine(R) . specific composition of total parenteral nutrition solution listed below) (Tech info ProcalAmine(R).IntermediateToDocumentPrintLink 69/317 . but compatibility is questionable because HPLC results were erratic. 2) Physical Findings a) Intravenous 1) Monitor for improvement of signs and symptoms of specific carcinoma. b) Topical 1) Monitor for improvement signs and symptoms of actinic/solar keratosis or superficial basal cell carcinoma [403].0 Dextrose 50% Calcium gluconate 10% Multivitamins 500 mL 10 mL 5 mL 3) Total parenteral nutrition (with fluorouracil 1 or 4 g/L physically compatible for 42 hours at room temperatures. specific composition of total parenteral nutrition solution described below) [619]: Amino acids 8.25/10/12 Drug details . 2) Monitor serum glucose in diabetic patients. 1985): Amino acids Glycerol Electrolytes 3% 3% present CLINICAL APPLICATIONS Monitoring Parameters A) Therapeutic 1) Laboratory Parameters a) Monitor white blood counts with differential before each intravenous dose [402].MICROMEDEX® 2.with fluorouracil 500 mg/L physically compatible for 48 hours under refrigeration followed by 24 hours at 25 degrees C.

Your doctor will prescribe your dose and tell you how often it will be given. and stomach. or IV.25/10/12 Drug details . breast. you should be given a special container for the used needles. away from heat. How to Store and Dispose of This Medicine: If you get your treatments at a clinic. and herbal products. pancreas. you may need to store your medicine.MICROMEDEX® 2. usually in your arm. You should not use aspirin or any product that has aspirin it (such as some cold medicines) unless you have talked to your doctor. flu. If a Dose is Missed: This medicine needs to be given on a regular schedule. Also called 5-FU. Make sure you understand why you are getting it and what the risks and benefits of treatment are. If you miss a dose. bone marrow problems. Before you start your treatments. This is called intravenous (in-tra-VEEN-us). call your doctor. or the clinic where you get your treatments for instructions. It is important for you to work closely with your doctor. and tubes. the staff at the clinic will keep your medicine there. moisture. and light. Put it where children or pets cannot reach it. When This Medicine Should Not Be Used: You should not be treated with this medicine if you have had an allergic reaction to fluorouracil. rectum. Your medicine will be given through a tube that is put in a vein. or hand and sometimes in your chest.IntermediateToDocumentPrintLink 70/317 . Warnings While Using This Medicine: Do not breastfeed while you are being given this medicine. Talk to your doctor before getting any vaccines (such as flu shots).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.0 Patient Instructions A) Fluorouracil (Injection) Fluorouracil Treats cancer of the colon. thomsonhc. Stay away from crowds or people with colds. How to Use This Medicine: Injectable This medicine is very strong. Avoid drinking alcohol. Drugs and Foods to Avoid: Ask your doctor or pharmacist before using any other medicine. vitamins. If you get your treatments at home. or liver or kidney disease. wrist. Keep the IV liquid at room temperature. A nurse or other caregiver trained to give cancer drugs will give your treatment. You may get infections more easily while getting this medicine. tell your doctor if you have any infections. home health caregiver. or other infections. medicine bag. including over-the-counter medicines. If you get your treatments at home. Keep all medicine out of the reach of children.

IntermediateToDocumentPrintLink 71/317 . B) Fluorouracil (On the skin) Fluorouracil Treats actinic keratoses or solar keratoses (red wart-like growth on the skin). Do not get pregnant while you or your sexual partner are receiving fluorouracil. trouble breathing Severe rash or hives If you notice these less serious side effects. talk to your doctor before you start your treatments. tell your doctor. loose watery stools Mouth sores that keep you from drinking liquids Severe vomiting Wheezing. flu. If it does get on these areas. Do not get it in your eyes.25/10/12 Drug details . or other infections. This medicine is for use on the skin only. Do not use this medicine if you have dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. nose. rinse it off right away. How to Use This Medicine: Cream. Keep your mouth clean to prevent infection. If you are pregnant.0 with colds. Your doctor may prescribe medicine to keep you from feeling sick and throwing up. Also treats skin cancer (superficial basal cell carcinoma). This medicine may make your mouth sore and irritated. If the medicine does not help (you can't keep liquids down). Wash your hands with soap and water before and after using this medicine. call your doctor. Do not use this medicine if you are or may become pregnant. This medicine can cause nausea and vomiting. Brush your teeth with a soft-bristle toothbrush or mouth swab. talk with your doctor: Loss of appetite Stomach cramps Hair loss Mild rash Darkening of skin If you notice other side effects that you think are caused by this medicine. Possible Side Effects While Using This Medicine: Call your doctor right away if you notice any of these side effects: Fever. Do not use more medicine or use it more often than your doctor tells you to. chills. When This Medicine Should Not Be Used: You should not use this medicine if you have had an allergic reaction to fluorouracil. Use an effective method of birth control while you are getting this medicine.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. or mouth. or sore throat Unusual bleeding or bruising Diarrhea.MICROMEDEX® 2. Liquid Your doctor will tell you how much of this medicine to use and how often. Do not use it on skin areas that have cuts or scrapes. Wash the skin to be treated with soap and water and wait 10 minutes before applying the thomsonhc.

Use a sunscreen when you are outdoors. or watering. You may use a glove. If you think you have become pregnant while using the medicine. trouble breathing Fever. use a gauze bandage with tape.IntermediateToDocumentPrintLink 72/317 .MICROMEDEX® 2. Drugs and Foods to Avoid: Ask your doctor or pharmacist before using any other medicine. Eye burning. Stomach pain. Ask your pharmacist. Hair loss. or diarrhea that contains blood. apply it as soon as you can. Tell your doctor if you are sensitive to preservatives. swelling in your face or hands. talk with your doctor: Change in skin color where medicine is put on. swelling or tingling in your mouth or throat. nonmetal applicator. Use an effective form of birth control to keep from getting pregnant. Do not cover the treated area with a bandage unless your doctor has told you to. If your doctor tells you to use a bandage. or vomiting. Avoid sunlamps and tanning beds. Do not use cosmetics or other skin care products on the treated skin areas. or if you have any other medical conditions. vitamins. chest tightness. stinging. tell your doctor right away. itching. or your fingers to apply this medicine. thomsonhc. A plastic bandage is more likely to cause skin irritation. Make sure your doctor knows if you are breast feeding. If it is almost time for your next dose. away from heat and direct light. You will also need to throw away old medicine after the expiration date has passed.0 medicine. This medicine may make your skin more sensitive to sunlight. Possible Side Effects While Using This Medicine: Call your doctor right away if you notice any of these side effects: Allergic reaction: Itching or hives.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. If you notice these less serious side effects. and herbal products. Rub it in gently. How to Store and Dispose of This Medicine: Keep the medicine at room temperature. Mild skin itching or burning. including over-the-counter medicines. doctor. Severe skin rash or itching. chills. Do not apply extra medicine to make up for a missed dose. Keep all medicine away from children and never share your medicine with anyone. If a Dose is Missed: If you miss a dose or forget to use your medicine. or health caregiver about the best way to dispose of the used medicine container and any leftover medicine after you have finished your treatment.25/10/12 Drug details . Do not freeze. wait until then to apply the medicine and skip the missed dose. Warnings While Using This Medicine: Using this medicine while you are pregnant can harm your unborn baby. Apply a thin layer to the affected area.

Mechanism of Action / Pharmacology A) MECHANISM OF ACTION 1) 5-Fluorouracil (5-FU) is a fluorinated pyrimidine antimetabolite which undergoes anabolic and catabolic reactions the same as uracil except it is converted to thymidine. and doxorubicin). prolongation of time to recurrence and survival was observed primarily in premenopausal patients as compared to a postmenopausal population.0 Pain where the medicine is put on. or peeling of skin. islet cell carcinoma (with streptozocin and/or doxorubicin). breast cancer became the most common indication for stem-cell transplantation. This creates a thymine deficiency resulting in cell death. redness. Fluorouracil is indicated for the palliative management of pancreatic cancer. especially in cells which grow more rapidly and take up fluorouracil rapidly [385]. However. carboplatin. This also held true when subgroups were analyzed according to estrogenreceptor status and primary site of metastasis. tell your doctor. If you notice other side effects that you think are caused by this medicine. fluorouracil is commonly considered as a first-line therapy for breast cancer (CMF or CMFP). cervical cancer. cyclophosphamide. and ovarian cancer. gastric cancer (with doxorubicin and cisplatin).25/10/12 Drug details . Place In Therapy A) In combination with other chemotherapeutic agents.MICROMEDEX® 2. blistering. in a randomized trial comparing conventional-dose chemotherapy with high-dose chemotherapy (with cyclophosphamide. Therapeutic Uses Actinic keratosis FDA Labeled Indication 73/317 . There was a perception that treatment with high-dose chemotherapy and transplantation resulted in an improved outcome over historical controls using conventional-dose chemotherapy. endometrial cancer. In this study. 5-Fluorouracil blocks the methylation reaction of deoxyuridylic acid to thymidylic acid and interferes with DNA synthesis and to a lesser extent inhibits the formation of RNA [385][400]. B) In the late 1980s. and prostatic cancer (with cisplatin. It is recommended that this approach of high-dose chemotherapy with transplant be abandoned in favor of well-justified alternative experimental approaches [3][10]. Fluorouracil is considered an alternate therapy for bladder cancer. methotrexate and cyclophosphamide) as adjuvant chemotherapy in early breast cancer may be secondary to ovarian suppression in premenopausal patients. squamous cell head and neck cancer (with cisplatin). overall survival and time to disease progression were not favorably affected by use of the latter treatment. The efficacy of the combination was observed only when permanent amenorrhea occurred in premenopausal patients [401]. 2) Evidence has been provided that the mechanism of action of CMF therapy (fluorouracil. thiotepa) and autologous stem-cell transplant. fluorouracil-based chemoradiation is recommended as adjuvant therapy. Swelling.

p=0. and week 52 prior to optional cryosurgical removal of residual AK lesions per investigator discretion.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.4%. Effective Recommendation: Adult.1% vs 4. thomsonhc.001). 1975.028). Basal cell carcinoma and squamous cell carcinoma were the most common serious adverse events [83].8% vs 26. 1976. the combination of cryosurgery with topical fluorouracil cream was more effective in reducing the mean number of AK lesions on sunexposed areas compared to cryosurgery with vehicle cream. The study comprised of 3 treatment cycles. p=0. New involvement of AK lesions on all treatment areas was lower with fluorouracil than vehicle cream at the start of week 26 (80% vs 93. Litwin.007). neck. randomized.001 each cycle).8%. Lesions may not completely heal for 1 to 2 months after treatment discontinuation of 2% or 5% solution or cream [82] 3) Adult: a) In a 52-week. were more prevalent with fluorouracil than vehicle cream. 1970).7%. Based on the intent-to-treat analysis. vehicle-controlled study evaluating the safety and effectiveness of topical 0. 4.7 at week 26 (p=0. p=0.002). 1972. fluorouracil resulted in total AK lesion clearance in all treatment areas at week 5 (12. at week 26 (51. Dogliotti.2 at week 5 (p less than 0.9% vs 0%) and application site reactions (18.9 vs 7 at week 52 (p=0.0 1) Overview FDA Approval: Adult. The proportional reduction in total AK lesions from baseline was consistently greater with fluorouracil than vehicle cream (p less than 0. prospective. 1973. week 26. and at week 52 (36.122).5% vs 0%. double-blind. and lips.001).5 vs 7. yes (Topical). Patients were assessed 4 weeks post-treatment at week 5.MICROMEDEX® 2. Rash (6.2 vs 13.5% fluorouracil incorporated in microsphere applied once daily for up to 4 weeks [81] Several studies have documented the efficacy of a 2% or 5% solution or cream applied 1 to 2 times daily for 2 to 4 weeks (Breza et al. Eaglstein et al. Compared with vehicle cream.25/10/12 Drug details .5% fluorouracil or vehicle cream once daily for 7 days to the face and 1 or more treatment areas. including erythema. no Efficacy: Adult. ears. the reduction of AK lesion in all treatment areas was statistically significant for both treatment groups long term. 1972. Class IIa Strength of Evidence: Adult.6 +/.4% vs 15.6 years) applied either 0.10.5% fluorouracil cream (Carac(TM)) as pretreatment prior to cryosurgery among patients with at least 5 visible or palpable actinic keratosis (AK) lesions on the face (n=144). Robinson & Kligman. pain and burning.2%). including scalp. Pediatric. and 7.IntermediateToDocumentPrintLink 74/317 . during which patients (mean age 62. however. Simmonds. p=0. p less than 0. fluorouracil cream resulted in fewer mean AK lesion count in all treatment areas than vehicle cream: 8.4% vs 90%.015) but was similar between the 2 groups at week 52 (79.002). Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical fluorouracil is indicated in the treatment of actinic and solar keratoses [82][81] Safety and effectiveness have been demonstrated with 0.

57. p=0. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Cisplatin-based induction chemotherapy and chemoradiation failed to improve disease-free survival and resulted in increased colostomy rates compared with standard mitomycinbased chemoradiation in patients with carcinoma of the anal canal (n=644) [89]. or cloacogenic carcinoma of the anal canal with T2 to T4. node-positive disease. and 85 to 88. and 85. Combination chemotherapy with fluorouracil and radiotherapy was active in the treatment of anal cancer in a trial of 35 patients [90]. Baseline characteristics were similar with the exception of more anal canal and perianal cancers in the cisplatin-based group (24%) vs the mitomycin-based group (16%. Pediatric. no. 3 patients developed recurrent AKs [84]. Radiation therapy. All patients received at least 45 gray (Gy) in 25 fractions over 5 weeks to the primary tumor while patients with T3. fluorouracil. The total radiation dose administered was 55 to 59 Gy in 30 to 32 fractions over 5.MICROMEDEX® 2. All patients developed anticipated severe inflammation with erosions and crusting. any N. 20 mg/course) plus fluorouracil 1000 mg/m(2)/day as a continuous IV infusion on days 1 to 4 and 29 to 32) with concurrent radiation (n=324) or cisplatin-based chemotherapy (cisplatin 75 mg/m(2) IV over 60 minutes on days 1. Patients (n=644) with squamous. Anal cancer 1) Overview FDA Approval: Adult.045).IntermediateToDocumentPrintLink 75/317 .com/micromedex2/librarian/PFDefaultActionId/evidencexpert. with days 57 and 85 corresponding to radiotherapy days 1 and 29) (n=320).5 to 6. Patients received topical fluorouracil 5% twice daily plus oral isotretinoin 20 milligrams twice daily for a median of 21 days. 29. and cisplatin resulted in a complete response rate of 68% of 19 patients with anal cancer in a phase II study [91]. 57 to 60. 3) Adult: a) Cisplatin-based induction chemotherapy and chemoradiation failed to improve diseasefree survival and resulted in increased colostomy rates compared with standard mitomycinbased chemoradiation in patients with carcinoma of the anal canal in the United States Radiation Therapy Oncology Group (US RTOG) 98-11 trial. Class IIb Strength of Evidence: Adult. The study was designed to detect an thomsonhc. 29 to 32.0 b) A combination of topical fluorouracil and oral isotretinoin was effective in treating disseminated actinic keratoses (AK) on photo-damaged skin in 27 patients. Palpable AKs regressed completely in 22 of the 27 subjects and almost completely in the remaining five.25/10/12 Drug details .5 weeks. and fluorouracil 1000 mg/m(2)/day as a continuous IV infusion on days 1 to 4. or T2 residual disease after 45 Gy received an additional 10 to 14 Gy in 2-Gy fractions. basaloid. no Efficacy: Adult. Over the ensuing 10 to 26 months. Evidence favors efficacy Recommendation: Adult. T4. and M0 tumors were randomized to receive mitomycin-based chemotherapy (mitomycin 10 milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 and 29 (maximum.

02). 1. Therefore. 15 developed toxicity of grade 3 or higher. but having a lower local recurrence rate (6% vs 24%) [90]. cisplatin 75 mg/m(2) was administered intravenously. 95% CI. and a 60minute infusion of cisplatin 100 mg/m(2) on day 1. 95% CI. 2 patients received only one course of chemotherapy. Radiotherapy and chemotherapy adherence rates were similar between groups. 67% to 81%) in the mitomycin-based arm and 70% (95% CI. the 5-year estimated DFS rates were 60% (95% confidence interval (CI).001). Radiation therapy (59. On days 1 to 4 of RT. radiation therapy (RT). respectively (hazard ratio. a continuous infusion of fluorouracil 1000 milligrams/square meter/day (mg/m(2))/day was administered. and radiation.65. 95% CI. p=0. 6% to 14%) in the cisplatin-based group vs the mitomycin-based group. clinically positive nodes (p less than 0. patients received a 24-hour intravenous infusion of fluorouracil 750 milligrams/square meter (mg/m(2)) days 1 through 4. On days 1 and 21. When RT was restarted after the 2-week break. 95% CI. Cumulative colostomy rates were significantly higher at 3 years (16%. Grade 3 or 4 hematologic toxicity occurred in 61% in the mitomycin-based group and 42% in the cisplatin-based group [89] b) Combination chemotherapy/radiotherapy with fluorouracil and cisplatin resulted in a complete response rate of 94% with 6% local recurrence in 35 patients with untreated epidermoid cancer of the anus. and tumor size greater than 5 centimeters (p=0. 95% CI. Of 19 treated patients. Pediatric.IntermediateToDocumentPrintLink 76/317 .4 Gy) was delivered over 60 days with a 2-week break after delivery of 36 Gy. Cancer-related deaths were lower in the mitomycin-based group (28 patients) compared with the cisplatin-based group (54 patients). Evidence favors efficacy thomsonhc. A third cycle of chemotherapy was administered 6 weeks after the start of therapy to younger patients who had shown minimal toxicity to earlier courses. fluorouracil.8 Gy dose up to a total of 38 Gy in 4 weeks. Palliative FDA Labeled Indication 1) Overview FDA Approval: Adult. 1.51 years. yes (Injectable). mitomycin. The incidence of toxicity with this regimen was similar to that of standard treatment with RT.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.02).MICROMEDEX® 2.07-2. Concurrent radiotherapy was administered at a daily 1. fluorouracil. measurable anal cancer at 33 months of follow-up. and one treatment related death occurred. and cisplatin are not recommended at this time for treating patients with anal cancer [91]. Investigators considered this combination similar in efficacy to a traditional chemoradiotherapy regimen of fluorouracil. 13% to 24% vs 10%. 63% to 76%) in the cisplatin-based arm. 46% to 60%) in the cisplatin-based group (p=0. The anoperineal region and metastatic inguinal nodes received a total dose of 18 to 24 Gy in 10 fractions.17). After a median followup time of 2. c) In a phase II clinical trial.0 improvement in 5-year disease-free survival (DFS) from 63% with the mitomycin-based group to 73% with the cisplatin-based group. Results were released when the second interim analysis found that results crossed the futility boundary and would not show a statistically significant difference in DFS even with additional events. 6% to 14%) and 5 years (19%.004). 53% to 67%) in the mitomycin-based group and 54% (95% CI. The 5-year overall survival rate was 75% (95% CI. RT. and cisplatin resulted in a complete response in 68% of patients with biopsy-proven. Independent prognostic factors for worse DFS were male sex (p=0.68. On day 1. however. fluorouracil. 12% to 20% vs 10%. Breast cancer. and mitomycin-C. a second course of chemotherapy was administered.25/10/12 Drug details . no Efficacy: Adult.

3) Adult: a) General Information Approaches to the therapy of breast cancer include surgery. Holleb et al. tamoxifen for receptor-positive and/or hormone-responsive disease Response rates of 60 to 80% have been achieved with combination chemotherapy. For primary disease: cyclophosphamide plus methotrexate plus fluorouracil. There was a perception that treatment with high-dose chemotherapy and transplantation resulted in an improved outcome over historical controls using conventional-dose chemotherapy. and in patients with distant metastases [4][5][6]. decreasing the likelihood of relapse. Surgical resection is most frequently used. carboplatin. and radiotherapy controls residual microscopic cancer. breast cancer became the most common indication for stem-cell transplantation. (receptor-negative and/or hormone refractory patients): cyclophosphamide plus methotrexate plus fluorouracil. Class IIb Strength of Evidence: Adult. Adjuvant chemotherapy also provided better relapse-free survival and total survival for node-positive breast cancer patients than surgery alone [9].MICROMEDEX® 2. in advanced disease. whereas single agents (doxorubicin. tamoxifen For metastatic disease. 1991.25/10/12 Drug details . radiotherapy. Chemotherapy and endocrine therapy reduce cancer recurrence in early disease (usually in high-risk patients). 1991).0 Recommendation: Adult. methotrexate) have produced responses rates of 20% to 40% (Skeel.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. chemotherapy and endocrine therapy. cyclophosphamide plus doxorubicin with or without fluorouracil. A 27% overall response rate was achieved with combination oxaliplatin plus fluorouracil in advanced or metastatic breast cancer patients (n=64) with prior taxane and anthracycline treatment [2]. No difference in survival or time to disease progression when stem-cell transplant is added to combination high-dose therapy and compared to standard-dose therapy [3]. in a randomized trial comparing conventionaldose chemotherapy with high-dose chemotherapy (with cyclophosphamide.IntermediateToDocumentPrintLink 77/317 . thomsonhc. However. 1) In the late 1980s. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil is indicated in the palliative management of breast cancer [1]. and is included among the drugs of choice recommended by the Medical Letter consultants for adjuvant treatment of both primary and metastatic disease [8]. or cyclophosphamide plus doxorubicin with or without fluorouracil. cyclophosphamide. Fluorouracil is indicated in the palliative management of breast cancer [7].

compared to 14 and 24. and ifosfamide (FAI). doxorubicin.D. The overall response rate of 48% included complete response in 23% of patients. the median progression free survival (PFS) and median overall survival (OS) were 11.5 and 21. or (4) the above combinations with bacillus Calmette. Standard.line therapy [12].com/micromedex2/librarian/PFDefaultActionId/evidencexpert. leukopenia.1973 to 1982) were: (1) fluorouracil. and cyclophosphamide (FAC). 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized.Guerin. 2) With Bone Marrow Transplantation Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone. thiotepa) and autologous stem-cell transplant. Of 553 patients enrolled.0 dose chemotherapy with high-dose chemotherapy (with cyclophosphamide.5% partial response (PR). and 16% of patients. and weekly vincristine 0.8 months. b) A 15-day continuous ambulatory infusion of fluorouracil 350 milligrams/square meter (mg/m(2)) daily with oral cyclophosphamide 100 mg/m(2)/day. respectively. b) Combination Therapy 1) Metastatic Disease a) A 27% overall response rate was achieved with combination oxaliplatin plus fluorouracil in advanced or metastatic breast cancer patients (n=64) with prior taxane and anthracycline treatment. All patients were treated at M. (2) vincristine. doxorubicin. This regimen was well tolerated. levamisole. This analysis provides a useful reference for comparison of new single-agent chemotherapy agents [11]. and thrombocytopenia occurring in 34%. The primary regimens used (period of study . patients received a median of 6 treatment cycles. repeated every 3 weeks. and day 15. Patients who achieved a CR had a median PFS and OS of 22.3 months. Patients received oxaliplatin 130 milligrams/square meter on day 1 plus fluorouracil 1000 milligrams/square meter/day on days 1 to 4. 2) Analysis of data from 1581 patients with metastatic breast cancer (MBC) treated with doxorubicin-containing chemotherapy revealed a 16. It is recommended that this approach of high-dose chemotherapy with transplant be abandoned in favor of well-justified alternative experimental approaches [3][10]. Anderson Cancer Center and were enrolled in clinical trials all of which included doxorubicin. overall survival and time to disease progression were not favorably affected by use of the latter treatment.IntermediateToDocumentPrintLink 78/317 . respectively.6% complete response (CR) and a 48. respectively.2 and 41. Thirty-three percent of patients experienced grade 2/3 peripheral neuropathy (8% with grade 3) [2].8 mg/m(2) and doxorubicin 15 mg/m(2) on day 1. doxorubicin. day 8.25/10/12 Drug details .6 months for patients with a PR. 19%. carboplatin. This study is described in greater detail below in the subsection entitled: Regimen Comparisons. enhanced efficacy and reduced toxicity in metastatic breast cancer.MICROMEDEX® 2. and cyclophosphamide (VAC) plus fluorouracil and methotrexate. or hormonal therapy. Cycles were repeated every 28 days in 34 patients as first-line therapy and 49 patients as second. vitamin E. (3) fluorouracil. This also held true when subgroups were analyzed according to estrogen-receptor status and primary site of metastasis. Treatment-related toxicity included grade 3/4 neutropenia.and high-dose chemotherapy were administered according to the following schema: Induction and Maintenance High-Dose (Continuous Infusion) Doxorubicin 30 mg/m(2) days 1 and 8 thomsonhc.

epirubicin (120 mg/m(2).dose/transplant groups (9 and 9. respectively. and anemia was observed in the highdose/transplant group. thrombocytopenia. overall survival in this intention-to-treat analysis was not significantly different between standard. diarrhea. In addition to that.IntermediateToDocumentPrintLink 79/317 . alopecia. vomiting. carboplatin 1600 mg/m(2) and PBPC reinfusion. respectively. fatigue. no. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. Class IIb Strength of Evidence: Adult.6 months. a) No difference in survival or progression free survival was detected in patients with breast cancer receiving high-dose chemotherapy with peripheral blood progenitor cell (PBPC) support compared to those who did not.MICROMEDEX® 2. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of well.justified alternative experimental approaches [10][3]. those randomized to the high-dose regimen received cyclophosphamide 6 grams/square meter. Median followup was 37 months. Toxicities were greater in the high-dose group but both groups experienced nausea. All randomized patients received a fourth course of the up-front chemotherapy regimen. Pediatric.25/10/12 Drug details . At 3 years. thiotepa 480 mg/m(2).and high.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. median time to progression was not different between the standard. and cyclophosphamide (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.0 Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 14 days oral Fluorouracil 500 mg/m(2)days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 1500 mg/m(2)/day for 4 days IV 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg. Subgroup analyses (estrogen-receptor status. Likewise. Evidence is inconclusive Recommendation: Adult. Category B thomsonhc. (500 milligrams/square meter (mg/m(2)). phlebitis.31). Three cases of reversible renal failure were reported in the high-dose group [13].23). Carcinoid tumor 1) Overview FDA Approval: Adult. Four to six cycles of induction therapy were given every 28 days. All patients received up-front chemotherapy with fluorouracil.and high-dose/transplant therapy (38% and 32%. mucositis occurred at a similar rate for both groups [3]. p=0. radiation therapy and 2 years of tamoxifen therapy. mucositis. no Efficacy: Adult. and neutropenia. A greater incidence of severe leukopenia. p=0.

Overall survival for the fluorouracil plus streptozocin regimen ranged from 64 weeks [101] to 30.4 months [100]. median age.5 months [100].IntermediateToDocumentPrintLink 80/317 . Two patients in the fluorouracil plus streptozocin arm died from hematologic toxicity. There was no difference in the overall response rate (ORR) for fluorouracil plus streptozocin (n=80. The remainder of patients who were included in the study (n=73) were assigned directly to the appropriate treatment arm based on prior chemotherapy or a thomsonhc. median age. Patients previously untreated with chemotherapy were randomized to receive fluorouracil 400 mg/m(2) IV on days 1 to 5 and 36 to 40 plus streptozocin 500 mg/m(2) IV on days 1 to 5 every 10 weeks (n=88. or chemotherapy 4 weeks prior to study entry. radiation therapy. 13% to 31%). 5 to 110 weeks) and 64 weeks for the fluorouracil plus streptozocin arm and 26 weeks (range. 62.25/10/12 See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In randomized phase 2 and 3 studies of patients with unresectable metastatic carcinoid tumor. Patients who failed fluorouracil plus streptozocin and were switched to doxorubicin (n=33) experienced an ORR of 18% and those who failed doxorubicin and were switched to fluorouracil plus streptozocin (n=35) had an ORR of 29%. Additionally. respectively. and every 4 weeks thereafter (n=86 ). 2%). however. Patients (median age. 4 to 73 weeks) and 48 weeks (p less than 0. complete response (CR). 4%). 22% (95% CI. CR. The median duration of response and the median survival were 31 weeks (range. there were no significant differences in overall response rate (ORR) or progression free survival (PFS) .25) for the doxorubicin arm. overall survival (OS) was significantly prolonged in patients with unresectable advanced carcinoid tumors who received fluorouracil plus streptozocin compared with fluorouracil plus doxorubicin. Patients (n=200) receiving fluorouracil plus streptozocin or doxorubicin experienced myelosuppression (grade 3 or 4 white blood cell and platelets. 58. and grade 4 heart failure (0%. no heart disease or prior chemotherapy were randomized to receive fluorouracil 400 mg/m(2) IV daily on days 1 to 5 and 36 to 40 plus streptozocin 500 mg/m(2) IV daily on days 1 to 5 of a 10 week cycle (n=86) or doxorubicin 60 mg/m(2) IV on days 1. n=2) compared with doxorubicin (n=81. 12% to 30%). 21% (95% CI. 27%. Two doxorubicin patients died from heart failure [101]. or interferon alfa [100].3 [102] to 5.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.2 years). 20%. treatment with fluorouracil plus streptozocin produced similar overall response rates (ORR) compared with doxorubicin in patients with metastatic carcinoid tumor. n=1). vomiting (grade 3. range. fluorouracil plus doxorubicin [102]. 60 years. b) In a randomized phase 2 and 3 study (n=249). fluorouracil plus streptozocin therapy produced an overall response rate (ORR) of 3% [100] to 22% [101] and a median progression free survival (PFS) of 5. there was no significant differences in ORR for patients who received fluorouracil plus streptozocin compared with doxorubicin [101]. 3) Adult: a) In a randomized phase 2 and 3 study (n=232). The remainder of patients who were included in the study (n=38) were assigned directly to the appropriate treatment arm based on prior chemotherapy or a history of heart disease. Patients must have completed any major surgery. 43. 28 to 83 years) with unresectable or progressive disease. Renal toxicity was reported in 10 patients who received fluorouracil plus streptozocin. crossover was allowed at disease progression. 25%).5 years) or fluorouracil 400 mg/m(2) IV daily on days 1 to 5 plus doxorubicin 40 mg/m(2) IV on day 1 every 5 weeks (n=88. 22. including 1 death from renal failure with tubular necrosis.

3 months. 60 +/. 1 to 83 months). 23 to 59 months). there was no significant difference in median PFS between the 2 groups (4. however. the median PFS was 5. according to WHO criteria.5 months (95% CI.9 to 25 months) in the fluorouracil plus streptozocin arm compared with 14.9 to 60. or who experienced disease progression during the study while receiving combination chemotherapy were assigned to receive dacarbazine 250 mg/m(2) IV daily on days 1 to 5 every 4 weeks (n=21). fluorouracil plus doxorubicin (n=113). c) In a randomized. 2. Renal toxicity occurred in 34.7 to 21. interferon alfa.7 months to not reached. and second-line dacarbazine (n=91). no Efficacy: Adult.9 months. and 3 patients who received fluorouracil plus streptozocin (n=115). Major surgery was required to be completed 3 weeks before study entry and prior chemotherapy or radiation therapy needed to be completed 1 month prior. n=32. Prior immunotherapy and radiotherapy to the primary area of measurable disease was not allowed. Patients (median age. 28%).0 history of heart or renal disease. 53%) or interferon alfa 3 x 10(6) subQ three times weekly (6 week cycle.4 months) vs 19. 24. 13. p=0. multicenter.2 months) in the interferon alfa arm (p=0. 6. 21 months to not reached) vs 44 months (95% CI. respectively. including life-threatening renal failure in 2 patients [102].5 months (95% CI. 3%. There were no statistically significant differences in median time to progression (8. however. Adverse events (all grades) that were more common in the fluorouracil plus streptozocin arm compared with interferon alfa included proteinuria (41% vs 6%) and nausea (50% vs 22%). and 9 patients with life-threatening cases in 8 (1 fatality). hematologic toxicity (63% vs 31%) and fever (25% vs 6%) were more common compared with fluorouracil and streptozocin [100]. p=0. 9 PR. The median OS was significantly prolonged for fluorouracil plus streptozocin (24.4 months (95% CI. Patients who received prior therapy with fluorouracil or both doxorubicin and streptozocin. 31% to 68%). Evidence is inconclusive thomsonhc.8% of patients who received fluorouracil plus streptozocin. p=0.MICROMEDEX® 2. p=0. the ORR was 8.1 months (95% CI. the 1-year PFS (primary endpoint) was 44% (95% CI. were low in both arms (fluorouracil plus streptozocin.IntermediateToDocumentPrintLink 81/317 . 6. In the interferon alfa arm.6 months (95% CI.82). Among all patients.21) or median OS (30.2% (2 CR. lymph node metastasis. there were no statistically significant differences in progression free survival (PFS) or overall survival (OS) in patients with unresectable malignant carcinoid tumor who received fluorouracil plus streptozocin or interferon alfa. 12 partial response (PR)) compared with the fluorouracil plus doxorubicin arm (13. with heart and renal disease. There was no difference in ORR in the fluorouracil plus streptozocin arm (16%. Response rates. no. After a median follow-up of 46 months (range. lymph node metastasis. Pediatric. 26% to 60%) and 51% (95% CI. 2 complete response (CR). the study was not powered to detect a difference in PFS.34). chemotherapy must have been completed at least 6 weeks prior to study entry.3 months) compared with fluorouracil plus doxorubicin (15. 9%). In patients who received second-line therapy with dacarbazine (n=61).25/10/12 Drug details .7 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. phase 3 trial (n=64).0267).83) in the fluorouracil plus streptozocin arm compared with interferon alfa. p=0.5%. respectively. Carcinoma of bladder 1) Overview FDA Approval: Adult. respectively. Each treatment was administered for at least 12 weeks and for a maximum of 8 cycles.5 vs 5. severe hematologic toxicity occurred in 15.17). 3 PR) and the median PFS was 11. 2.10 years) were randomized to fluorouracil 400 mg/m(2) plus streptozocin 500 mg/m(2) IV over 2 hours daily on days 1 to 5 of a 6-week cycle (n=32.

Pediatric. The drug was administered initially in doses of 15 milligrams/kilogram/day for 10 days followed by 2500 mg every other week [95]. no. Carcinoma of pancreas. however. A multicenter randomized trial (n=289. but failed to show a benefit in 2-year survival for patients receiving chemoradiotherapy compared with no chemoradiotherapy in the adjuvant treatment of pancreatic cancer [68]. In a randomized. multicenter. multicenter trial (ESPAC-3) demonstrated no difference in overall survival between adjuvant treatment with fluorouracil plus folinic acid (n=551) and gemcitabine (n=537) in patients with completely resected pancreatic cancer [67]. 1970). no Efficacy: Adult.25/10/12 Drug details .IntermediateToDocumentPrintLink receiving adjuvant chemoradiotherapy compared with observation [69]. phase 3 trial no benefit in overall survival or progression-free survival was demonstrated in patients with pancreatic head and periampullary cancers thomsonhc.0 Recommendation: Adult. Nevin et al. Prout et al. 82/317 . 1974) 3) Adult: a) Hypogastric intra-arterial infusion of fluorouracil achieved partial to complete responses in 19 of 30 patients with advanced bladder carcinoma. Two studies. fluorouracil. Early studies indicated no advantage of intravenous fluorouracil in combination with radiotherapy over radiotherapy alone in bladder carcinoma (Edland et al. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil is most effective against transitional cell carcinoma of the bladder and Stage III squamous cell carcinoma [95]. randomized. reported improved survival rates with intra-arterial fluorouracil combined with mega-voltage radiation versus radiation alone in patients with advanced bladder carcinoma and non-resectable estrogen-resistant prostate carcinoma (Nevin et al.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 1973. phase 3. Class IIb Strength of Evidence: Adult.MICROMEDEX® 2. 1970. Class IIb Strength of Evidence: Adult. b) One study reported good results in 17 of 19 patients with carcinoma of the bladder following treatment with Adriamycin(R) (doxorubicin). and levamisole combined with radiotherapy [96]. Adjuvant 1) Overview FDA Approval: Adult. Evidence favors efficacy Recommendation: Adult. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: An open-label. ESPAC-1) demonstrated a statistically significant increase in 2-year survival for patients receiving chemotherapy compared with resection alone.

median age.5 months (95% CI.71. range.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Median survival for patients receiving chemoradiotherapy (n=145) was 15.4 to 26.9 months for patients not receiving chemoradiotherapy (n=144) (95% CI.6). ESPAC-3) demonstrated no difference in overall survival between adjuvant treatment with fluorouracil plus folinic acid and gemcitabine in patients with completely resected pancreatic cancer.8 to 23.10. Patients with resected pancreatic ductal adenocarcinoma were randomly assigned to receive chemotherapy (n=75). chemoradiotherapy (n=73).1 to 25) and 23. b) A multicenter randomized trial (ESPAC-1) demonstrated a statistically significant increase in 2-year survival for patients receiving chemotherapy compared with resection alone.001) and stomatitis (p less than 0.39 ) or progress-free survival (HR. There was no statistically significant difference in overall survival (primary endpoint) (hazard ratio (HR).08) [67].6 months (95% CI 21. Among patients in the chemoradiotherapy and no chemoradiotherapy groups. randomized. Two. phase 3. The most significantly increased grade 3 or 4 toxicities for patients receiving fluorouracil were diarrhea (p less than 0.001). 31 to 81 years). Patients with a successful complete resection of ductal adenocarcinoma were randomized to receive either folinic acid 20 mg/m(2) IV bolus plus fluorouracil 425 mg/m(2) IV bolus on 5 consecutive days every 28 days for 6 cycles (n=551. There was no significant difference between treatment groups in quality-of-life scores (p=0. CI.003).7) compared with 15. 63 years. 0.009).year survival rates between the chemotherapy versus no chemotherapy groups and the chemoradiotherapy versus no chemoradiotherapy groups were the primary outcomes. 95% CI.08. 21. 13. the median survival was 23 months (95% confidence interval (CI).05). 13. neither (n=69).02) among patients in the chemotherapy and non-chemotherapy groups. 95% CI. the median survival for patients receiving chemotherapy (n=147) was 20. open-label. At a median follow-up of 34. Risk of death in the chemotherapy group was reduced by 21% compared to the non-chemotherapy group (hazard ratio (HR) 0.2 months. Chemoradiotherapy consisted of 20 Gray administered in 10 daily fractions over a 2week period plus fluorouracil 500 mg/m(2) IV bolus on each of the first 3 days of radiotherapy and again after a planned break of 2 weeks. while the most significantly increased toxicity for patients receiving gemcitabine was hematologic toxicity (p=0. At a median follow-up of 47 months.4) for patients treated with fluorouracil plus folinic acid and gemcitabine.7) for the patients not receiving chemotherapy (n=142). median age.7 to 19.7 months and thomsonhc.84 to 1. range. 3) Adult: a) An international.4 months (p=0. 95% CI. 0.66. but failed to show a benefit in 2-year survival for patients receiving chemoradiotherapy compared with no chemoradiotherapy in the adjuvant treatment of pancreatic cancer.MICROMEDEX® 2.0 to 17.96.1 months (95% confidence interval (CI).IntermediateToDocumentPrintLink 83/317 . 0. multicenter trial (European Study group for Pancreatic Cancer. p=0.5 to 22.53) between the two treatment groups.3 months and 9.9) compared with 17. p=0.9 months (95% CI. the median time to recurrence was 10.0 receiving adjuvant chemoradiotherapy compared with observation [69].28. Chemotherapy consisted leucovorin 20mg/m(2) IV bolus followed by fluorouracil 425 mg/m(2) IV bolus for 5 consecutive days every 28 days for a total of 6 cycles. 0.81 to 1.99 to 1.92.55 to 0. The median time to recurrence was 15. 14.25/10/12 Drug details . p=0. or both treatments (n=72).94. Risk of death in the chemoradiotherapy group was increased by 28% compared to the non-chemoradiotherapy group (HR 1. respectively. 34 to 85) or gemcitabine 1000 mg/m(2) infused IV over 30-minute once per week for 3 out of 4 weeks for 6 cycles (n=537. Combination therapy consisted of the radiochemotherapy followed by chemotherapy. 0. 16. p=0. 0. 63 years.

5 months and 51% (95% confidence interval (CI). 28% to 48%). or 5 days of fluorouracil.0 15. Median duration of survival for patients with pancreatic head cancer receiving chemoradiotherapy was 17. the hepatic arterial infusion of fluorouracil was tolerated but minimally effective in the treatment of liver metastases from pancreatic carcinoma. 41% to 61%) in the chemoradiotherapy group compared with 19 months and 41% (95% CI. After 2 weeks the treatment was repeated to total absorbed dose of 40 Gy. Carcinoma of pancreas. range. Intraarterial fluorouracil was administered continuously at a rate of 500 84/317 .25/10/12 Drug details . 27% to 47%) and 38% (95% CI.MICROMEDEX® 2. 3) Adult: a) Monotherapy 1) Among 13 patients enrolled in a pilot study. multicenter. no Efficacy: Adult. 24 to 78 years) or observation (n=103. . respectively (p= 0.6 months for observation. median age.17) [68]. c) In a randomized. range. Chemoradiotherapy consisted of radiotherapy starting 2 to 8 weeks after surgery (absorbed daily dose 2 gray (Gy). Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil is indicated for the palliative management of pancreatic cancer [1]. 59 years. 47% of patients developed no signs of toxicity and only 1 patient developed major toxicity (major duodenal ulcer). yes (Injectable). There were no significant differences in quality of life between patients who received chemotherapy and those who did not receive chemotherapy or between patients who received chemoradiotherapy and those who did not receive chemoradiotherapy (p=0. Grade 3 or 4 adverse events were reported in 29 of 220 patients receiving chemotherapy (13%).643). Class IIa Strength of Evidence: Adult. 62 years. 39 to 80 years). Median survival and 2-year survival rates were 24. 5 fractions a week during 2 weeks).2 months (p=0. The 2-year progression-free survival rates for the chemoradiotherapy and observation groups were 37% (95% CI. 3.04).208) in the observation group. median age. Of the 81 patients evaluated for toxicity. phase 3 trial no benefit in overall survival or progressionfree survival was demonstrated in patients with pancreatic head and periampullary cancers receiving adjuvant chemoradiotherapy compared with observation. depending on toxicity. p=0. Evidence favors efficacy Recommendation: Adult. Palliative FDA Labeled Indication 1) Overview FDA Approval: Adult. Pediatric. Patients with T1-3N01aM0 pancreatic head cancer or T1-3N0-1aM0 periampullary cancer were randomized to chemoradiotherapy (n=104. Combination chemotherapy has demonstrated minimal activity [70][71]. The most commonly reported toxicity was nausea and vomiting [69]. 31% to 51%. Fluorouracil 25 mg/kg/24 hours (maximum 1500 mg) was started on the same day before radiotherapy. respectively.1 months compared with 12. The second course consisted of 0.

patients received fluorouracil 500 milligrams/square meter (mg/m(2)) as a bolus. and 6 other).MICROMEDEX® 2. respectively [72]. three patients (23%) with hepatic artery obstruction. diarrhea with or without flushing) had a symptomatic response. followed by fluorouracil 500 to 700 mg/m(2) over 10 minutes. Ten of the 13 patients received external-beam radiation therapy. Disease progression was evident in all 13 patients. and epirubicin. Only 2 objective responses were obtained in a phase II trial of prolonged continuous infusion fluorouracil plus subcutaneous interferon-alfa 2b three times weekly [75]. neuroendocrine tumors (NET) (15 pancreatic. dacarbazine 200 mg/m(2). during treatment with fluorouracil. One patient with Stage II/III localized disease was resected after treatment and remained disease-free 14 months after surgery [74]. dacarbazine. and epirubicin 30 mg/m(2). While this regimen showed about a 30% response rate.9 weeks. After 3 treatments.IntermediateToDocumentPrintLink 85/317 . The most common treatment-related toxicity was nausea and vomiting (grade 1 in two patients. and five cycles in one patient. On 3 consecutive days. none of the patients with endocrine hypersecretion syndrome (ie.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. NETs are a heterogeneous group of neoplasms for which there is no standard chemotherapy regimen or a standard time for initiation of chemotherapy. respectively. b) A 37% total response rate was achieved in 32 patients with unresectable pancreatic cancer. three cycles in one patient. extracorporeal hemofiltration was initiated and continued until 30 minutes after completion of drug administration. and the six-month and oneyear survival rates were 38% and 0%. grade 2 in 10 patients.25/10/12 Drug details . produced partial responses in 12. six patients (46%) showed no change.0 milligrams (mg)/square meter daily for five days with 100 mg of hydrocortisone and 5000 units of heparin every four weeks through a battery-operated ambulatory infusion pump.5% of 40 chemotherapy-naive thomsonhc. with hepatic tumor progression observed in 10 patients (77%) and extra hepatic progression observed in nine patients (69%). Of the six patients with no change. using regional delivery of mitomycin-C and fluorouracil followed by hemofiltration. The median survival time was 15. Chemotherapy was delivered via intraarterial infusion. b) Combination therapy 1) Unresectable/Advanced disease a) Of 30 patients with unresectable. cycles were repeated every 3 weeks. Discontinuation of treatment occurred in eight patients (62%) with hepatic or extra hepatic disease progression. Six patients underwent surgery with a complete pathologic response in 2 patients. mitoxantrone 20 to 25 mg/m(2) replaced fluorouracil in 9 patients. d) Combination leucovorin as a 2-hour infusion followed by fluorouracil. two patients showed a minor response. and grade 3 in one patient). Prior to chemotherapy. One treatment cycle was administered to seven patients. two cycles in one patient. c) Combination chemotherapy regimens containing fluorouracil have demonstrated minimal activity in advanced pancreatic cancer. This regimen was tolerated well although 14 patients required a treatment delay due to myelotoxicity. and one patient with nausea and vomiting. four cycles in three patients. 2 (pancreatic NET and Merkel cell carcinoma) and 7 patients achieved a complete and partial response. and oral hydroxyurea 6 hours later. and six patients (46%) had progressive disease. The overall response rate was 8% (95% confidence interval: 0 to 22%). mitomycin C 20 to 24 milligrams/square meter (mg/m(2)) was delivered over 20 to 25 minutes. more active regimens are needed [73]. 9 carcinoid. Patients were evaluated every four weeks after the start of treatment by computed tomography. One patient (8%) demonstrated a partial response.

Response duration ranged from 39 to 74 weeks. and increasing the fluorouracil dose in 25-mg increments in subsequent patients.8 months [71].4 to 9 Gy of radiation in 3 to 5 fractions. handfoot syndrome. respectively. leucovorin.3 months. e) Fluorouracil plus folinic acid (leucovorin) achieved 1 partial response and fluorouracil plus leucovorin plus ifosfamide resulted in 1 complete and 2 partial responses among 51 chemotherapy-naive patients with advanced pancreatic cancer. Seventeen patients (85%) completed the scheduled chemoradiotherapy. fluorouracil 500 mg/m(2) bolus was given weekly until disease progression. The regimen consisted of: (1) 45 Gray (Gy) in 25 fractions of radiation. Grade 4 (life-threatening) anorexia and nausea was observed in 6 patients receiving 125 mg/m(2)/day of fluorouracil.9 weeks to 42.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. c) The median survival was 8. one patient experienced Grade 3 hepatic toxicity.4 gray (Gy) in 28 fractions over 5. This regimen was only investigational and phase III trials must be done before using this regimen clinically [79].5 weeks and (2) protracted infusion of 5-fluorouracil 200 milligrams/square meter/day (mg/m(2)/day) throughout radiotherapy. (2) oral leucovorin 10 milligrams/day. In a study conducted by the Gastrointestinal Tumor Study Group (GITSG.25/10/12 Drug details . One week after chemoradiotherapy. median survival was increased from 22. nausea. Hematologic toxicity was mild. 2) With Radiotherapy a) The National Comprehensive Cancer Center (NCCN) Guidelines state that chemoradiation is a popular conventional option for the management of unresectable locoregional pancreatic cancer. and mucositis). Carcinoma of penis 1) Overview FDA Approval: Adult. skin toxicity. pancreatic (11 patients) or extrapelvic colon cancer (5 patients) who were treated with fluorouracil.5 months for 24 patients with locally advanced or locally recurrent gastric (8 patients). b) In a phase II trial involving 20 patients with nonresectable pancreatic cancer. vomiting. which recovered after terminating chemoradiation. Pediatric. Partial response was achieved in 2 patients and disease was stable in 16 (80%) patients. followed by 5. and radiation therapy. Six of the 15 patients receiving 150 mg/m(2) day experienced Grade 3 (severe) toxicity (vomiting. Median survival was only 5. The chemoradiotherapy-regimen consisted of: (1) radiation therapy 50. Four patients developed Grade 3 toxicities (nausea.9 months and 10. d) The addition of epirubicin and cisplatin to combination fluorouracil and radiation did NOT prolong survival in patients with locally advanced pancreatic cancer and is NOT recommended for further study [70].MICROMEDEX® 2. however. one death occurred following leukopenia and grade 4 diarrhea [76]. diarrhea.2 weeks with the use of fluorouracil and radiation therapy compared with radiation alone. no thomsonhc. catheter-related infection. (3) continuous infusion of fluorouracil 125 milligrams/square meter/day beginning on the first day of radiation. no. and stomatitis).0 patients with advanced disease.IntermediateToDocumentPrintLink 86/317 . 1981). and had no advantage over fluorouracil monotherapy. Death from cancer was documented in 14 [78]. the median progression-free survival and the median overall-survival was 4. The combination of fluorouracil and split-course radiation (total dose 4000 centigray (cGy)) was compared with the combination of fluorouracil and 6000 cGy radiotherapy and with radiotherapy alone [77].

carbon dioxide laser vaporization alone. 68. PIN I. PIN I only). n=101.MICROMEDEX® 2. 5fluorouracil plus interferon alfa-2a low dose. combination therapy with 5-fluorouracil plus carbon dioxide laser vaporization and interferon alfa-2a yielded the least number of treatment failures compared with other standard therapies for the treatment of penile intraepithelial neoplasia (PIN) [174]. PIN I. PIN III. Regardless of grade of lesion (among all patients). 5-fluorouracil followed by interferon alfa-2a 1. PIN II (n=4).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. PIN II and III only). respectively.29% success). 80%. and 5-fluorouracil plus carbon dioxide laser vaporization plus interferon alfa-2a high dose.25/10/12 Drug details . n=67) were treated with various combinations depending on the PIN lesion: 5-fluorouracil 5% cream topically every night for 5 days (followed by 5 treatmentfree days) for 4 courses (n=19.15%. n=32. there was no significant difference between treatments (p>0.75%. 5-fluorouracil topically (two 5-day courses) followed by interferon alfa-2a 1.5 x 10(6) international units subQ daily for 6 days (low-dose. For patients with PIN I. This was followed by success rates of 87. PIN I and III only). with or without urethritis. For patients with PIN II. the best treatment was 5-fluorouracil followed by carbon dioxide vaporization plus interferon alfa-2a high-dose (100% success).81%. combination therapy with 5-fluorouracil plus carbon dioxide laser vaporization and interferon alfa-2a yielded the least number of treatment failures compared with other standard therapies for the treatment of penile intraepithelial neoplasia (PIN). for 5-fluorouracil followed by carbon dioxide vaporization. the best treatment was 5-fluorouracil followed by carbon dioxide vaporization (96.0 Efficacy: Adult. 81. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In a retrospective study (n=208). II. Evidence favors efficacy Recommendation: Adult. 3) Adult: a) In a retrospective study (n=208). n=10.84%. and 5-fluorouracil alone. carbon dioxide vaporization plus interferon alfa-2a high-dose. and PIN III (n=2) occurred in 3 to 6 months in patients who received 5-fluorouracil plus carbon dioxide laser vaporization. corresponding to a success rate of 96. PIN I only). carbon dioxide laser vaporization alone (n=33. respectively. 54.IntermediateToDocumentPrintLink 87/317 . For patients with PIN III. and III). carbon dioxide vaporization plus interferon alfa-2a 3 x 10(6) International Units subQ daily for 6 days (high-dose. topical 5-fluorouracil therapy resulted in lesion clearing in all patients [175]. Treatment failure was defined as a recurrence within the first year of therapy. PIN I and II only). 5-fluorouracil topically (two 5-day courses) followed by carbon dioxide vaporization (n=62.5 x 10(6) low dose. 5-fluorouracil followed by carbon dioxide vaporization plus interferon alfa-2a high-dose resulted in the lowest number of treatment failures (n=2/52).54% and 36. Inflammation subsided 2 to 4 weeks thomsonhc. Class IIb Strength of Evidence: Adult. or 5-fluorouracil topically (two 5day courses) followed by carbon dioxide vaporization plus interferon alfa-2a high dose subQ for 6 days (n=43. 7 to 24 days following administration (14%). age between 26 and 35 years. In a retrospective case series of adult male patients with biopsy confirmed erythroplasia of Queyrat (n=7).05). Patients (n=208. Adverse events of topical 5fluorouracil treatment included inflammation of the penis and scrotum. Recurrences of PIN 1 (n=7). PIN II. n=40.09%.

7 years.74 (90% CI. Pediatric.6%) [103][104] Fluorouracil with high-dose leucovorin yields poor response and undesirable toxicity. All patients received external irradiation. Evidence favors efficacy Recommendation: Adult. 32. cisplatin 50 mg/m(2) over 2 hours.018). 31.00001) [106]. no. After a follow-up of 3 to 70 months. and bleomycin 50 mg/m(2) as a continuous infusion over 48 hours. the combination of fluorouracil and cisplatin was superior to hydroxyurea alone as an adjunct to radiation therapy. biopsy in 4 patients revealed histologically normal epidermis. radiation plus fluorouracil-containing regimens yield high response rates (97. and 33. Twenty-one patients received etoposide 100 milligrams/square meter (mg/m(2)) over 1 hour. no recurrences were reported [175]. Class IIb Strength of Evidence: Adult. The median duration of therapy in both groups was 9 weeks. 4.79 (90% confidence interval. The only statistically significant difference in toxicity was more frequent/severe neutropenia with hydroxyurea (p less than 0. some also received intracavitary brachytherapy. 30.58 to 0. Patients randomized to oral hydroxyurea received 80 milligrams/kilogram/day twice weekly. respectively. 3. NOT recommended [105] 3) Adult: a) In a Phase III trial of 388 subjects with locally advanced stage IIB to IVA cervical carcinoma. 5. 0. b) In a retrospective case series of adult male patients with biopsy confirmed erythroplasia of Queyrat (n=7). Cervical cancer 1) Overview FDA Approval: Adult. topical 5-fluorouracil therapy resulted in lesion clearing in all patients. Patients (age range. respectively.99) and 0. while fluorouracil was dosed at 1 gram/m(2)/day on days 2. Relative risks for progression/death and mortality were 0.to 3-year disease-free survival rates (56% to 97. the rates of disease progression were 43% and 53% in the fluorouracil/cisplatin and hydroxyurea groups. 0. 9 weeks to 10 years) applied 5fluorouracil 1% to 5% cream or liquid topically twice daily for 3 to 7 weeks. Lesion clearing was noted after an average of 9 weeks (range.6% complete response and 2-year overall disease-free survival of 97.later after treatment with chamomile washings [174]. repeated every 2 weeks for 3 planned . duration of lesions.62 to 0. additionally. 4 to 17 weeks) following the beginning of 5fluorouracil therapy. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In Stage IIB to IVA disease.6%) survival rates (66%) and 2.6% in patients with Stage IIB to IVA cervical cancer. no Efficacy: Adult. After a median follow-up of 8.95). b) Combined chemotherapy and radiation therapy (with brachytherapy) resulted in a 97. Cisplatin 50 milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation on days 1 and 29. Corresponding overall mortality rates were 45% and 57% (p=0. 23 to 72 years. both favoring the fluorouracil/cisplatin regimen.

d) External/intracavitary radiotherapy and concurrent chemotherapy with fluorouracil and cisplatin resulted in 3-year disease-free survival in 56% and overall survival in 66% of women with Stage IIIB cervical cancer. Adjuvant 1) Overview FDA Approval: Adult. no. Further study of this regimen is NOT recommended since other regimens have produced higher response rates [105]. diarrhea.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: For adjuvant therapy. Toxicity consisted of granulocytopenia. and fluorouracil 800 mg/m(2) administered weekly as a continuous infusion over 24 hours for 5 or 6 cycles [103]. therapy was repeated every 5 weeks. Fifty patients were treated with fluorouracil 370 milligrams/square meter (mg/m(2)) and leucovorin 200 mg/m(2) for 5 days every 4 weeks for 2 cycles. fluorouracil.0 cycles. Class IIb Strength of Evidence: Adult. anemia. Colorectal cancer. and leucovorin (described by Saltz thomsonhc. Chemotherapy was given concurrently with external radiation therapy. preoperative chemo-radiotherapy more beneficial than postoperative chemoradiotherapy 3) Adult: a) Important Note 1) an unexpectedly high death rate occurring within 60 days after the initiation of treatment in patients receiving a regimen of irinotecan. bleomycin 10 mg/m(2). Evidence favors efficacy Recommendation: Adult. fluorouracil. fluorouracil with high-dose leucovorin produced a response of 8. cisplatin 20 mg/m(2).IntermediateToDocumentPrintLink 89/317 . Another 21 patients received etoposide 50 mg/m(2). and leucovorin for colorectal cancer was revealed in an interim analysis of data from two separate cooperative-group clinical trials sponsored by the national cancer institute and conducted throughout out the united states and canada. fluorouracil plus levamisole or leucovorin is recommended Addition of oxaliplatin to adjuvant therapy with fluorouracil and leucovorin (FL) improved 3year disease-free survival and reduced the risk of relapse in patients with stage II/III colon cancer [34] For rectal cancer. Pediatric. and nausea. Fluorouracil 750 milligrams/square meter (mg/m(2)) was administered as a continuous infusion on days 1 to 5 and days 15 to 19. cisplatin 6 mg/m(2) was administered as a 30-minute infusion on days 8 to 12 and days 22 to 26. adjuvant therapy consists of fluorouracil plus radiation. stomatitis. c) In a phase II study. thrombocytopenia. No grade 4 toxicity or deaths were reported [104]. no Efficacy: Adult.25/10/12 Drug details . one trial of patients with metastatic colon cancer compared the regimen of irinotecan.8% and grade 3 or 4 toxicity in 30% of patients which makes this an unattractive regimen for patients with recurrent squamous cell carcinoma of the cervix.MICROMEDEX® 2.

grade 3/4 toxicities were observed in 60 patients in the FLOX group and 50 patients in the FULV group. the combination of oxaliplatin with fluorouracil and leucovorin (FL) reduced the risk of relapse of colon cancer when compared to FL alone. Eligible patients (n=2246) had previously undergone surgical resection of stage II or III disease. had no prior anti-tumor therapy (including radiotherapy). FULV was defined as bolus fluorouracil 500 milligrams/square meter (mg/m(2)) intravenously (IV) and leucovorin 500 mg/m(2) IV weekly for six weeks of an 8-week cycle for three cycles. While on treatment. However. an adjuvant study of patients with resected stage III colon cancer. p=0. DFS at three years was significantly greater in the FLOX group compared to FULV (76. an alternative is the FDAapproved infusional schedule described in the dosing section of this monograph. nausea.4% improvement in DFS]. and irinotecan [17]. [16]. bowel ischemia/infarct (n=1). 0. In the surgical adjuvant study. dehydration and neutropenia (n=1). respectively [33]. sepsis (n=3). and unknown (n=1). and leucovorin is recommended. aspiration (n=3). vigilant monitoring of all patients who are receiving the combination of irinotecan. The other trial. Median follow-up was 34 months and the oxaliplatin protocol-stipulated cumulative dose of 765 mg/m(2) was received by 73% of patients assigned to the FLOX arm. whereas there were 34 in the FULV arm.67 to 0. representing a 21% reduction in risk for the FLOX regimen. The regimen should continue to be an option in the treatment of patients with advanced colorectal cancer. fluorouracil. 3. 2) It has been suggested that the early deaths reported by Sargent et al may be due to the bolus administration of fluorouracil. Three large ongoing European trials have not reported an increased incidence of early deaths with infusional fluorouracil. and vomiting).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Dose modifications were made in both trials in an attempt to ameliorate the toxicity of the regimen. and a Karnofsky performance status score of at least 60. Patients (n=2407) with stage II or III colon cancer were eligible. cerebrovascular accident (n=1). b) Clinical Trials 1) In a randomized. and sepsis. specific clinical factors that increase the risk of adverse effects have not been identified. 8-week cycles.25/10/12 Drug details . respectively.6%. Overall. open-label phase III trial. fluorouracil. respectively. Fifty-six patients in the FLOX arm experienced diarrhea and dehydration requiring hospitalization. 2) In a randomized. and leucovorin (FLOX) for colon cancer had a better disease-free survival (DFS) rate at three years than patients on fluorouracil and leucovorin alone (FULV) [abstract]. neutropenia. Enrollment in both trials was suspended. fluorouracil. The hazard ratio was calculated to be 0.MICROMEDEX® 2. and irinotecan. and leucovorin regimen.004) [powered at 89% to detect a 5.IntermediateToDocumentPrintLink 90/317 . The global test to determine interaction between treatment and tumor stages II and III was not significant (p=0. myocardial infarction (n=1). 2000) with a regimen of oxaliplatin. FLOX was the same FULV regimen plus oxaliplatin 85 mg/m(2) IV on weeks 1. patients receiving oxaliplatin.79 (95% confidence interval. and leucovorin and a regimen of oxaliplatin and irinotecan. and 5 for three. leucovorin.93). Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease included: dehydration (from diarrhea.0 et al. leucovorin. the reported causes of 14 deaths included pulmonary emboli (n=3).7). Neurotoxicity (grade 3) was observed in 8% and 1% of FLOX and FULV patients. An intravenous (IV) bolus of fluorouracil 400 milligrams/square meter (mg/m(2)) was given followed by a 600 mg/m(2) 22-hour thomsonhc. compared fluorouracil and leucovorin with the irinotecan. there were 15 and 14 deaths in the FLOX and FULV groups. fluorouracil.5% and 71. phase III trial.

1% (p=0. Toxicities in the doxifluridine and fluorouracil groups included grade I/II of nausea and vomiting (30% versus 53%).7%.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. anorexia (20% versus 18%).05). p=0. The reduced risk of recurrence was similar in patients with stage II and III disease when given oxaliplatin plus FL (p=0. with 3 patients being hospitalized secondary to electrolyte imbalances. Patients were randomly assigned to either oral doxifluridine 700 milligrams per square meter per day (mg/m(2)/d) plus oral leucovorin 20 mg/m(2)/d on days 1-21 followed by 1 week of rest every month or an intravenous bolus infusion of fluorouracil 450 mg/m(2)/d with leucovorin 20 mg/m(2)/d for 5 consecutive days every month.0 infusion on days 1 and 2 of a 14-day cycle for 12 cycles.5% versus 12. 75. Higher quality of life. diarrhea. Survival probability was 87.2% (95% confidence interval (CI). 0. and DFS at three years for this group was 72. Significant differences between the groups included all grades of diarrhea (39% versus 20%.3% for the FL-only group. The most common grade 3/4 adverse reactions in the treatment group were neutropenia (41. For those with stage III disease in the oxaliplatin group. 0.6% to 80.76 (95% CI.05).9% (95% CI.IntermediateToDocumentPrintLink 91/317 . with no reports of grade III/IV leukopenia in the doxifluridine group.1% of patients had died or relapsed in the oxaliplatin group compared to 26. alopecia (14% versus 28%.80 (95% CI.90 (95% CI. For stage II disease. thrombocytopenia.3% for the FL-only group. Fluorouracil was preceded by leucovorin 200 mg/m(2).2% compared to 65.MICROMEDEX® 2.1%).71 to 1.8%) [34].15) in the oxaliplatin group and DFS at three years for this group was 87% compared to 84. comparable efficacy and less toxicities make the oral doxifluridine and leucovorin regimen an alternative option for patients with advanced rectal cancer [35]. and leukopenia (18% versus 41%. 88% versus 52%) in both the doxifluridine and fluorouracil groups.5%). At three years. Quality of life scores were measured after the first. respectively. One hundred thirty-three patients had died from the treatment group at the primary analysis cutoff date compared to 146 in the control group.002).002 for comparison between groups). which increased after the second (72% versus 47%) and plateaued thereafter (79% versus 47%. respectively.937) for doxifluridine and fluorouracil. the probability of disease-free survival for those in the oxaliplatin group was 78.9 months. allergic reaction all occurred more often in patients in the FL plus oxaliplatin group compared to FL only (all p values less than 0. By the third cycle all patients were also receiving radiotherapy. vomiting. nausea. the HR for recurrence was 0. The hazard ratio (HR) for recurrence was 0. Relapses of the non-colorectal tumors type were disregarded in the analysis of disease-free survival. neutropenia. 3) Postoperative adjuvant chemotherapy with oral doxifluridine was as effective as intravenous fluorouracil.1%). 0.05). and was less toxic in 166 post curative surgery patients with stage II/III advanced rectal cancer.77 (p=0.56 to 0.62 to 0.2% to 75.8%).13). p less than 0. neutropenia with fever or infection. At a median follow-up of 37.1.77). A nadir good quality of life score was noticed after the first cycle (49% versus 19. The rate of recurrence was 6. respectively. Each group received a median of 12 cycles with a cumulative oxaliplatin dose of approximately 1020 mg/m(2)). nausea (5. p less than 0. and vomiting (5.1% in the FL-only group. 4) No difference in disease-free survival (DFS) or overall survival (OS) was observed in a comparison of adjuvant fluorouracil and levamisole with or without concomitant interferon thomsonhc.25/10/12 Drug details .92). The hazard ratio for death was 0. For those randomized to receive oxaliplatin.7% and 86.6% for the treatment and control groups. Treatment continued for 12 cycles. third. the dose was 85 mg/m(2) IV on day one of the cycle (given simultaneously with leucovorin). and abdominal pain (17% versus 9%). p less than 0.001). 70. Grade 3/4 paresthesia. representing a reduction in risk relapse of 23%. diarrhea (10.7%) and those receiving FL alone it was 72. improved quality of life. second. and sixth cycle of chemotherapy. 21. the HR for recurrence was 0.

Combination therapy with fluorouracil+levamisole was associated with significantly longer disease-free survival than the FULV group (p=0. doubleblind study of adjuvant fluorouracil with levamisole.04).0%) than the placebo group (34. Patients with stage II or III disease and an Eastern Cooperative Oncology Group (ECOG) status of less than or equal to 2 were eligible to participate in this prospective. The control group did not receive interferon-alfa-2a (n=138). 691 fluorouracil+levamisole patients. and 696 FULV+levamisole patients. Control therapy was associated with 23 deaths (16. Patients randomized to receive interferon-alfa-2a received 3 million units of interferon-alfa-2a 3 times a week for 1 year (n=141). High-dose folinic acid was associated with slightly more deaths (801) compared to the low-dose arm (775). The fluorouracil+levamisole regimen consisted of fluorouracil 450 mg/m(2) daily for 5 days then once weekly beginning on day 29 and levamisole 50 mg three times a day for 3 days repeated every 14 days. randomized. Levamisole therapy was associated with significantly more reports of toxic dermatologic events (p less than 0. Twenty-five mg of L-folinic acid is equivalent to 50 mg DL-folinic acid. No difference in 3-year DFS was observed between the two groups (83. More deaths were reported in the levamisole arm (815) compared to the placebo arm (755).0 comparison of adjuvant fluorouracil and levamisole with or without concomitant interferon alfa-2a in patients with colorectal cancer. Five-year disease-free survival was 65% in the FULV arm and 60% in the fluorouracil+levamisole arm.3%).25/10/12 Drug details . Recurrence rates. The remaining patients were given levamisole 50 mg 3 times daily for 3 days every 2 weeks for 12 courses (n=2429) or matching placebo (n=2434). and other toxic events than placebo. or FULV+levamisole in this prospective study. Patients who received levamisole experienced a greater risk of recurrence at 3 years (37.MICROMEDEX® 2. Most side effects reported were anticipated with the respective chemotherapeutic regimens (Anon. Diarrhea was the major side effect reported in 92/317 . or alone in patients with colorectal cancer.000 patients to compare various fluorouracil chemotherapeutic regimens. double-blind trial. 6) The addition of levamisole to a regimen of adjuvant fluorouracil plus leucovorin (FULV) did not provide additional clinical benefit to patients with Dukes' B or C colon cancer. Patients were randomized to receive FULV. The Quick And Simple And Reliable (QUASAR) study enrolled almost 5. 3-year risk of recurrence.7%) compared to interferon-alfa-2a therapy with 30 deaths (21. vomiting. high-dose folinic acid. 2000).1% for control and 75.0001) and 20% more reports of nausea. In addition. All patients received levamisole 500 milligrams/square meter (mg/m(2)) over 2 hours and fluorouracil 600 mg/m(2) at mid-infusion every 6 weeks followed by a 2 week rest. The FULV regimen consisted of six 8-week cycles of leucovorin 500 milligrams/square meter (mg/m(2)) over 2 hours weekly for 6 weeks and fluorouracil 500 mg/m(2) over 1 hour weekly for 6 weeks followed by 2 weeks of rest. low-dose folinic acid.9%). fluorouracil+levamisole. No significant difference in the occurrence of severe toxicities was demonstrated between the two treatment groups [36]. Patients randomized to receive folinic acid received L-folinic acid and were either in the high-dose group at 175 mg (n=2464) or the low-dose group at 25 mg (n=2463).9% for interferon-alfa-2a). The FULV+levamisole regimen received the same treatment as the FULV patients and levamisole in the same dose used in the fluorouracil+levamisole regimen. randomized. OS was not affected by the addition of interferon-alfa-2a. Efficacy was analyzed in 691 FULV patients. The addition of levamisole to FULV treatment was not associated with a survival advantage. and 3-year survival were not different between the 2 folinic acid groups. 5) No difference in clinical efficacy was observed in a prospective. Fluorouracil was administered to all patients as 30 doses of 370 milligrams/square meter (mg/m(2)). No advantage of high-dose folinic acid or levamisole therapy was observed following subgroup analysis.

IV push levamisole 20 mg/m(2) was administered immediately before fluorouracil on days 1 to 5 with re-treatment on day 29 and day 57 and then every 5 weeks. respectively. fluorouracil/leucovorin with or without levamisole) after surgical resection found an overall mortality reduction of 30% after 5 years follow-up with adjuvant therapy as compared to observation alone in the subset with Dukes' B colon carcinoma (n=1565).88 and failed to reach statistical significance. In contrast. of patients receiving treatment for 6 months with fluorouracil plus levamisole versus fluorouracil plus leucovorin plus levamisole were alive. a bolus infusion of leucovorin 500 milligrams/square meter (mg/m(2)) intravenously over 30 minutes daily was administered followed 1 hour later by fluorouracil 270 mg/m(2) bolus infusion (1088 patients).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Adjusted and unadjusted hazards ratios for both outcome variables ranged from 0. (a) Fluorouracil plus levamisole arm: This regimen consisted of intravenous (IV) push fluorouracil 450 milligrams/square meter/day (mg/m(2)) for 5 days followed by once weekly administration beginning on day 29. These investigators concluded that a notreatment control arm is appropriate for this patient population [38]. multicenter trial involving 2176 patients with Dukes' stage B or C colon cancer who had recently undergone curative resection. Diarrhea was the major side effect reported in patients who received leucovorin and stomatitis was more frequently reported in the fluorouracil+levamisole group [37].75 years of follow-up. Patients received six 28-day cycles. 6 months of chemotherapy was as effective as 12 months. 60% and 70%. Patients assigned to the interferon arm received subcutaneous thomsonhc. With 12 months of chemotherapy.IntermediateToDocumentPrintLink 93/317 . For high-risk patients with complete resection of adenocarcinoma of the colon. Median event-free survival rates in the treatment and control groups were 76% and 73%. 7) A pooled analysis of data from 5 studies in which 1016 subjects with B2 colon cancer were randomized to fluorouracil plus leucovorin or observation alone after surgical resection failed to demonstrate survival benefit after a median 5. survival was greater with triple versus double drug therapy 8) In a randomized. respectively.81 to 0. 5-day courses were repeated on day 29 and day 57 and then every 5 weeks. Patients receiving each regimen were treated for 6 or 12 months. fluorouracil via portal venous infusion. the addition of interferon alfa2a did not produce any significant benefits beyond that seen with fluorouracil plus leucovorin [41]. At 5-years median follow-up. The conflicting conclusions presented here highlight the limitations of retrospective analyses and the need for additional prospective research to delineate the optimal management of Dukes' B colon cancer following surgical resection. (b) Fluorouracil plus levamisole and levamisole arm: This regimen consisted of IV push fluorouracil 370 mg/m(2) on days 1 to 5.MICROMEDEX® 2. respectively. Levamisole 50 mg 3 times daily was given on days 1 to 3 and days 15 to 17 of each treatment cycle. These investigators concluded that adjuvant chemotherapy should be considered for all such patients. regardless of prognostic factors [39]. During the first 5 days of each cycle. oral levamisole 50 mg 3 times daily was started on days 1 to 3 and was repeated every 2 weeks beginning on day 15.25/10/12 Drug details . however. while corresponding overall survival rates were 82% and 80%. semustine/vincristine/fluorouracil. a pooled analysis of 4 trials employing different chemotherapy regimens (ie. the 3-drug regimen consisting of fluorouracil plus leucovorin plus levamisole was superior to fluorouracil plus levamisole [40].0 associated with a survival advantage.

66% and 54% of patients were alive without a recurrence in the treatment and control group. 72% and 65% were alive in the treatment and control group. 6 months. Adjuvant FA and fluorouracil is tolerated well and is effective for reducing recurrences and prolonging survival in patients with colon cancer [42]. advantages included reduced local recurrences. respectively. preoperative chemoradiotherapy proved advantageous compared to postoperative chemoradiotherapy in patients with stage T3 or T4 or node-positive resectable rectal cancer. low-dose leucovorin (20 mg/m(2) and fluorouracil (425 mg/m(2)) was administered daily for 5 days. respectively) in patients receiving chemotherapy and surgery compared with those undergoing surgery only [43]. At 5 years. 6 cycles were planned. Patients with histologic confirmation of Dukes B2 and C colon cancer were randomly assigned to adjuvant treatment with fluorouracil 370 milligrams/square meter (mg/m(2)) plus FA 200 mg/m(2) daily for 5 days every 4 weeks. In one trial. the results of these trials suggest that high-dose leucovorin/fluorouracil is as effective as levamisole/fluorouracil [42]. this regimen was repeated at 4 and 8 weeks and then every 5 weeks for a total of 6 cycles. Diarrhea was the most common side effect associated with high-dose leucovorin. In patients with Dukes' stage C colorectal cancer. and an increased rate of sphincter thomsonhc. All patients (n=309) had complete resection of the primary tumor (Stage II or Stage III colon cancer) but were at high-risk for tumor relapse. superior compliance. a) With Radiotherapy 1) According to a randomized trial (n=799). and leukopenia were more common in patients receiving low-dose leucovorin.02. A seventh dose of interferon was administered in each cycle 24 hours after the last bolus dose of fluorouracil. high-dose leucovorin ranged from 200 milligrams/square meter (mg/m(2)) administered every day for 5 days to 500 mg/m(2) weekly and fluorouracil dosage ranged from 350 to 425 mg/m(2) administered every day for 5 days.0 interferon (5 x 10(6) Units/m(2)) 24 hours before the first dose of leucovorin. diarrhea. 9) Adjuvant. 10) Surgery plus fluorouracil and leucovorin was superior to surgery alone in preventing tumor relapse and improving survival in patients with colon cancer. Since racemic FA was no longer available. At randomization. 11) A meta-analysis of published clinical trials and abstracts presented at the 1996 American Society of Clinical Oncology (ASCO) revealed that adjuvant treatment with highdose leucovorin/fluorouracil in patients with Dukes' stage B and C colorectal cancer demonstrates significant improvements in disease-free survival (62% to 77%) and overall survival (69% to 89%) compared to controls (58% to 64% and 63% to 77%. similarly. toxicity was tolerable and was managed by adjusting the dose of fluorouracil.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.004 and p=0. Patients were randomly assigned to surgery only or adjuvant chemotherapy consisting of leucovorin 20 milligrams/square meter/day (mg/m(2)) followed by fluorouracil 425 mg/m(2)/day administered by intravenous push for 5 consecutive days. respectively. respectively). then daily immediately before chemotherapy for the first 5 days of each cycle. In four randomized trials. reduced toxicity. and 12 months. whereas.IntermediateToDocumentPrintLink 94/317 . high-dose leucovorin (FA) and fluorouracil improved event-free and overall survival. Toxicity was noted to increase with addition of interferon.MICROMEDEX® 2. the last 148 patients were treated with pure LFA at 100 mg/m(2).25/10/12 Drug details . Response duration and survival were significantly longer (p=0. a quality-of-life questionnaire did NOT reveal any significant differences between the treatment and control groups. stomatitis. Patients in the treatment group with Dukes B had higher overall survival and event free survival than patients with Dukes C.

occurring in 34% and 34. Acute toxicity of grade 3 or 4 severity occurred in 27% and 40% of the PREOP.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. every 4 weeks) were started 4 weeks after surgery in the preoperative treatment group (PREOP group. occurring in 12% and 10% of the postoperative and preoperative radiochemotherapy treatment groups. Radiotherapy consisted of a total of 5040 centi. respectively (p=0. respectively (p=0. n=384). During the first and fifth weeks of radiotherapy.0 preservation in patients with low-lying tumors. with less than 3% of patients in each treatment group experiencing grade 3 or greater leukopenia or nausea.IntermediateToDocumentPrintLink 95/317 . either progression-free or overall. Grade 4 diarrhea was evident in 1% of patients in both treatment groups. respectively (p=0. In the preoperative radiochemotherapy group. with the postoperative study group receiving an additional small-volume boost at 5. Overall 5-year survival rates were 76% and 74%. The most common toxicity was Grade 3 diarrhea. survival benefits. Surgery consisted of total mesorectal excision. respectively. except for a 540-cGy boost delivered to the tumor bed in the postoperative group. neoadjuvant preoperative radiochemotherapy was well tolerated and effective compared to standard postoperative adjuvant radiochemotherapy in patients with advanced operable rectal cancer.MICROMEDEX® 2. leukopenia and nausea. an additional four cycles of bolus injection fluorouracil were administered at a dose of 500 mg/square meter daily for five consecutive days every four weeks for a total of six cycles. Complete toxicity data was available for 162 and 230 patients in the postoperative and preoperative radiochemotherapy study groups.treated subjects. respectively (p=0.8 Gy). Overall postoperative complication rates were similar between the two study groups. However. Other frequent toxicities included erythema. n=415) or 4 weeks after chemoradiotherapy in the postoperative treatment group (POSTOP group. five times weekly. five times weekly.and POSTOP. Surgical mortality and morbidity information was available for 280 postoperative radiochemotherapy group patients and 258 preoperative radiochemotherapy group patients. while corresponding rates of long-term toxicity were 14% and 24%. The stratification according to surgeons involved was provided for. respectively.006). Patients in both treatment groups received radiotherapy to the tumor bed and pelvic lymph nodes at a total of 50. Four cycles of bolus fluorouracil (500 mg/m(2)/day. while surgery techniques were standardized and quality-controlled. Patients in the postoperative radiochemotherapy group received chemotherapy within four weeks after immediate surgery. were not significantly different comparing preoperative with postoperative chemoradiotherapy.001).01) [44].4 Gy for three days. fluorouracil was given as a 120-hour continuous infusion at a dose of 1000 milligrams (mg) per square meter (m(2)) per day. Five-year cumulative incidence of local relapse was 6% and 13% among those in the PREOP and POSTOP groups.4 Gray (Gy) delivered in 28 fractions (single dose 1. A total of 628 patients with histologically confirmed stage II or III locally advanced operable rectal cancer were randomized to receive postoperative radiochemotherapy (n=310) or preoperative radiochemotherapy (n=318).5% of thomsonhc. Radiotherapy was identical in both the preoperative and postoperative groups. respectively. Following concurrent radiochemotherapy.80).25/10/12 Drug details . Fluorouracil was administered as a 120-hour continuous infusion at a dose of 1000 milligrams (mg)/square meter daily during the first and fifth week of radiotherapy. Median follow-up was 45 months and 49 months in the PREOP and POSTOP groups.Grays (cGy) delivered in 28 fractions of 180 cGy. 2) In an interim analysis of a prospective randomized phase-III trial. surgery was scheduled four to six weeks after completion of an identical concurrent radiochemotherapy regimen and the four cycles of fluorouracil bolus injections were to be started within three to four weeks following surgery.

9%.8 Gy over 5 weeks.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Three hundred forty nine patients were randomized to receive 12 cycles of leucovorin 100 milligrams (mg)/square meter plus fluorouracil 400 mg/square meter (increased to 450 mg/square meter after the first cycle) intravenously (IV) over 30 minutes on days 1-5 every four weeks.5%) patients in the fluorouracil plus leucovorin group and in 130 (39.8%. ARM 2: Fluorouracil 425 mg/m(2)/day with leucovorin 20 mg/m(2)/day on days 1 through 5 and 29 through 33. and for 3 days during weeks 1 and 5 of radiation therapy. In patients with locally advanced rectal cancer. After radiotherapy. thomsonhc. adjuvant postoperative treatment with fluorouracil plus leucovorin was well tolerated and significantly more effective than fluorouracil plus levamisole in surgically curative stage III colon cancer patients.4 Gy also was given.25/10/12 Drug details . fluorouracil was administered once a week for 44 weeks with four weekly infusions considered one chemotherapy cycle. The total number of toxic reactions per chemotherapy course was higher but not significant in the fluorouracil plus leucovorin group compared with the fluorouracil plus levamisole group.0059).5%. 3) In a prospective randomized multicenter trial. All patients received radiotherapy equal to 45 Gray (Gy. After a median follow. adjuvant therapy with fluorouracil plus leucovorin demonstrated a significantly superior disease-free survival and overall survival on univariate analysis compared with fluorouracil plus levamisole (p=0. fluorouracil 450 mg/m(2)/day on days 1 through 5 and 29 through 33. and 36.MICROMEDEX® 2. 680 (96.2%.1%. of patients receiving fluorouracil plus leucovorin compared with 13.3%) patients in the fluorouracil plus levamisole group after a median time of 15 and 12 months. fluorouracil 380 mg/m(2)/day and leucovorin 20 mg/m(2)/day on days 1 through 5 and 29 through 33.IntermediateToDocumentPrintLink 96/317 . Twenty-eight days following the induction cycle.up time of 46. and nausea/vomiting occurred in 22. a boost of 5.0089. randomized study involving 1696 chemotherapy. combination chemotherapy/radiotherapy does NOT provide a significant advantage in disease-free or overall survival compared with single-agent FLUOROURACIL with radiotherapy. of patients receiving fluorouracil plus levamisole [46].037 and p=0. respectively [45]. Three hundred thirty one patients were randomized to receive levamisole 50 mg orally three times daily for three days every two weeks and fluorouracil 450 mg/square meter daily IV over 30 minutes for five days. 13.025). This was a prospective. and 28.0 patients in the postoperative and preoperative radiochemotherapy study groups. respectively). Among the 702 patients enrolled. and for 4 days during weeks 1 and 5 of radiotherapy (but fluorouracil dose reduced to 400 mg/m(2)/day). respectively.9%) patients were eligible to begin adjuvant treatment within 42 days after tumor resection. Diarrhea. a unit of absorbed radiation dose equal to 100 rads) delivered in daily treatments of 1. A multivariate proportional hazards model established a significant overall survival advantage for the fluorouracil plus leucovorin treatment in comparison with the fluorouracil plus levamisole treatment (p=0. Chemotherapy was delivered in 3 separate regimens: ARM 1: Fluorouracil 500 milligrams/square meter (mg/m(2)) daily on days 1 through 5 and 29 through 33.5 months. respectively (p=0.and radiotherapy-naive patients with a median follow-up of 48 months. 4. respectively. mucositis. After radiotherapy. Relapse occurred in 117 (33.6%.

2 cycles of fluorouracil 400 mg/m(2)/day on days 1 through 5 and 29 through 33 with 4 cycles of levamisole as above. After radiation. patients received fluorouracil plus semustine or fluorouracil alone before and after radiation therapy.25/10/12 Drug details . During radiation. the benefit with leucovorin and fluorouracil is possible and awaits long-term follow-up. the protracted infusion consisted of fluorouracil 225 milligrams/square meter (mg/m(2)) daily via ambulatory infusion pump administered during the entire period of radiation therapy (5 weeks) or until severe chemotherapy-induced toxicity occurred. yes (Injectable). Pediatric. however. Class I Strength of Evidence: Adult.0 ARM 3: Fluorouracil 450 mg/m(2)/day on days 1 through 5 and 29 through 33 with levamisole 50 mg 3 times daily for 3 days every 2 weeks for 4 cycles. Colorectal cancer. but fluorouracil dose reduced to 380 mg/m(2)/day Levamisole plus fluorouracil provided no benefit versus fluorouracil alone. no Efficacy: Adult. patients receiving the protracted infusion had longer remission and an improved survival versus patients receiving bolus injections. same regimen as before radiation. Toxicity affected primarily the gastrointestinal and hematologic systems. Evidence favors efficacy Recommendation: Adult.MICROMEDEX® 2. levamisole was given as in arm 3. ARM 4: Fluorouracil 425 mg/m(2)/day and leucovorin 20 mg/m(2)/day on days 1 through 5 and 29 through 33. and was greatest in the leucovorin-containing arm [47]. c) Bolus versus Continuous Infusion 1) A protracted infusion of fluorouracil was superior to a bolus injection when used as adjuvant therapy in a study of 660 patients with Stage II or III rectal cancer. fluorouracil 400 mg/m(2)/day and leucovorin 20 mg/m(2)/day for 4 days during weeks 1 and 5. however. patients receiving bolus fluorouracil received 500 mg/m(2) for 3 consecutive days during weeks 1 and 5 of radiation therapy. In addition. patients received either intermittent bolus injections (n=332) or protracted venous infusions (n=328) of fluorouracil during postoperative radiation of the pelvis. After radiation. Palliative FDA Labeled Indication 1) Overview FDA Approval: Adult. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil is indicated for palliative management of colorectal cancer [1] 97/317 . the patients receiving bolus injections potentially received far less total fluorouracil than patients receiving protracted infusions [48]. fluorouracil 500 mg/m(2)/day for 3 days during weeks 1 and 5 without levamisole. During radiation therapy.

and sepsis. fluorouracil. The combination of irinotecan.0001). and leucovorin for colorectal cancer was revealed in an interim analysis of data from two separate cooperative-group clinical trials sponsored by the National Cancer Institute and conducted throughout out the United States and Canada. vigilant monitoring of all patients who are receiving the combination of irinotecan. nausea. p=0.2 months. fluorouracil.0 Treatment with weekly irinotecan in combination with high-dose fluorouracil infusion (FUIRI) was as effective as biweekly irinotecan plus fluorouracil and leucovorin (FOLFIRI) as first-line treatment for patients with metastatic colorectal cancer in a multicenter. and leucovorin regimen. an alternative is the FDA-approved infusional schedule described in the dosing section of this monograph. Three large ongoing European trials have not reported an increased incidence of early deaths with infusional thomsonhc. aspiration (n=3).12) [15]. fluorouracil. and irinotecan.7 months.0001) and better response rate (50% versus 21. and leucovorin (described by Saltz et al. overall survival also increased. Dose modifications were made in both trials in an attempt to ameliorate the toxicity of the regimen.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details . fluorouracil.2 versus 14. myocardial infarction (n=1). phase 3 trial (n=346) [14] The addition of oxaliplatin to therapy with leucovorin and fluorouracil for advanced colorectal cancer (n=420) resulted in significantly longer progression-free survival (9. 2000) was associated with an unexpectedly high death rate (2.9%. dehydration and neutropenia (n=1). an adjuvant study of patients with resected stage III colon cancer. p=0. the reported causes of 14 deaths included pulmonary emboli (n=3). neutropenia. and leucovorin is recommended. Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease included: dehydration (from diarrhea. and bolus fluorouracil/ leucovorin (as described by Saltz et al.IntermediateToDocumentPrintLink 98/317 . and vomiting). and leucovorin and a regimen of oxaliplatin and irinotecan. leucovorin. but not significantly (16. The regimen should continue to be an option in the treatment of patients with advanced colorectal cancer. p=0. Enrollment in both trials was suspended. cerebrovascular accident (n=1). and unknown (n=1).MICROMEDEX® 2. compared fluorouracil and leucovorin with the irinotecan. randomized. However. [16]. prospective.5% to 3. Specific clinical factors that increase the risk of adverse effects have not been identified. Intrahepatic arterial fluorouracil plus leucovorin (folinic acid) offered no survival benefit compared to IV fluorouracil plus folinic acid in patients with colorectal cancer with unresectable liver metastases (n=290) [18]. bowel ischemia/infarct (n=1). sepsis (n=3). 3) Adult: a) Important Note An unexpectedly high death rate occurring within 60 days after the initiation of treatment in patients receiving a regimen of irinotecan. fluorouracil. The other trial. One trial of patients with metastatic colon cancer compared the regimen of irinotecan. 2000) with a regimen of oxaliplatin.5%) in one study of patients with advanced colorectal cancer and one surgical adjuvant study [16] but may be due to bolus versus infusional administration [17]. It has been suggested that the early deaths reported by Sargent et al may be due to the bolus administration of fluorouracil.0 versus 6. In the surgical adjuvant study.

Diarrhea (grade 3 or 4) occurred more frequently in the FUIRI arm compared to the FOLFIRI arm (p less than 0. For each arm. weekly irinotecan in combination with high-dose fluorouracil (FUIRI) was as effective as biweekly irinotecan plus fluorouracil and leucovorin (FOLFIRI) as first-line treatment for patients with metastatic colorectal cancer. as first-time treatment of patients with inoperable metastatic colorectal cancer. death.9 mo) in the FUIRI arm compared with the FOLFIRI arm. After a median follow-up of 17. 49% to 64%) (p=0. administered every 2 weeks (FOLFIRI. phase 3 trial (n=346).25/10/12 fluorouracil. The overall response rate for the patients who received FUIRI was 51% (95% confidence interval (CI). and irinotecan [17]. In an outpatient.4 mo (95% CI. b) Clinical Trials 1) In a multicenter. sudden death (n=1). or until the patient was lost to follow-up. 7. 1 cycle to 24 cycles) .2809). 7.2941). the safety and efficacy of irinotecan and bolus fluorouracil/leucovorin (Saltz regimen) were demonstrated [19]. followed by fluorouracil 400 mg/m(2) via IV bolus and then 600 mg/m(2) as a 22-hr continuous IV thomsonhc. The median progression free survival was 8. After median 11 months of follow-up. with manageable toxicity. For the patients in the FUIRI arm. 17.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Patients (median age 63 years) with histologically confirmed metastatic colorectal cancer (MCRC). Close monitoring and early aggressive treatment are paramount. triple drug therapy utilizing irinotecan. n=173). the treatment cycle lasted for 6 weeks and therapy was continued until disease progression.9 mo to 25. but projected probability was 75% at 1 year. a 9-month median duration of response.8 mo) compared to 21. treatment refusal.3 mo) in the FOLFIRI arm (p=0.1 mo) compared to 8. leucovorin.6 mo (95% CI.IntermediateToDocumentPrintLink 99/317 . the median overall survival (OS) was 19. n=173) or irinotecan 180 mg/m(2) IV infused over 90 min on day 1 with fluorouracil 400 mg/m(2) bolus and 600 mg/m(2) as 22-hr continuous infusion. severe toxicity. randomized. oxaliplatin. and diarrhea (n=1)) compared to 5 the FOLFIRI (therapy related sepsis (n=1) and febrile neutropenia (n=1)) during the first 60 days [14].4339). 2) In a multicenter phase 2 trial (n=31).2 mo (95% CI.3 mo (95% CI.1 mo to 9. An overall response rate of 35% was similar to that established in the initial Saltz trial (39%).2 months (mo) 91% of the patients who received FUIRI and 92% of the patients who received FOLFIRI had progressed or died. and fluorouracil/leucovorin produced a 58. median survival time had not been reached. The chemotherapeutic regimen consisted of: irinotecan 150 milligrams/square meter (mg/m(2)) as a 30-minute intravenous (IV) infusion on day 1.00001) and the FOLFIRI arm experienced neutropenia (grade 3 or 4) with a higher frequency compared to the FUIRI arm (p less than 0. with the majority of patients tolerating the regimen. The median number of cycles administered was 4 (range. open-label.00001).3 mo to 8. 19. plus leucovorin 200 mg/mg(2) on days 1 and 2. multicenter trial in patients with metastatic colorectal cancer (n=46). severe gastrointestinal toxicity and thromboembolic events were rare and never fatal. leucovorin given at a dose of 200 mg/m(2) as a 2-hour (hr) IV infusion. prospective. and a 13-month median time to disease progression. respectively (p=0. The study was conducted by the Greek Cooperative Group for Colorectal Cancer.4 mo to 23. Four deaths occurred in the FUIRI arm (therapy related septic shock (n=2). chemotherapy naive or prior adjuvant chemotherapy were randomized to receive either irinotecan 80 milligrams/square meter (mg/m(2)) intravenously (IV) infused over 30 minutes (min) followed immediately by fluorouracil 2250 mg/m(2) IV as a 48 hour (hr) continuous infusion administered weekly without rest periods (FUIRI. 43% to 59%) compared with 57% of patients who received FOLFIRI (95% CI.1% response rate.

Subsequent doses were adjusted to obtain a therapeutic plasma concentration between 2000 and 3000 micrograms/liter (mcg/L) and to minimize toxicity.001). 4) Dose optimization of fluorouracil using pharmacokinetic monitoring improved the overall response rate (43. a 2-hour infusion of leucovorin (200 milligrams(mg)/square meter(m(2))/day) followed by fluorouracil (bolus of 400 mg/m(2)/day and 22-hour infusion of 600 mg/m(2)/day) was administered for 2 consecutive days every 2 weeks. unacceptable toxicity. p less than 0.5%. The mean dosage of fluorouracil after 3 months was 1803 mg/m(2). controlled studies of pharmacokinetic dosage adjustment are needed to verify the positive results obtained [21].25/10/12 Drug details . Toxicity was more common in patients receiving oxaliplatin and included Grade 3/4 neutropenia (41. 12 reported relief of pain.015). fluorouracil doses required to reach therapeutic plasma concentrations varied widely. grade 3 neurotoxicity (18. Of 31 subjects.2 months. whereas. In this open study.2 versus 14.12). involving the colon-rectum.8%) had stable disease and 5 (16. Additional. p=0. 2 (6. A significant (p=0.9%.0 versus 6.9% versus 5. patients (n=152) with metastatic colon or rectal cancer were treated with an initial dose of fluorouracil 1300 milligrams/square meter (mg/m(2)) weekly administered as an 8-hour continuous infusion with leucovorin 200 mg/m(2) administered immediately before and 4 hours into the infusion. patients with disease control reached the optimal dose within 1 to 3 courses.0001) and better response rate (50% versus 21.8% versus 1.0%. p=0. stomach. 5) Double biochemical modulation of fluorouracil with methotrexate and levo-folinic acid (LFA) was administered to 94 patients with advanced digestive tract malignancies. p=0. and 2 of these developed febrile neutropenia. overall survival also increased.1%. and 16 (52%) had grade 2 to 3 fatigue [20]. Patients with adenocarcinoma of the colon or rectum with unresectable metastases were included.5%) experienced complete response and 16 (51. Of 14 patients who presented with abdominal pain. median recurrence-free survival duration (11 months). In this study. p less than 0. Treatment was given every 2 weeks until disease progression.001). requiring hospitalization and IV antibiotics.029) correlation was identified between response and the number of cycles required to reach optimal plasma concentrations.0001). any previous adjuvant chemotherapy must have been completed at least 6 months prior to study entrance.019) [15]. followed by LFA 250 thomsonhc. Ten patients (32%) suffered grade 3 to 4 diarrhea.0 infusion on days 2 and 3.7% versus 5. Dosage adjustments were required for all but 6 of 152 patients with 58 patients requiring at least a 50% increase in dose. Most common adverse effects were diarrhea and neutropenia. and median survival duration (19 months). and grade 3/4 mucositis (5. oxaliplatin 65 mg/m(2) on day 2 was administered as a 2-hr IV infusion in parallel with leucovorin dosing. a 2-hour infusion of oxaliplatin (85 mg/m(2) on day 1 only) was administered concurrently with leucovorin.3%. or patient withdrawal.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. p=0. grade 3/4 diarrhea (11. 14 patients required an immediate reduction in dose due to toxicity. 14 patients (45%) had grade 3 to 4 neutropenia. response rates and survival were higher than reported previously. Patients received methotrexate 500 milligrams/square meter (mg/m(2)) as a 2-hour infusion on day 1. p=0. or biliary tract.MICROMEDEX® 2.6%) partial response. Eight subjects (25.7 months. In the oxaliplatin arm. 3) The addition of oxaliplatin to therapy with leucovorin and fluorouracil for advanced colorectal cancer (n=420) resulted in significantly longer progression-free survival (9.1%) had disease progression.3%.4%). but not significantly (16. 3 (9%) had grade 3 to 4 neurotoxicity. In both arms of the study.IntermediateToDocumentPrintLink 100/317 . antiemetic prophylaxis was administered only to patients in the oxaliplatin arm. for an overall response rate of 58.2% versus 0.

cisplatin. Dose-related hypotension occurred in all 11 patients receiving zidovudine 7 to 10 g/m(2). Of 34 assessable patients. 7) The addition of azidothymidine greater than or equal to 6 grams/square meter (g/m(2)) to combination fluorouracil and leucovorin produced an overall response rate of 44% in previously untreated patients with metastatic colorectal adenocarcinoma. leucovorin 300 mg/m(2)/day. twenty-four patients were treated previously with chemotherapy including leucovorin. treatment was administered weekly for 6 weeks followed by a 2-week rest. leucovorin.5 to 10 g/m(2) (90-minute infusion for doses of 7 g/m(2) or less.5% in patients who received at least 7 g/m(2). 24 courses). 8) The combination of fluorouracil. The dosage of fluorouracil administered via continuous infusion ranged from 200 to 750 milligrams/square meter/day (mg/m(2)). 15% had a complete response and 29% had a partial response within a median of 8 weeks. The investigators recommend an zidovudine dose of 8 grams/m(2) with this combination [24]. mean response duration was 21 weeks. administered via time/dose pump infusion and repeated every 2 to 3 weeks. Grade 3 or 4 toxicity was primarily hematologic with bolus administration versus the hand-foot syndrome with the continuous infusion. 120minute infusion for higher doses) for a maximum of 26 to 34 weeks (median. 6) Of 36 patients with gastric or colorectal adenocarcinoma and progressive disease. fluorouracil.3 versus 2. Median response duration was 44 weeks and complete responses lasted 50 to 76 weeks.1 months versus 11. This technique achieved a 5-year disease-free survival in 36% of patients. The study identified that a 24-hour methotrexate serum concentration greater than 2 micromoles was significantly predictive of response (37% versus 5%). the duration varied from 5 days per cycle to continuous infusion without interruption.8 versus 8. or epirubicin [23]. c) Routes of Administration 1) Bolus versus Continuous Infusion a) In a meta-analysis of controlled studies (n=7) of patients (n=1219) with metastatic colorectal cancer. There was a slight zidovudine dose-response relationship: overall response was 54. 24).0 mg/m(2) as a 2-hour infusion and fluorouracil 600 mg/m(2) bolus on day 2. Thirty-five patients received standard-dose fluorouracil and leucovorin followed by zidovudine in doses ranging from 0. and oxaliplatin effectively downstaged initially unresectable colorectal liver metastases so that aggressive surgical resection could be performed.3 months). Responses were correlated with a 24-hour methotrexate level above 2 micromoles in 31% of previously treated colorectal patients and in 38% of chemotherapy-naive colorectal patients [22]. the dosage ranged from 400 to 600 mg/m(2) for 5 days. A total of 53% of 33 patients responded to fluorouracil 700 to 1200 milligrams/square meter (mg/m(2)) daily. and oxaliplatin 25 mg/m(2)/day for 4 to 5 days. and 33% in patients receiving 2 g/m(2) or less.MICROMEDEX® 2. fluorouracil 600 mg/m(2) bolus after the first hour of leucovorin infusion. 3% achieved a complete response and 27% a partial response following treatment with leucovorin 500 milligrams/square meter (mg/m(2)) over 2 hours.Drug details . and hydroxyurea 35 mg/kilogram/day divided and given every 8 hours starting 6 hours after fluorouracil.3 months). median survival was 28 weeks. For bolus administration. and overall survival (10. longer progression-free survival (5. with cycles every 2 weeks until tumor progression (maximum. which is comparable to primary liver resections for colorectal metastases [25]. repeat courses were administered from every 7 to 101/317 . Six patients (17%) had severe diarrhea. fluorouracil administered as a continuous infusion versus a bolus injection demonstrated a higher tumor response (22% versus 14%) and a better median survival advantage (12.3 months).

a combination of leucovorin and fluorouracil continuous infusion was found to have lower toxicity. then fluorouracil 400 mg/m(2) IV bolus and fluorouracil 600 mg/m(2) IV infusion over 22 hours. 2) Hepatic Arterial Infusion a) In a multicenter. or toxicity [27]. and performance status. sex. In most trials. for Arm B. primary tumor site. tumor stage.2% for the modulated regimen and 30. and median survival was 18 months [28]. followed by 400 mg/m(2) fluorouracil IHA infusion in 100 milliliters (mL) saline over 15 minutes and fluorouracil 1600 mg/m(2) over 22 hours. The IV group (n=145) received folinic acid 200 mg/m(2) (maximum 350 mg) IV over 2 hours. In a randomized trial. a 2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) was given on 2 consecutive days and a 48-hour infusion of fluorouracil (1.7% with 15% of patients experiencing Grade 3 to 4 toxicity.53 g/m(2)/week) in Arm A and 18 (range of 1 to 27. Median progression-free survival was 8 months. The overall objective response rate was 19.5 grams(g)/m(2) in 500 milliliters (mL) of normal saline over 48 hours every week (155 patients).5 to 2 grams/m(2) per 24 hours was started on day 1 of leucovorin treatment. the response rates obtained with administration via continuous infusion were similar to those achieved with fluorouracil plus leucovorin [26]. respectively. there was no significant difference between the 2 regimens with regard to patient survival. was administered every 14 days. folinic acid (200 milligrams per square meter (mg/m(2)). fluorouracil dose intensity of 3.0 35 days. site of metastases.3% for the continuous infusion schedule (p less than 0. on day 1 and 2. every 14 days (de Gramont regimen). Thirty of 145 (22%) patients in the IHA group could not start treatment due to catheter problems (abnormal vasculature or catheter malfunction). repeated for 5 consecutive days every 4 weeks for 2 cycles then every 5 weeks thereafter (151 patients). fluorouracil dose intensity of 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. the study was performed in 101 patients with advanced colorectal carcinoma.5 weeks and 42 weeks. Patients were well matched with regard to age. 36% thomsonhc. arterial fluorouracil plus leucovorin (folinic acid) offered no progression-free or overall survival advantage compared to intravenous fluorouracil plus folinic acid in patients with colorectal cancer with unresectable metastases confined to the liver. In the IHA group (n=145). this regimen was repeated every 2 weeks until evidence of progression. The overall response rate was 33. Analysis was based on the intention to treat population. 306 consecutive patients with histologically proven colorectal cancer received either of two drug regimens: Arm A: intravenous leucovorin 20 milligrams/square meter (mg/m(2)/day) by bolus injection followed immediately by fluorouracil 425 mg/m(2)/day by rapid intravenous infusion. respectively (p=ns).IntermediateToDocumentPrintLink of all IHA patients experienced 102/317 .25/10/12 Drug details . The median number of courses was 5 (range of 1 to 22. however.05). Toxicities were similar. randomized study. Arm B: fluorouracil 3. Patients (n=290) were randomly assigned to receive fluorouracil by either the intravenous (IV) or intrahepatic arterial (IHA) route.MICROMEDEX® 2. patients randomized to continuous infusions received 2 to 3 times more fluorouracil than with bolus injection. 25 and 48 weeks. combination therapy with low-dose intravenous leucovorin plus fluorouracil given by bolus injections was more effective in decreasing tumor size than high-dose fluorouracil as a continuous infusion (CI).1 g/m(2)/week) in Arm B. maximum 350 mg) IV over 2 hours. on day 1 and 2. time to progression. permitting its use in combination with other drugs. The median time to progression and overall survival for Arm A was 23. c) One phase II study demonstrated that a fluorouracil bolus can safely be replaced by a fluorouracil infusion at a higher dose. Although not directly comparable due to potential differences in patient condition. b) In patients with metastatic colorectal cancer.

14 days in IV group versus 35 days in IHA group). 36% of all IHA patients experienced catheter thrombosis and 14% were unable to complete at least 6 cycles of IHA treatment for this reason. and patients with more advanced stage (p less than 0. Chemotherapy was associated with a median survival time of 34. response rates were 22% and 19% in the IHA and IV groups.3% in the chemotherapy group compared to 36. The delay in starting chemotherapy in the IHA group while patients waited for laparotomy for catheter insertion might account for this difference (median time from randomization to start of chemotherapy. One hundred twenty-nine patients with follow-up of at least 18 months were assessed for tumor recurrence (adjuvant therapy n=69. respectively.8 months for the IHA and IV groups. No group differences were reported for serious adverse events (grades 3 or 4).7% in control.25/10/12 Drug details .7 months and 14. of the patients who did not start treatment or received fewer than 6 cycles. nausea. an increase in the risk of death in the chemotherapy arm was observed.01). Using the intent-to-treat analysis. The chemotherapy regimen was given every 28 days and consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily for 5 days as a 24-hour continuous HAI plus folinic acid 200 mg/m(2)/day for 5 days over 10 minutes. Univariate analysis showed a poorer prognosis for older patients (p less than 0. Overall survival was similar for both treatment groups.01).IntermediateToDocumentPrintLink 103/317 . versus 9% in IV group).02). The authors do NOT recommend use of the IHA regimen for unresectable metastatic colorectal cancer outside of a clinical trial setting [18]. resection only n=60). The most frequently reported adverse events in the chemotherapy arm were stomatitis.0 (abnormal vasculature or catheter malfunction).4% overall response rate (6 complete) among 57 patients thomsonhc.5 months compared to 40. respectively.8 months for the resection only group. Twelve weeks after the start of chemotherapy. and diarrhea [29]. pain. Only 38% of IHA patients received 6 or more chemotherapy cycles. Median PFS was 7. and median OS was 14. A higher number of early deaths was observed in the IHA group (23% by 12 weeks after start of chemotherapy.7 months and 6. d) A combination of floxuridine alternating with fluorouracil administered by hepatic artery infusion (HAI) resulted in a 54. The infusion was made into the portal vein and began as soon as catheter placement was confirmed. none of these factors showed a significant interaction with treatment. Radiotherapy was permitted in patients with rectal cancer but only 39 patients with Dukes C tumors received adjuvant systemic chemotherapy. skin reaction.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. No significant differences were seen in progression-free survival (PFS) or overall survival (OS) between the groups. c) Adjuvant portal-vein infusion of fluorouracil with heparin is NOT recommended as the only adjuvant treatment for patients with colorectal cancer at risk for recurrence. Patients (n=1232) with histologically confirmed colon or rectal cancer and no evidence of distant metastases were randomly assigned to surgery only or surgery plus continuous infusion of fluorouracil 500 milligrams/square meter per 24 hours and heparin 5000 International Units for 7 days. 45 (51%) switched to the IV regimen. This study did NOT exclude a small benefit if this therapy is used with mitomycin or with systemic chemotherapy [30]. Relapse rates at 18 months were not different between the two groups with a rate of 33. b) Planned interim analysis of a randomized trial using adjuvant hepatic arterial infusion (HAI) of fluorouracil plus folinic acid versus surgery alone in patients with radical resection of colorectal liver metastases did not show clinical benefit with chemotherapy and resulted in early termination of the study.MICROMEDEX® 2.01). alopecia.7 months. patients with rectal cancer (p=0. men (p less than 0.

no. thomsonhc. Class IIb Strength of Evidence: Adult. intravaginal fluorouracil 1% gel cured significantly more women than placebo (83. Treatment consisted of floxuridine 0. In men with flat or acuminata condylomata.0 with nonresectable colorectal cancer and liver metastases.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The majority of patients (82. Pediatric. vomiting.0001). Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In women with vaginal condylomas. 5) for 4 weeks. double-blind trial (n=60).3%) in a randomized.8%) (ie. fluorouracil 15 milligrams/kilogram added to 1 L of dialysis fluid (buffered with sodium bicarbonate 50 mEq/L) was instilled on postoperative days 2 to 5 and drained after 23 hours each day [32]. involvement of 1 or 2 abdominopelvic regions (p=0. 3) Adult: a) Intravaginal fluorouracil 1% gel cured significantly more women with vaginal condylomas than placebo in a randomized. Long-term survival was statistically correlated with no tumor or distant tumor less than 5 cm (p=0.IntermediateToDocumentPrintLink Women with external condylomas. no Efficacy: Adult.6%). Mitomycin 10 to 12 milligrams/square meter in 1 L of dextrose 1.25/10/12 Drug details .5% was instilled by gravity on postoperative day 1 and drained after 23 hours. placebo-controlled. placebo-controlled. During cytoreductive surgery. controlled trial (n=505) [108]. diarrhea. nausea. 104/317 . Toxicity consisted of elevated alkaline phosphatase or bilirubin requiring interruption of floxuridine (24. and complete cytoreduction (p=0. histopathology-intestinal type adenocarcinoma (p=0.0001).0001). 3) Intraperitoneal a) Cytoreductive surgery and intraperitoneal chemotherapy in patients with peritoneal carcinomatosis secondary to colon cancer resulted in a 23% disease-free survival and a 16% survival with disease at a median follow-up of 12 months. women were instructed to refrain from sexual intercourse during the 4-week treatment period. double-blind trial (n=60) [107]. and 29 administered via HAI.012).4%) maintained normal work and home activities during treatment [31]. 24.2 warts/patient) were randomized to fluorouracil 1% hydrophilic gel (n=30) or to placebo gel (n=30) administered intravaginally at bedtime 3 times/week (days 1. thrombocytopenia).5%). a Tenckhoff catheter was placed for administration of intraperitoneal chemotherapy on postoperative days 1 to 5. biliary sclerosis (3. Evidence favors efficacy Recommendation: Adult. cures were reported in 76. 22.6 years) with vaginal condylomas (mean. 3. This cycle was repeated every 35 days.1 milligram/kilogram/day (mg/kg/day) for 7 days and fluorouracil 15 mg/kg on days 15.3% vs 13.MICROMEDEX® 2.6% of subjects who were treated with fluorouracil 5% cream in a randomized. and systemic side effects (8. 5. Median survival was 18 months and 3 of the 6 complete responders were alive and disease-free at 14 to 71 months. Condyloma acuminatum 1) Overview FDA Approval: Adult. Women (mean age.

erosive chemoinflammation of the penis or scrotum with or without urethritis occurred in 11% of patients who received fluorouracil [108].72% of men with combined flat and acuminata condylomata in a randomized.6% (n=29) (n=218) 30% 57.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.74% (n=20) (n=71) 105/317 . The carbon dioxide (CO2) laser + fluorouracil treatment was two 5-day courses of topical fluorouracil followed by CO2 laser vaporization. After a mean follow-up of 18. Nonimmunosuppressed men (62% between 21 and 30 years old.25%). respectively. Adverse effects occurred in 73.05 months (range. included erythema (3 and 0 patients).41% of men with flat condylomata. or cervical intraepithelial neoplasia) who had human papillomavirus (HPV) lesions identified on peoscopy were assigned to 1 of 3 treatment groups: condylomata acuminata (n=102). Table: Proportion of Men Without a Recurrence Within 1 Year Condyloma Flat Combined Acuminata Condylomata Fluorouracil CO2 laser vaporization 75. The CO2 laser vaporization + fluorouracil + high-dose interferon alfa-2a consisted of two 5-day courses of topical fluorouracil followed by CO2 laser vaporization and interferon alfa-2a 3 x 10(6) international units subQ daily for 6 consecutive days. or combination of flat and acuminata condylomata (n=78). and 51.25/10/12 Drug details . and malaise. chills. and relapse after 8 months (2 and 1 patients) [107].3% of women and 87% of lesions in the fluorouracil group and 13. 6 to 49 months). treatment continued for 3 more courses of 5 days of treatment followed by 5 days without treatment. b) Fluorouracil 5% cream cured 75. and CO2 laser + fluorouracil was the best treatment for flat condylomata (100%)(see Table). women who had used immunosuppressive or topical antiviral medication within 2 months. edema (4 and 0 patients).IntermediateToDocumentPrintLink Total 51.5 x 10(6) international units subQ daily for 6 consecutive days. flat condylomata (n=325). The fluorouracil + low-dose interferon alfa-2a treatment was two 5-day courses of topical fluorouracil followed by interferon alfa-2a 1. condylomata acuminata. cure (total elimination of vaginal warts with no signs of infection by colposcopy and negative human papillomavirus (HPV) DNA) was achieved by 83. Men in each treatment group were randomized to 1 of 4 to 6 treatments (see Table). sexual partners of women with flat condylomata. Acute. Mild pain was reported by 4% of patients during laser therapy. Adverse effects in the fluorouracil group and the placebo group. 81. erosion (4 and 1 patients).96% of patients at initiation of therapy with interferon alfa-2a and included fever.23% (n=12) (n=39) thomsonhc.0 sexual intercourse during the 4-week treatment period. if no response.3% of women and 14% of lesions in the placebo group (p less than 0. controlled trial (n=505).75% (n=33) 81.66% 69.MICROMEDEX® 2. The fluorouracil + high-dose interferon alfa-2a treatment was two 5-day courses of topical fluorouracil followed by interferon alfa-2a 3 x 10(6) international units subQ abdominally daily for 6 consecutive days.75% of men with condyloma acuminata.72% 76. After 4 weeks.0001).41% (n=156) 66. and women who had received treatment for intravaginal warts within 8 weeks were excluded. Women with external condylomas. fatigue. The fluorouracil treatment consisted of topical application of fluorouracil 5% cream in the condylomatous region (preceded by an application of vaseline oxide de zinc 10% to the area) every night for 5 consecutive nights. Preparation of 1% fluorouracil hydrophilic gel incorporated 1% fluorouracil by weight into hydroxyethylcellulose Natrosol(R) 1% solution in distilled water. CO2 laser vaporization + fluorouracil + high-dose interferon alfa-2a was the best treatment (proportion of men without 1-year recurrence) for condyloma acuminata (100%) and combined flat and acuminata condylomata (81.

1987. penile and urethral condylomata acuminata was cured in 6 of 18 men who were treated with 5% fluorouracil cream and 10 of 19 men who were treated with podophyllin.2% (n=58) n=0 98. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Although chemotherapy has only moderate activity. Men (n=42) with condylomata acuminata (mean age.0 (n=12) (n=39) (n=20) (n=71) CO2 laser + fluorouracil n=0 100% (n=34) 53.23% (n=47) Fluorouracil + low-dose interferon alfa-2a 74. Holleb et al.S. carbon dioxide c) In a randomized. or mitomycin. and superficial painful ulcerations. range. alternative single-agent therapies include either doxorubicin.93% (n=66) CO2. 24 years. the 5-year survival rate for esophageal carcinoma remains approximately 5%. cures were recorded in 6/18 men in the fluorouracil group and 10/19 men in the podophyllin group. no treatment for genital warts within previous 6 months) were randomized to self-applied topical application of 5% fluorouracil cream every evening for 2 weeks (n=18) or to physician-administered 25% podophyllin once weekly for 4 weeks (n=19). These recommendations do not imply that these agents have been approved for use in this indication by the U. Food & Drug Administration (Anon. At the final visit (mean follow-up.MICROMEDEX® 2.27% (n=58) CO2 laser vaporization + fluorouracil + high-dose interferon alfa-2a 100% (n=30) 95% (n=20) 81. 19 to 36 years. 1997). Patients were advised to refrain from sexual intercourse during the 4-week treatment period and to use a condom during the follow-up period.8 months. however. range. Pediatric. A major goal in the treatment of esophageal cancer is restoration thomsonhc. cures were achieved by 10/18 men in the fluorouracil group and 11/19 men in the podophyllin group. 1991. Skeel. paclitaxel.84% (n=13) 87.25% (n=16) 93. Four weeks after start of treatment. 5. no. 4 to 9 months).IntermediateToDocumentPrintLink 106/317 . Esophageal cancer 1) Overview FDA Approval: Adult. methotrexate. The preferred regimen is cisplatin plus fluorouracil. Evidence favors efficacy Recommendation: Adult. approximately 60% of patients will receive palliative benefit from combined radiation and chemotherapy (Braunwald et al.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Class IIa Strength of Evidence: Adult.88% (n=18) n=0 80% (n=45) Fluorouracil + high-dose interferon alfa-2a n=0 98.25/10/12 Drug details . itching. 1991). Regardless of therapy. controlled trial. Adverse effects with podophyllin were small erosions on the glans after the third application in 1 patient [109]. specific drugs or combination drug regimens of choice are recommended by the Medical Letter consultants. no Efficacy: Adult.07% (n=27) 88. Adverse effects were reported in 55% of the fluorouracil group and included erythema.

Of the subset (n=14) who attained complete histologic response to the preoperative regimen. and fluorouracil for squamous cell (n=31) or adenocarcinoma (n=30) of the esophagus. On day 42. and 2 patients were alive at more than 2 years. squamous cell histology and age over 70 years.8 months. which was an unexpected side effect. response duration and median survival were comparable between the two groups. High-dose radiation and chemotherapy resulted in rapid improvement in dysphagia with restoration of normal swallowing in 120 patients. The regimen consisted of paclitaxel 175 milligrams/square meter (mg/m(2)) on day 1. and cisplatin.9 and 17. c) Complete response was observed in 44% of 32 eligible patients with locoregional esophageal carcinoma receiving a regimen of radiotherapy.7 months) [115].0 and long-term maintenance of the swallowing function. continuous fluorouracil. Chemoradiation consisted of cisplatin 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5 and days 17 through 21. and cisplatin 25 mg/m(2)/day on days 1 through 3 during weeks 1 and 4. 1993). Cycles were repeated every 28 days. Complete responses were significantly higher in patients with squamous cell carcinoma than in patients with adenocarcinoma (20% versus 3%. accompanied by continuous fluorouracil 250 milligrams/square meter (mg/m(2)) daily. usually with radiotherapy (Coia et al.IntermediateToDocumentPrintLink 107/317 . and continuous fluorouracil 300 mg/m(2)/day for 21 days during weeks 7 through 9 and weeks 11 through thomsonhc. Patients with locally controlled disease and distant metastases are candidates for systemic chemotherapy.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Forty-five patients in each arm obtained complete surgical resection of the carcinoma. and a continuous infusion of fluorouracil on days 1 through 5 at a dose of 1000 mg/m(2) in the first 10 patients and an attenuated dose of 750 mg/m(2) in the remaining 51 patients. cisplatin 20 mg/m(2) on days 1 through 5 (attenuated to 15 mg/m(2) after cycle 3). vinblastine 1 mg/m(2)/day on days 1 through 4 and days 17 through 20. b) Seven (12%) complete and 22 (36%) partial responses were achieved in patients receiving paclitaxel. and twice. 86% and 64% were alive at 1 year and 3 years. This trial was powered to detect only large overall survival differences.04 Chi squared). but 11 patients (18%) had a debilitating peripheral neuropathy. However. The overall median survival duration was 10. Following completion of radiotherapy. patients received additional cisplatin 75 mg/m(2) on day 1 of weeks 7 and 11. Patients underwent radiotherapy for 5 weeks. The median survival in the preoperative chemoradiation and surgery-only groups were 16. Significant negative independent prognostic factors included tumor size greater than 5 centimeters. one without relapse.MICROMEDEX® 2. Corresponding 1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ statistically. p=0. 3) Adult: a) Preoperative Chemoradiation vs Surgery Alone: The addition of a preoperative chemoradiation regimen offered no statistical survival advantage over surgery alone in a randomized trial of 100 patients with previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma (n=25) of the esophagus.6 months. Complete responses were durable for up to 15 months. High-grade hematologic toxicities were manageable with dose reduction. subjects underwent transhiatal esophagectomy. partial responses for up to 18 months. cisplatin. Generalized fatigue of grade 3 or higher severity occurred in 35% of patients [116].25/10/12 Drug details .daily radiation on days 1 through 5. respectively (median survival: 49. 8 through 12 and 15 through 19 for a total dose of 45 Gy. respectively (p=NS). fluorouracil 300 mg/m(2)/day as a continuous infusion on days 1 through 21.

2 developed metastatic disease and were not candidates for surgery. g) Combination cisplatin. While the results appear favorable. and fluorouracil 750 milligrams/m(2) daily for 5 days. leucovorin 500 mg/m(2) on days 2 to 6. nausea. cisplatin 100 milligrams/square meter (m(2)) for one dose. then 750 mg/m(2) weekly. 5 died. As a result. and cisplatin in a phase II study. tumor resection was complete in 46% and incomplete in 54%.0 13. other toxicities included fatigue. and stomatitis [119]. resection was complete in 56% and incomplete in and 44%. fluorouracil. objective responses occurred in 56%. for 2 to 3 cycles. Patients received a maximum of 4 courses of chemotherapy before surgery: epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) administered every 3 weeks. however. Symptoms improved in 62% of patients. Among control patients. Sargramostim 5 micrograms/kilogram was administered subcutaneously on days 2 to 5 and days 7 to 13 after chemotherapy. hearing loss. Among treated patients.IntermediateToDocumentPrintLink 108/317 . All patients received concurrent radiation therapy. Eleven patients underwent surgical resection. the chemotherapy regimen included cisplatin 100 milligrams/square meter (mg/m(2)) and mitomycin 10 mg/m(2) on day 1. and fluorouracil followed by surgery were alive at a median of 36 months. Treatment was administered in the following order: Interferon-alfa-2b 10 million units subcutaneously on day 1. e) An overall response rate of 65% (1 complete. The major toxicity was hematologic (eg. h) Poor results were observed with combination cisplatin and fluorouracil in esophageal cancer patients who had not undergone palliative surgical resection. Adverse effects included neutropenia (grade intravenous in 3 patients). and 4 early deaths. f) Three (27%) of 11 patients had a partial response to interferon alfa-2a 5 x 10(6) units/square meter (m(2)) on days 1 to 7. versus 33% among 12 patients who did not undergo surgical resection. 2 are disease-free. vomiting. dizziness. and mitomycin. fluorouracil 370 milligrams (mg) per m(2) on days 2 to 6. mucositis. This marked thomsonhc. This regimen was associated with severe toxicity. a randomized. fluorouracil 200 mg/m(2)/day was administered as a continuous infusion via an ambulatory pump for 12 weeks. thrombocytopenia). cisplatin. controlled trial is required to thoroughly evaluate the efficacy and toxicity of this regimen [118].25/10/12 Drug details . Four patients are alive at 27 months. Median survival was 20 months and the 1-year survival rate was 59%. with irradiation and esophagectomy elicited a 61% complete response rate among 13 esophageal cancer patients. all patients having undergone incomplete tumor resection died within 4 years whereas 6 patients (9%) with complete resection survived to 7 years. vomiting. Median survival was significantly longer (10 versus 5 months) among patients undergoing surgery [120].MICROMEDEX® 2. 7 of 9 resected patients relapsed. and cisplatin 40 mg/m(2) on day 6 (increased to 50 mg/m(2) if well-tolerated). d) In an open study. then 25 mg/m(2) weekly. During 26 months of follow-up. Patients were randomized to receive either no chemotherapy (n=68) or cisplatin and fluorouracil (n=52) in 5-day courses every 28 days. dose delays and reductions. only 1 patient had recurrent disease.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. gait disturbance. 14 partial) and 30% survival at 2 years was achieved with fluorouracil. and hallucinations. 8 (30%) of 27 patients with esophageal or stomach cancer treated with epirubicin. Dosage adjustments were necessary for myelosuppression (13%). diarrhea. Median survival of 14 months was similar between the two groups. interferon-alfa-2b. but there were no treatment-related deaths [53]. and continuous infusion fluorouracil 1000 mg/m(2) per day on days 1 through 4. and exfoliation. investigators question the utility of this complex and toxic regimen [117]. Nine patients underwent surgical resection after completing chemotherapy.

25/10/12 Drug details . Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil may be useful for adjuvant or neoadjuvant treatment of gastric cancer 3) Adult: a) Numerous chemotherapy regimens have been evaluated for gastric cancer to increase resectability of tumors and to prevent relapse after potential surgical cure.IntermediateToDocumentPrintLink 109/317 . no. Fifty-nine patients with invasive primary gastric adenocarcinoma were enrolled in a clinical trial and received systemic chemotherapy prior to surgery. At 14 to 18 months follow-up. 31 out of 59 patients (53%) were alive. The authors conclude that a prospective randomized trial is needed to confirm the long median survival observed in this trial [52]. b) Preoperative and postoperative intraperitoneal chemotherapy with fluorouracil. Adjuvant or neoadjuvant 1) Overview FDA Approval: Adult. occurring in 4 patients and lasting 3 to 4 days. nine had recurrent carcinoma. A second cycle was repeated in 3 weeks. and mild skin rashes. Pediatric. intraperitoneal (IP) chemotherapy was administered as (1) fluoro-2'deoxyuridine (FUdR) 3000 milligrams daily for 3 days followed on day 4 by cisplatin 200 mg/m(2). which was not observed in previous trials. Class IIb Strength of Evidence: Adult. In patients who undergo resection of gastric carcinomas. cisplatin and 5-fluoro-2'-deoxyuridine decreased recurrence rates and possibly increased survival in patients with gastric carcinoma.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. followed by intraperitoneal chemotherapy 3 to 4 weeks postoperatively.0 difference in actuarial and median survival times was independent of treatment or nontreatment assignment [121].MICROMEDEX® 2. Gastric cancer. mitomycin. mild diarrhea. Evidence favors efficacy Recommendation: Adult. stomatitis. thomsonhc. An early study found that fluorouracil monotherapy was as effective as combination therapy (with doxorubicin and mitomycin) [49]. Toxicity associated with systemic chemotherapy included Grade 4 thrombocytopenia (7 patients). one study indicates that doxorubicin. and leucovorin did improve survival rates in patients who had undergone curative surgery [50]. Nonhematological toxicity included nausea and vomiting. fluorouracil. Leucovorin IV 20 mg/m(2) was given and repeated weekly during fluorouracil therapy. There were two deaths associated with surgery. After surgery (21 to 42 days). all 15 patients with stage IV gastric carcinoma died after palliative surgery. no Efficacy: Adult. At a median follow-up of 43 months. and fluorouracil [51]. Another study found that leucovorin significantly increased toxicity (although not to unacceptable levels) when added to epirubicin. Preoperative systemic chemotherapy included: (1) Intravenous (IV) cisplatin 100 milligrams/square meter (mg/m(2)) followed by fluorouracil 200 mg/m(2)/day on days 1 through 21. While most studies have determined no improvement in survival with combination chemotherapy. Surgery was scheduled 3 to 4 weeks after chemotherapy. Of the 40 patients with stage 0 to III B gastric carcinoma that underwent curative surgery. the peritoneal cavity is often the first site of cancer recurrence. Granulocytopenia was the most common side effect from IP chemotherapy.

yes (Injectable). Fluorouracil with doxorubicin and mitomycin has produced responses ranging from 25% to thomsonhc. versus 38% of control patients [50]. Gastric cancer.3%) and 36 treated patients (75%). During the first 7 months of the study (chemotherapy treatment period).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. cisplatin. Symptoms improved in 62% of patients.0 c) In an open study. Patients were randomized to receive either 7 months of combination chemotherapy (n=48) or no treatment (n=55) during the 32-month study. 20. Within two weeks of surgery.MICROMEDEX® 2. 92 patients were randomly assigned to treatment with mitomycin 10 milligrams/square meter (mg/m(2)) on day 1. 8.IntermediateToDocumentPrintLink 110/317 . and exfoliation. but there were no treatment-related deaths [53]. and 36. relapse occurred in only 10% of treated patients. 8 (30%) of 27 patients with esophageal or stomach cancer treated with epirubicin. vomiting. or who had poorly differentiated tumors. Dosage adjustments were necessitated by myelosuppression (13%). diarrhea. d) Combination doxorubicin (epidoxorubicin). Palliative FDA Labeled Indication 1) Overview FDA Approval: Adult. and fluorouracil followed by surgery were alive at a median of 36 months. fluorouracil 600 mg/m(2) days 1. Toxicity was manageable and included neutropenia. objective responses occurred in 56%. and fluorouracil 200 mg/m(2)/day administered as a continuous infusion via an ambulatory pump for 12 weeks. However. leucovorin. Median relapsefree survival was significantly extended with chemotherapy. 3) Adult: a) Response rates with combinations in advanced disease have ranged from 35% with etoposide. Pediatric. Eleven patients underwent surgical resection.6 months for untreated patients. patients with lymph node metastases or low grade tumor differentiation showed a trend toward longer overall survival. epirubicin 45 mg/m(2) days 1 and 29. Patients were followed for a median of 5 years [54]. nausea/vomiting. fluorouracil. to 45% with cisplatin and fluorouracil [55][56].4 months for treated patients versus 13. and mitomycin did NOT produce a statistically significant difference in disease-free survival compared with no chemotherapy in patients with Stage I to III gastric cancer who had undergone complete resection of the tumor and lymph nodes. This cycle was repeated 3 times. and fluorouracil. mucositis. only 1 patient had recurrent disease. mucositis. Death resulted from relapse in 48 control patients (87. and leucovorin improved survival rates in node-positive patients with advanced gastric cancer (n=103) who had undergone curative surgery. Class IIa Strength of Evidence: Adult. no Efficacy: Adult.25/10/12 Drug details . 29. Patients received a maximum of 4 courses of chemotherapy before surgery: epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) administered every 3 weeks. e) Fluorouracil. and alopecia. Evidence favors efficacy Recommendation: Adult. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil is indicated for palliative management of gastric cancer [1]. epirubicin.

and 5. the intravenous administration of fluorouracil combined with leucovorin and interferon-alpha produced minimal therapeutic benefit and moderate toxicities in 28 adults with advanced gastric carcinoma.6%). stomatitis. (35. 7. 3.46) in the CF arm (HR. the Medical Letter consultants recommend fluorouracil with or without leucovorin as the regimen of choice [8]. etoposide.2% and 21. The 5-FU/S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by fluorouracil 370 mg/m(2) daily on days 1 to 5.29. c) In a phase II study. Median survival was 9. 95% CI. While most studies have determined no improvement in survival with combination chemotherapy.38 to 10.IntermediateToDocumentPrintLink 111/317 . 9 months).MICROMEDEX® 2. 3. respectively. partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1. 8.45 to 4.91) in the TCF arm (n=221) and 3. The low response rate was responsible for early termination of the study and suggests that further study of this combination in the treatment of advanced gastric carcinoma cannot be supported [61]. Overall response rate was 36. Both regimens were repeated every 4 weeks [62].16 to 9. The primary endpoint was time to progression (TTP). 1.7% for the TCF group and 25. who had not received prior chemotherapy for advanced disease. An open-label clinical trial randomized patients (n=445.25/10/12 Drug details . fluorouracil.9% of patients treated with 5-FU/6S-LV and EEP-L. In 24 evaluable patients. b) The addition of docetaxel (T) to cisplatin (C) and fluorouracil (F) improved overall survival in patients with advanced gastric adenocarcinoma. Another study found that leucovorin significantly increased toxicity (although not to unacceptable levels) when added to epirubicin. 1. including adenocarcinoma of the gastroesophageal junction. partial responses were achieved in 18. and lonidamine 50 mg orally 3 times daily continuously. p=0. Grade 3 or 4 toxicities included granulocytopenia (25%). Treatment was comprised of recombinant interferon-alpha-2b (5 million units per square meter (m(2)) administered subcutaneously daily on days 1 to 7 of each 4-week cycle. 95% CI. this was followed by an intravenous infusion of leucovorin (500 milligrams (mg)/m(2) over 30 minutes and an intravenous bolus of fluorouracil 370 mg/m(2). hazard ratio (HR). 8 months) and EEP-L (epirubicin. In both groups.58) in the TCF arm compared to 8. Although chemotherapy has only minor activity in gastric cancer. both were administered by intravenous bolus injection. Treatment was tolerated well with no treatmentrelated deaths. Each patient received a median number of 6 cycles of TCF (range.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Median TTP was 5. On days 2 through 6.47) in the CF arm (n=224.6 months (95% CI. Neither regimen produced a complete response. fluorouracil 1000 mg/m(2)/day for 5 days) every 4 weeks. Fluorouracil dosage reductions were required during the first or second cycles in 7 patients (29%) due to toxicity. one study indicates that doxorubicin. and leucovorin did improve survival rates in patients who had undergone curative surgery [50]. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. median survival was similar for 5-FU/6S-LV (fluorouracil and leucovorin. 4. p=0. and fluorouracil [51].7%) and diarrhea (28. cisplatin 30 mg/m(2) on days 2 and 4.83. cisplatin.2 months (95% CI.0106) [60].0201).04 to 1. for an overall response rate of 12. 1 to 16) or 4 cycles of CF (range. mitomycin. d) In a phase II study (n=65). lonidamine. 1 to 12). 55 years) with advanced gastric adenocarcinoma.6 months (95% confidence interval (CI). thomsonhc.5%.0 55% [8][57][4][5][58][59].0004).19 to 1. to TCF (docetaxel 75 milligrams/square meter (mg/m(2)) on day 1.7 months (95% CI. however. etoposide 100 mg/m(2) on days 1. 1.4% for the CF group (p=0. a median of 3 cycles per patient was associated with 3 partial responses.61. median age. fluorouracil 750 mg/m(2)/day for 5 days) every 3 weeks or CF (cisplatin 100 mg/m(2) on day 1.47.86 to 5. 1. cisplatin 75 mg/m(2) on day 1.

0 e) In a phase II study. thrombocytopenia. mucositis. in the leucovorin group.MICROMEDEX® 2. 8. patients also received glutathione 1. The primary grade III to IV toxicity was hematologic with few episodes of mucositis (n=6) and nausea/vomiting (n=6).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Dose reductions among the other agents also were greater in the leucovorin regimen. Patients received methotrexate 500 milligrams/square meter (mg/m(2)) as a 2-hour infusion on day 1.and 2-year survival rates were 42% and 5%. and this regimen resulted in a greater number of patients with stable disease [51].003).3 months). The chemotherapy regimen which included fluorouracil. patients with a response or stable disease received 6 additional weeks of therapy. more patients had stable disease (p=0. randomized. and fewer had progressive disease (p=0. and fatigue.IntermediateToDocumentPrintLink 112/317 . there were no differences in complete or partial responses. and epi-doxorubicin 35 mg/m(2) given as a bolus injection. and epi-doxorubicin with modulation by leucovorin produced an objective tumor response of 62% and a median survival time of 11 months. and 36. the toxicity of the leucovorin-containing regimen was acceptable. fluorouracil. fluorouracil 500 mg/m(2) given as a 30-minute infusion. and cisplatin (FLAP) was as follows: (1) Intravenous (IV) leucovorin 500 milligrams/square meter (mg/m(2)) over 2 hours weekly during weeks 1 through 6. however.048). toxicity was greater in the group receiving leucovorin.8 versus 8. diarrhea. or the same regimen plus leucovorin 200 mg/m(2)/day administered on the same days as fluorouracil. in patients with advanced gastric cancer. and overall survival (10. h) Median survival was 30 weeks from 42 (34 had gastric carcinomas and 8 had gastroesophageal junction carcinomas) previously untreated patients involved in a multiinstitutional. the 1. phase-II trial. this must be confirmed in a long-term.3 months). cisplatin. controlled trial. followed by LFA 250 mg/m(2) as a 2-hour infusion and fluorouracil 600 mg/m(2) bolus on day 2. Response rates and median survival times compared favorably to other chemotherapy regimens. with cycles every 2 weeks until tumor progression (maximum.25/10/12 Drug details . f) double biochemical modulation of fluorouracil with methotrexate and levo-folinic acid (LFA) was administered to 94 patients with advanced digestive tract malignancies. leucovorin. respectively.3 versus 2. (2) fluorouracil 500mg/m(2) IV delivered midway through leucovorin infusion thomsonhc. To prevent neurotoxicity and hematologic toxicity. stomach. epirubicin 45 mg/m(2)/day on days 1 and 29. doxorubicin. Toxicity was significantly greater with the leucovorin regimen and consisted of neutropenia. 29. This regimen consisted of weekly administration of cisplatin 40 milligrams/square meter (mg/m(2)) given as a 30-minute infusion. mitomycin. however.5 grams/m(2) and filgrastim 5 micrograms/kilogram from the day after to the day before each course of chemotherapy. involving the colon-rectum. g) Combination therapy with fluorouracil. and mitomycin 10 mg/m(2)/day on day 1. epirubicin. The study identified that a 24-hour methotrexate serum concentration greater than 2 micromoles was significantly predictive of response (37% versus 5%). Responses were correlated with a 24-hour methotrexate level above 2 micromoles in 31% of previously treated colorectal patients and in 38% of chemotherapy-naive colorectal patients [22]. This regimen was repeated weekly for 8 weeks. or biliary tract. chemotherapy was repeated every 8 weeks for 6 cycles or until disease progression. 24 courses). the 6S-stereoisomer of leucovorin 250 mg/m(2) given over 4 hours. no grade III or IV neurotoxicity or treatment related deaths were reported [63]. Overall. and leucovorin produced a survival duration similar to this combination without leucovorin. however. longer progression-free survival (5. Eighty-eight patients with advanced gastric cancer were randomly assigned to receive fluorouracil 600 milligrams/square meter (mg/m(2)) per day on days 1.

Trabeculectomy usually fails due to fibroblast proliferation and scarring which are prevented by FLUOROURACIL. This regimen may be useful for treating patients on an outpatient basis [55]. with a median survival of 11 months. repeated at 4 and 8 weeks. In 31 patients with locally advanced or metastatic cancer.MICROMEDEX® 2. Median survival was 9 months in complete responders and 13 months in partial responders. oral UFT 195 mg/m(2) every 12 hours on days 1 to 14. Therapy was repeated every 28 days for a minimum of 3 courses. and Grade 3 thrombocytopenia was found in 3 patients. Grade 3 to 4 diarrhea was noted in 4 patients. The response rate found with this FLAP regimen is similar to other phase II trials using doxorubicin and fluorouracil in gastric carcinomas [64]. Evidence favors efficacy Recommendation: Adult. Complete and partial response was observed in 2 (5%) and 13 (31%) patients. j) Combination fluorouracil and low-dose cisplatin has shown activity in advanced gastric cancer. oral etoposide 100 mg/m(2) every 12 hours on days 2 and 3. Median time to disease progression and survival for responders was 28 weeks.IntermediateToDocumentPrintLink 113/317 . (3) On weeks 1 and 4 IV bolus doxorubicin 30 mg/m(2) along with cisplatin IV 60 mg/m(2) over 60 minutes. and 40 weeks. Glaucoma 1) Overview FDA Approval: Adult. k) Survival rates with fluorouracil alone were similar to those observed with FLUOROURACIL plus doxorubicin with or without mitomycin in patients with advanced pancreatic and gastric carcinoma (n=305). the overall response rate was 45%. no. Myelosuppression (Grade 3 to 4 leukopenia) was found in 18 patients. The regimen comprised etoposide 100 milligrams/square meter (mg/m(2)) and leucovorin 500 mg/m(2) as an intravenous infusion on day 1. Due to the greater cost and toxicity of combination therapy.25/10/12 Drug details . and oral leucovorin 15 mg every 12 hours on days 2 to 14. Class IIb Strength of Evidence: Adult. Major toxicities included grade III/IV hematologic or gastrointestinal effects. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil significantly decreases intraocular pressure when administered as a subconjunctival injection after trabeculectomy or applied directly by sponge during surgery in patients with glaucoma [122][123] (Gandolfi & Vecchi. 1997).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and every 5 weeks thereafter. and UFT (a prodrug of fluorouracil and uracil in a 4:1 molar ratio). produced a 9% complete response and 26% partial response in a phase II study of patients with advanced adenocarcinoma of the stomach. no Efficacy: Adult. Single-agent FLUOROURACIL was administered as 500 milligrams/square meter per day for 5 days. Pediatric. respectively. the authors advocate FLUOROURACIL monotherapy in advanced pancreatic or gastric cancer [49]. but survival rates have not been remarkable compared with other chemotherapy regimens. thomsonhc. A particularly higher response of 60% was observed in patients with liver metastases [56].0 from weeks 1 through 6. respectively. leucovorin. an inhibitor of fibroblast proliferation [122]. i) Combination etoposide.

10 of 12 fluorouracil-treated eyes and 1 of 12 untreated eyes had an IOP less than 15 mmHg (p=0. with significantly more fluorouracil recipients experiencing cataract formation (16%) than the controls (2. respectively. and subconjunctival injections were used postoperatively as needed [122]. 1-year and 5-year rates of intraocular pressure (IOP) control were 90%. the average IOP reductions were 11.6%. At one month. p less than 0. All patients had previously undergone cataract surgery or had failed filtering surgery. patients were randomly assigned to receive no treatment or fluorouracil 5-milligram injections on postoperative days 8. visual acuity had decreased significantly. respectively. Clinicians also treated eight of 50 eyes with postoperative fluorouracil injections.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The most common postoperative complication was bleb encapsulation (16% to 18% incidence).0 3) Adult: a) In a prospective study of 50 eyes (n=43 patients) with uveitis-associated glaucoma undergoing primary trabeculectomy with intraoperative fluorouracil 25 milligrams/milliliter for 5 minutes.00064). respectively. 15.25/10/12 Drug details . Only 31.032) compared with trabeculotomy only. there were significantly fewer treatment failures among 105 eyes treated with trabeculectomy and subconjunctival fluorouracil compared with 108 eyes treated with trabeculectomy alone (51% vs 74%. 88%. Neither intraoperative nor postoperative fluorouracil produced ocular toxicity [124]. the 6-month. A sponge soaked in fluorouracil 50 mg/mL was directly applied during surgery.02) [125]. 30. Patients randomized to subconjunctival fluorouracil received 5-milligram postoperative injections twice daily on days 1 through 7 and once daily on days 8 through 14. p less than 0. The requirement for systemic glaucoma medications and/or additional surgery constituted failure of primary trabeculectomy. Laser suture lysis was performed in 10 fluorouracil-treated eyes and 9 untreated eyes. also called the Fluorouracil Filtering Surgery Study [123]. randomized trial.5 and 10. p=0. d) In a 16-month retrospective study of 140 eyes. and 67%. Fluorouracil treatment was associated with a significant increase in leakage of a filtering bleb (9% vs 2%. A successful outcome indicated IOP reduction to less than 21 millimeters of mercury with (partial) or without (complete) topical glaucoma medications.6% and 26. Complications occurred thomsonhc. c) During 5 years of follow-up. The fluorouracil regimen consisted of three 5-milligram injections over 11 days. e) Subconjunctivally injected fluorouracil resulted in significantly lower intraocular pressures (IOP) 1 year after combined cataract and trabeculectomy surgery for control of glaucoma.001).MICROMEDEX® 2. fluorouracil with trabeculectomy significantly decreased intraocular pressure (iop) and also reduced the number of postoperative medications needed to control glaucoma (p less than 0.IntermediateToDocumentPrintLink 114/317 . b) Post-trabeculectomy low-dose subconjunctival fluorouracil injections failed to show any benefit with respect to long-term intraocular pressure (IOP) control in a randomized trial of 80 eyes (n=80 patients) with low-risk glaucoma.2 millimeters of mercury (mmHg) in those who did and did not receive fluorouracil. One year later. attained a target IOP of less than 21 mmHg without additional medication or intervention. High-risk patients were less likely to maintain IOP below recommended guidelines (less than 15 mmHg) without medications. This was a multicenter. 22. In this small study (24 eyes with open-angle glaucoma and cataract).001). With a mean 1-year follow-up. Treatment failure was defined as reoperation for control of intraocular pressure or an intraocular pressure exceeding 21 mmHg after one year. and 37 if the IOP was elevated above 20 mmHg during the first 7 days after surgery. but vision recovered by 6 months and remained similar to untreated patients at 5 years.3% of the fluorouracil and control groups.

double blind study (n=60).3% grade 4 granular myringitis. and 8. Evidence favors efficacy Recommendation: Adult. Complications currently observed when fluorouracil is used during surgery may be minimized (eg. range. Further controlled studies with a larger number of patients are required to confirm the efficacy of delayed postoperative use of fluorouracil. Class IIb Strength of Evidence: Adult.7% grade 2. Mitomycin C was used in 192 (49. preliminary data suggest that postoperative subconjunctival injections of fluorouracil.1 milliliters) were given 2 weeks after surgery.MICROMEDEX® 2. multiple exostoses. Following cleansing of the external auditory canal and tympanic membrane surface.IntermediateToDocumentPrintLink 115/317 .1 milliliter of 5 milligrams/0. 35. is safe and may increase the success rate after trabeculectomy. a foreign body sensation. 5 treated with fluorouracil and 2 treated with MMC). Patients were excluded if there was marked external auditory canal stenosis.9%) eyes and fluorouracil was used in 193 eyes (50. Outcome measures included patient-reported discharge and endoscopically-observed granulation tissue at 3 months (mo) and persistent disease at 24 mo. 46. no Efficacy: Adult. Five to 8 subconjunctival injections of fluorouracil (0. 1997).1%). or eustachian tube dysfunction. At baseline 8. administered within the first 3 postoperative months only when clinical evidence of bleb failure is likely. no. Granular myringitis 1) Overview FDA Approval: Adult. and transient epithelial keratopathy (Gandolfi & Vecchi. f) The results of a retrospective study involving 304 patients (385 consecutive eyes) who underwent trabeculectomy with fluorouracil or mitomycin C (MMC) identified 7 cases with a late bleb leak.8% (7 eyes. Pediatric. g) In patients with uncontrolled open angle glaucoma undergoing glaucoma filtration surgery. conjunctival wound leaks.5 yr. The incidence of late (9 to 44 months) bleb formation was 1. Patients (mean age. patients were randomized to receive either placebo (n=30) or 3 cm of 5-fluorouracil 5% thomsonhc.0 primarily in the fluorouracil eyes and consisted of conjunctival redness.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. double blind study (n=60) [193].3% (n=5) patients had both ears affected and 15% had grade 1. 3) Adult: a) Topical fluorouracil treatment resulted in statistically significant improvements in symptoms of granular myringitis in adults compared with placebo according to a randomized. 18 to 53 yr) with endoscopically confirmed granular myringitis defined as a granulation over the intact tympanic membrane with normal audiography and a type A tympanogram were included in the study. Three of the 5 eyes treated with fluorouracil required surgical excision that revealed areas of thinned or absent conjunctival epithelium with stroma degeneration [126]. corneal epithelial defects) [127]. 30% grade 3. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical fluorouracil treatment resulted in significant improvements in symptoms (granulations and amount of discharge) of granular myringitis in adults compared with placebo according to a randomized.25/10/12 Drug details .

001). p less than 0.1% (3/30) There was also a significant difference between the fluorouracil and placebo groups in the percentage of patients with persistent disease at 24 months (10.7% (10/30) 18.7% (n=3) vs 74% (n=20).5% (5/30) resolved 53.8% (4/30) no improvement 10. and the majority are head and neck squamous cell carcinomas.001): Assessment at 24 months Discharge (patient reported) Granulations (endoscopically evaluated) fluorouracil (n=30) placebo (n=30) resolved 60. Surgery and radiation therapy remain the major curative modalities. and mild canal edema which resolved upon subsequent applications [193].7% (3/30) 59. redness.4% (6/30) 14. no. Class IIb Strength of Evidence: Adult.0 cream (n=30) applied to a 5 cm piece of gauze and using an operating microscope was packed on the outer side of the drum transmeatally. which was removed after 2 days.4% (2/30) moderate improvement 21. Although chemotherapy has only moderate activity. endoscopically-assessed granulation tissue. no Efficacy: Adult.25/10/12 Drug details .MICROMEDEX® 2.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.6% (1/30) 11.6% (15/30) 7.5% (5/30) no improvement 7. Evidence favors efficacy Recommendation: Adult. there were significant differences between treatment groups in patient-reported discharge.3% (16/30) worse 7. At the 3-mo assessment. The treatment was repeated every 2 wk for a total of 3 treatments. Head and neck cancer 1) Overview FDA Approval: Adult. however. and persistent disease (p less than 0.1% (2/30) 63% (17/30) worse 3.4% (2/30) moderate improvement 35. the Medical Letter consultants recommend fluorouracil with thomsonhc. In the fluorouracil group 3 patients experienced a mild local allergic reaction to the first treatment which included itching. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Head and neck cancers account for approximately 5% of all malignancies. Pediatric. chemotherapy may induce tumor regression in up to 50% of patients with metastatic or recurrent disease [128][129].1% (2/30) 18.7% (17/30) 7.IntermediateToDocumentPrintLink 116/317 .

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cisplatin as the regimen of choice in head and neck cancer and methotrexate as the
monotherapy of choice [8].
Induction usually consists of cisplatin 100 milligrams/square meter (mg/m(2)), vincristine 1
mg, bleomycin 30 units, OR cisplatin 100 mg/m(2) plus fluorouracil 1000 mg/m(2). These
regimens have produced good response rates (typically dependent on the extent of the
disease) [130][4][131][132].
For palliative therapy, the highest responses (50 to 95%) have been achieved with
combination cisplatin, vincristine, bleomycin, or cisplatin and fluorouracil, but these
regimens have not improved survival, and complete remissions have remained low (less
than 30%) [132][4][131][133][134][135][136]. The duration of remission is usually less
than or equal to 6 months. Even with combination therapy, results are disappointing when
treating advanced (Stage III to IV) disease [137].
3) Adult:
a) Combination with Cisplatin
1) In a phase III trial (n=497), time to laryngectomy was significantly increased in
patients with stage III/IV potentially resectable cancer of the larynx who received
concurrent cisplatin and radiotherapy (Arm A) compared to patients who received
induction chemotherapy with cisplatin and fluorouracil followed by radiotherapy (Arm B;
p=0.0094) and compared to patients who received radiotherapy alone (Arm C;
p=0.00035). The 2-year laryngectomy-free survival rates were 58% for Arm A, 66% for
Arm B, and 52% for Arm C. There were no significant differences in overall survival among
the 3 groups; induction chemotherapy showed no advantage over radiotherapy alone.
Induction chemotherapy consisted of cisplatin (100 milligrams/square meter (mg/m(2) on
day 1) and fluorouracil (1000 mg/m(2)/day continuous infusion for 5 days) every 21 days
for 2 or 3 courses. Concurrent chemotherapy consisted of cisplatin (100 mg/m(2)) on days
1, 22, and 43 of radiotherapy. Radiotherapy (2 Gray/fraction (Gy/fx)) was administered in
35 fractions in 7 weeks. Patients with N2 or N3 neck disease at presentation received neck
dissection 8 weeks after completing radiation. Laryngectomy and neck dissection was
performed for persistent or recurrent local or regional disease. Grade 3/4 toxicity was
experienced by 66% of patients during induction chemotherapy (grade 5=2%), 50% of
patients during radiotherapy following induction, 78% of patients during concurrent
chemotherapy/radiotherapy (grade 5=2%), and 48% of patients who received only
radiotherapy [138]. In a discussion of this phase III trial, it was noted that none of the 3
approaches provided better survival rates than surgery. Potential complications of
concurrent chemotherapy and radiotherapy are stricture, radiation necrosis, chronic
laryngeal edema, tracheotomy dependence, and swallowing disorders. [139].
2) In patients with locally advanced head and neck carcinoma, adding granulocyte-colony
stimulating factor (G-CSF) to a radiochemotherapeutic regimen did not reduce the acute
mucosal or hematological toxicity. In a phase I/II trial, 70 patients with stage III and IV
head and neck carcinoma were treated with: (1) hyperfractionated radiation at 1.20 grays
(Gy) twice daily 4 to 6 hours apart on days 2 through 43; (2) fluorouracil 1000
milligrams/square meter/24 hours (mg/m(2)/24 hours) as a continuous infusion for 72
hours on weeks 1, 5, 8; (3) weeks 1, 5 and 8, cisplatin 50 mg/m(2) before fluorouracil; and
(4) Mitomycin C 8 mg/m(2) on week 5. After 34 patients, G-CSF 5
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micrograms/kilogram/day subcutaneously Monday through Friday was administered on
days of radiation therapy. Toxicity for both treatments included: Grade 3 to 4 mucositis
(65%), Grade 3 dermatitis (44%), Grade 3 to 4 neutropenia (39%), Grade 3 to 4
thrombocytopenia (25%), Grade 3 to 4 anemia (17%). Swallowing dysfunction was a
chronic long-term toxicity, with a significant correlation between patients who had severe
mucositis for longer than 3 months. At 41 months, locoregional control rate was 68% for
patients with disease above the clavicle. At 12 months, 46 patients were alive [140].
3) Cisplatin 100 milligrams/square meter (mg/m(2)) plus fluorouracil 1 gram/m(2) was
superior to single agent fluorouracil or cisplatin in patients with advanced head and neck
cancer (n=249). patients were randomized to either cisplatin (n=84), fluorouracil (n=84)
or a combination of both (n=81) for 3 weeks. Overall response rates were 32% with
combination therapy, 17% with cisplatin, and 13% with fluorouracil. However, there were
no complete responses and there was no significant difference in median survival (5.7
months) among the 3 groups [141].
4) The use of cisplatin, methotrexate, vincristine, bleomycin, and fluorouracil in various
combinations has been disappointing in the treatment of patients with advanced head and
neck cancer. Although overall responses have been as high as 70%, few patients achieve a
complete response [141][137]. In a phase II study, fluorouracil, cisplatin, and bleomycin
achieved a complete response in only 1 of 31 patients [142]. However, another study
reported that cisplatin plus fluorouracil produced complete responses in 9 of 49 patients
with advanced or recurrent head and neck cancer [133].
b) Combination with Cisplatin and Leucovorin
1) Concomitant cisplatin 100 milligrams/square meter (mg/m(2)) on day 1, 5-day
continuous infusion of fluorouracil 1000 mg/m(2)/day, and high-dose oral leucovorin 100
mg every 4 hours during infusion resulted in a 29% complete response rate in 31
previously untreated patients with advanced head and neck cancer (Stage III & IV); the
overall response rate was 84%. This induction regimen was used on the front end of a
protocol involving concomitant chemoradiotherapy [143].
2) Induction therapy with high-dose leucovorin, fluorouracil, and cisplatin in 35 patients
with advanced head and neck cancer produced an overall response rate of 80%, with
complete responses in 23 patients (66%). The regimen consisted of cisplatin 25
milligrams/square meter (mg/m(2)) on days 1 through 5; fluorouracil 800 mg/m(2) on
days 2 through 6; and leucovorin 500 mg/m(2) on days 1 through 6; the cycle was
repeated every 28 days for 2 to 3 cycles [136].
3) The addition of vindesine to a cisplatin-based neoadjuvant chemotherapy did not
improve antitumor efficacy in the treatment of 28 consecutive patients with Stage IV head
and neck cancer. Chemotherapy consisted of cisplatin 100 milligrams/square meter
(mg/m(2)) on day 1, fluorouracil 600 mg/m(2) and vindesine 0.8 mg/m(2) infused over
days 1 through 4, and folinic acid (leucovorin) 150 mg/m(2) every 6 hours for 96 hours.
This cycle was repeated every 21 days. Complete response was achieved in 13% of
patients and partial response occurred in 42%. Adverse effects included grade IV
neutropenia (62%) and oral mucositis (65%). Median survival at 2 years was 27% [144].
c) Combination with Radiation Therapy
1) Impressive response rates (overall, 100%; complete, 75% and 89%) have been
reported with chemotherapy (ie, cisplatin, fluorouracil, bleomycin) plus radiation in patients
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with advanced and inoperable recurrent head neck cancer (Gasparini et al, 1991)[145][4];
(Taylor et al, 1989).
2) Survival was substantially improved (median, 37 months versus 12 months) compared
with previous study in patients with recurrent, advanced, inoperable head and neck cancer
who were treated with simultaneous chemotherapy and radiation. The complete response
rate was 55% (comparable to previous results). The 5-day chemotherapeutic regimen
consisted of cisplatin 60 milligrams/square meter (mg/m(2)) on day 1; fluorouracil 800
mg/m(2) on days 1 through 5. This cycle was given every other week with concurrent
radiation 2 Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) daily for 5 days.
Although the protocol called for 7 cycles, only 64% (34/53) received full treatment (Taylor
et al, 1989).
3) The addition of fluorouracil to cisplatin and fractionated radiation resulted in doselimiting mucositis, which forced subtherapeutic fluorouracil doses. Twenty-seven
postoperative patients with advanced and recurrent disease were enrolled in this study
[146].
d) Combination with Hydroxyurea and Radiation
1) Five-year progression-free survival was 82% for patients (n=60) with stage II or III
head and neck cancer treated with hydroxyurea, fluorouracil and radiation therapy. Patients
were administered hydroxyurea 1 gram orally every 12 hours starting the day before
radiotherapy for a total of 11 doses. Fluorouracil was given as a continuous infusion at a
dosage of 800 milligrams/square meter/day for 5 days. Radiotherapy was administered in
1.8- to 2-Gy fractions for 5 days. This cycle was repeated every 14 days until a total
radiation dose of up to 70 Gy was administered. The total radiation dose was dependent
upon extent of disease and location. The 5-year overall survival was 65% and ultimate
local/regional control at 2 years and beyond was 91%. ECOG grade 3 and 4 mucositis was
experienced by 34 patients. Forty-five patients developed grade 3 or 4 neutropenia.
Concomitant chemotherapy and radiotherapy is feasible with very good tumor control and
acceptable toxicity for this patient population [147].
Hepatoblastoma
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Two cisplatin-containing regimens were equivalent in efficacy but not toxicity in a
randomized trial of 173 children with hepatoblastoma. [148]
3) Pediatric:
a) Two cisplatin-containing regimens were equivalent in efficacy but not toxicity in a
randomized trial of 173 children with hepatoblastoma. The cisplatin dosage for both
regimens was 90 milligrams/square meter (mg/m(2))
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or
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regimens was 90 milligrams/square meter (mg/m(2)) for patients at least 1 year of age or
3 mg/kilogram for patients under 1 year of age, infused over 6 hours on day 1 of each cycle.
Cisplatin was combined with either vincristine 1.5 mg/m(2) plus fluorouracil 600 mg/m(2)
via intravenous push on day 2 (regimen A), or with doxorubicin 20 mg/m(2)/day as a 96hour continuous infusion starting on day 1 (regimen B). Four to eight cycles were
administered, with some patients undergoing post-induction surgery. Five-year event-free
survival rates (57% and 69%) and overall survival rates (69% and 72%) were statistically
similar in groups A and B, respectively. Survival was significantly improved with Stage Iunfavorable histology and Stage II disease as compared to Stage III or IV disease (p less
than 0.0001). Hematologic, cardiac, gastrointestinal and renal toxicities occurred at higher
frequencies in group B than in group A (p less than 0.03). Duration of hospitalization and
parenteral nutritional support requirements also significantly favored regimen A [148].
Intracranial tumor
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Combination thioguanine, procarbazine, dibromodulcitol, CCNU (lomustine), fluorouracil,
and hydroxyurea demonstrated significant anti-tumor activity in patients with recurrent
metastatic brain tumors associated with breast and small cell lung cancer (Kaba et al,
1997). A combination of carmustine and fluorouracil arrested tumor progression in 83% of
29 patients [98]
3) Adult:
A combination of thioguanine, procarbazine, dibromodulcitol, lomustine, fluorouracil, and
hydroxyurea demonstrated significant anti-tumor activity in patients with recurrent
metastatic brain tumors associated with breast and small cell lung cancer (n=115). Overall
response rate among 97 assessable patients was 28%; 4 complete, 14 partial, and 9 minor.
Stable or progressive disease was observed in 26% and 46%, respectively. Primary disease
sites included breast (n=28), non-small cell lung (n=39), small cell lung (n=9), melanoma
(n=9), and other origins such as colon, kidney, bladder, stomach, or "unknown" (n=12). The
16-day chemotherapy regimen included:
days 1 through 3: oral thioguanine 40 milligrams/square meter (mg/m(2)) every 6 hours
day 3 (hour 60): oral dibromodulcitol 400 mg/m(2), 4 doses of oral procarbazine 50
mg/m(2) every 6 hours;
hour 72: oral lomustine 110 mg/m(2);
day 14: fluorouracil 1 gram/m(2) continuous 48-hour infusion;
days 15 and 16: 3 doses of oral hydroxyurea 1 gram/m(2)
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days 15 and 16: 3 doses of oral hydroxyurea 1 gram/m(2) every 4 hours.
Dose reductions were required in 54% of patients because of hematologic complications.
Objective response rates and disease-free survival among primary tumor groups were
highest among patients with small cell lung cancer (6 patients/67%; 133 weeks) and breast
cancer (10 patients/36%; 27 weeks). Anti-tumor activity also was evident, but to a lesser
extent, in patients with non-small cell lung cancer (objective responses in 10 patients/25%,
disease-free survival 21 weeks). Median survival was 25 weeks among all patients, and 24%
were alive at 1 year. Younger patients and those previously treated with surgery or
chemotherapy progressed significantly faster. Myelosuppression was evident in 60% of
patients and mild nausea/vomiting occurred in 35%. Adverse effects necessitated treatment
withdrawal in only 2 patients, one because of fatigue and the other because of severe
gastrointestinal effects [99].
a) A carmustine (BCNU)-fluorouracil combination was superior to either BCNU alone or a
BCNU-procarbazine in recurrent malignant brain tumors. Among 29 patients, 83% had
arrested tumor progression [98].
Keratoacanthoma
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Topical 5% cream was effective in 2 case reports [150]
Intralesional injection has also been effective [151][152]; (Dubanks et al, 1982)[153].
3) Adult:
a) Keratoacanthomas of the outer ear and forehead in two elderly males were successfully
treated with topical 5% fluorouracil cream. With daily application of fluorouracil for up to 8
weeks, the benign tumor rapidly shrank and resolved completely in one patient, while the
other experienced an 80% reduction in size with the remainder removed via shave biopsy
and electrodesiccation. No scarring or adverse effects were noted. The authors advocate
topical fluorouracil for keratoacanthomas whose size or location render surgical excision
less desirable [150].
b) In several uncontrolled studies, intralesional fluorouracil produced regression of
keratoacanthomas [151][152]; (Dubanks et al, 1982)[153]. The volume of fluorouracil
intralesional injections ranged from 0.1 to 3 milliliters (mL) per treatment. The frequency of
injection ranged from weekly to every 4 weeks. In 2 studies, fluorouracil resulted in a 60%
to 80% regression of the lesion.
Leukoplakia
1) Overview
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FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Evidence supports the use of topical fluorouracil in leukoplakia [176][177][178]
Lung carcinoma
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Fluorouracil and mitomycin, in combination with doxorubicin or vincristine, has elicited
overall response rates of 33% to 41%, respectively in patients with lung cancer. However,
survival has ranged from only 28 weeks with the vincristine regimen to 10 months with the
doxorubicin regimen [159][160]. .
Fluorouracil monotherapy was significantly enhanced with concomitant radiation therapy
[161]
3) Adult:
a) Thirty patients with unresectable adenocarcinoma of the lung were treated with
fluorouracil, doxorubicin and mitomycin C. Objective responses were seen in 10 patients
with one complete response and nine partial responses. Median survival for responding
patients was 10 months or longer, while non-responders had a median survival of 5.21
months [160].
b) Fifty-six patients with extensive adenocarcinoma and large cell undifferentiated
carcinoma of the lung were treated with fluorouracil, vincristine and mitomycin C. The
overall response rate was 41% with four patients receiving a complete response and 19
patients achieving a partial response [159].
c) Overall responses were higher in patients treated with a combination of radiation
therapy and fluorouracil (P=0.035) versus radiation alone. However, there were no
significant differences in overall or progression-free survival or in palliation of symptoms.
Two hundred patients with non-small cell lung cancer were randomized to receive radiation
20 Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) in 5 daily fractions either
with or without a continuous infusion of fluorouracil (1 gram/square meter daily) for 5 days
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Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS thomsonhc. Pediatric. Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Evidence supports the use of fluorouracil for the treatment of endometrial carcinoma [112][113] The Medical Letter consultants recommend two specific drugs or combination drug regimens of choice in the treatment of endometrial cancer: megestrol or other progestin. Evidence is inconclusive Recommendation: Adult.IntermediateToDocumentPrintLink 123/317 . carboplatin. or altretamine. no Efficacy: Adult. in combination therapy. Alternative agents as monotherapy can include either fluorouracil. Pediatric. no. no. Malignant neoplasm of liver 1) Overview FDA Approval: Adult. is reasonable medical therapy at some point in the management of adrenocortical carcinoma [179][180][181][182][183] Malignant neoplasm of endometrium of corpus uteri 1) Overview FDA Approval: Adult. These recommendations do not imply that these agents have been approved for use in this indication by the U. Pediatric. no Efficacy: Adult. Evidence favors efficacy Recommendation: Adult.25/10/12 Drug details . Class IIb Strength of Evidence: Adult. no. 1997).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Food & Drug Administration (Anon. Class IIb Strength of Evidence: Adult. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil. Malignant neoplasm of adrenal cortex 1) Overview FDA Approval: Adult.0 [161]. or doxorubicin plus cisplatin with or without cyclophosphamide. tamoxifen. Class IIb Strength of Evidence: Adult. no Efficacy: Adult.MICROMEDEX® 2.S. paclitaxel. Evidence favors efficacy Recommendation: Adult.

cisplatin. respectively. 7. respectively. 1 and 2 patients had a complete and partial response.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. each given every 21 days. to carboplatin and fluorouracil modulated with leucovorin. The duration of response was 8. Median duration of response was 10 months [94]. to carboplatin and fluorouracil modulated with leucovorin [92] Of 32 assessable patients receiving treatment with fluorouracil and recombinant interferon alfa-2b for biliary tract cancer. unresectable gallbladder or biliary tree carcinoma. patients received epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) on day 1. and fluorouracil was well-tolerated and produced a 40% response rate in 20 evaluable patients with advanced biliary tumors [94]. 34% had a partial response with a median survival of 12 months [93] Combination leucovorin. Also. no. 1 and 2 patients had a complete and partial response. no Efficacy: Adult. Carboplatin 300 milligrams/square meter was administered as an intravenous infusion on day 1 only followed by fluorouracil 400 mg/m(2) and leucovorin 25 mg/m(2) given as a bolus on days 1 thomsonhc. Pediatric.5 months [71] 3) Adult: a) Of 14 patients with histologically confirmed. median survival was 6. and greater than 26 months (complete response) for the 3 responding patients. Class IIa Strength of Evidence: Adult. cisplatin. and fluorouracil was well-tolerated and produced a 40% response rate in 20 evaluable patients with advanced biliary tumors. Evidence favors efficacy Recommendation: Adult. Malignant tumor of biliary tract 1) Overview FDA Approval: Adult.25/10/12 Drug details . Epirubicin.0 2) Summary: Epirubicin. 3) Adult: a) Intrahepatic arterial infusions of fluorouracil have been used in patients with advanced disease [154][155][156]. fluorouracil. fluorouracil infusion via the portal vein and intravenous administration with concomitant artery ligation have been used for hepatocellular carcinoma and hepatic sarcoma [157][158]. b) There has been no effective systemic treatment for the rare and poor-prognosis hepatobiliary tumors.IntermediateToDocumentPrintLink 124/317 . and fluorouracil 200 mg/m(2)/day as a continuous 24-hour infusion throughout the treatment course. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Of 14 patients with histologically confirmed. unresectable gallbladder or biliary tree carcinoma. and hydroxyurea produced partial responses in 9 (30%) of 30 patients with previously untreated advanced gallbladder carcinoma.

Only 6% of patients developed grade 3 diarrhea with the remainder of patients reporting primarily grade 1 or 2 toxicity. b) Of 32 assessable patients receiving treatment with fluorouracil and recombinant interferon alfa-2b for biliary tract cancer. and fluorouracil 200 mg/m(2)/day as a continuous 24-hour infusion throughout the treatment course. Class IIb Strength of Evidence: Adult. After restaging. Pediatric. however. Each cycle was repeated every 28 days with a maximum of 6 courses. followed in 6 hours by 3 doses of oral hydroxyurea (1500 mg for a body surface area (BSA) less than or equal to 1. Median duration of response was 10 months [94]. Toxicity was manageable [93]. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: One study reported that streptozocin plus doxorubicin was superior to either streptozocin plus fluorouracil or chlorozotocin alone in the treatment of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients [149]. all patients with measurable cholangiocarcinoma and gallbladder carcinoma were treated with a continuous infusion of fluorouracil 750 milligrams/square meter/day for 5 days with subcutaneous injection of interferon-alfa-2b 5 million units/square meter on days 1. cisplatin. 3. no. Response rates in this trial are consistent with previous trials using fluorouracil. Myelosuppression was the dose-limiting toxicity with 29% of cycles followed by neutropenia and fever. d) There has been no effective systemic treatment for the rare and poor-prognosis hepatobiliary tumors. Evidence is inconclusive Recommendation: Adult. no Efficacy: Adult. This regimen was repeated weekly for 6 weeks followed by a 2-week rest. doxorubicin. and fluorouracil was well-tolerated and produced a 40% response rate in 20 evaluable patients with advanced biliary tumors. and hydroxyurea produced partial responses in 9 (30%) of 30 patients with previously untreated advanced gallbladder carcinoma.7 m(2) or 2000 mg for a BSA greater than 1. Patients received epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) on day 1. treatment was continued until disease progression or unacceptable toxicity occurred.5 months. fluorouracil. This regimen produced objective responses suggesting a possible role for biliary cancer but further evaluation in controlled studies is needed [92]. c) Combination leucovorin. 34% had a partial response with a median survival of 12 months. Malignant tumor of Islets of Langerhans 1) Overview FDA Approval: Adult. and mitomycin C or fluorouracil and cisplatin. median survival was 6. each given every 21 days. this regimen is tolerated better [71].7 m(2)).to 4. In this phase II study. repeated every 2 weeks. The regimen included leucovorin 100 milligrams/square meter (mg/m(2)) as a 2-hour infusion followed by fluorouracil 600 mg/m(2) as an intravenous injection. Toxicity was mild. Epirubicin. 3) Adult: . and 5 of the infusion.

who had no prior chemotherapy or radiotherapy to the head and neck region. respectively. Tumor regression occurred in 69% and 45% of patients receiving streptozocin plus doxorubicin and streptozocin plus fluorouracil. PR of 10% . and 7 consisted of hydroxyurea 500 milligrams (mg) orally twice daily for 9 doses. Progressive disease (PD) was defined as an increase of 25% or greater of the diameters of tumor lesions. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In a phase 2 trial. time to tumor progression was 20 versus 6. Patients were 75% Chinese males with a median age 47 years. and locoregional and distant control rates of 83% and 64%. or residual cervical lymphadenopathy of at least 1. Complete response (CR) was defined as the absence of local tumor with no progression of primary tumor. the use of paclitaxel. or the appearance of new lesions.9 months. respectively. the use of paclitaxel. the locoregional tumor response was CR of 86% and 71%. respectively. undifferentiated. Pediatric. and hydroxyurea with concurrent radiation resulted in a 3-year overall-survival rate and progression-free survival of 72% and 54%.a) One study reported that streptozocin plus doxorubicin was superior to either streptozocin plus fluorouracil or chlorozotocin alone in the treatment of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients. Class IIb Strength of Evidence: Adult. and no residual cervical lymphadenopathy. survival also was extended in the streptozocin plus doxorubicin group. with concomitant continuous intravenous infusion of fluorouracil 600 mg/square meter (m(2))/day. Evidence favors efficacy Recommendation: Adult. stage 3 or 4 nasopharyngeal carcinoma. fluorouracil. Toxicity was mild and the response rate was 25% with a median time to progression of 4 months and median survival of 10 months [163] 3) Adult: a) In a phase 2 trial. respectively. in 59 patients with undifferentiated. no.4 years. in 59 patients with World Health Organization (WHO) type III. no Efficacy: Adult. Chlorozotocin alone produced a 30% regression rate with length of time to tumor progression and survival time equivalent to the streptozocin plus fluorouracil group [149]. The chemotherapy regimen administered on weeks 1. and paclitaxel 20 mg/m(2)/day for 4 days. stage 3 or 4 nasopharyngeal carcinoma. Protracted continuous infusion of fluorouracil 300 milligrams/square meter daily for 6 consecutive weeks was palliative in previously-treated and refractory patients with nasopharyngeal cancer . 4. 2.5 centimeter maximum length. Malignant tumor of nasopharynx 1) Overview FDA Approval: Adult. fluorouracil and hydroxyurea with concurrent radiation resulted in a 3-year overall-survival rate of 72% and progression-free survival of 54% [162] Undifferentiated carcinoma of the nasopharynx differs from squamous cell carcinomas of the head and neck with respect to chemosensitivity and histology. Four and 12 months after chemoradiotherapy. A partial response (PR) was defined as the presence of residual tumor with no progression of primary tumor.2 versus 1.

respectively. Twenty-six patients had metastatic or recurrent disease (group A) and 23 patients were previously untreated with locally advanced nonmetastatic disease (group B). Median duration of response was 11 months for complete responses and 8.MICROMEDEX® 2.0 chemoradiotherapy. Patients were treated until disease progression. and death occurred in 16 patients. Other adverse events included severe neutropenia (22%). with a World Health Organization performance status of 0 to 1.5% (95% CI. Of 23 evaluable patients in group B. followed by locoregional radiation. Every 3 weeks. At a median follow-up of 51 months. patients in group A received fluorouracil (700 milligrams per square meter per day (mg/m(2)/d) by continuous IV infusion on days 1 through 4). bleomycin 10 mg IV push on day 1. the locoregional tumor response was CR of 86% and 71%. The survival rate was not improved. respectively.5% of patients). c) Symptomatic nasopharyngeal carcinoma (NPC) with distant metastasis follows a progressive course with less than 10% of patients surviving 2 years. 15 patients (65%) were alive without evidence of disease. Distant failure occurred in 36% (n=21) of patients. complete and partial responses were achieved in 9 and 9 patients. PR of 10% and 2%. but requires careful monitoring and supportive care of toxicities in patients with metastatic or recurrent disease [164]. with non-completions mostly related to toxicity. In group B. and PD of 0% and 8%. All patients experienced oropharyngeal mucositis. 15 to 69 years in age. and 32%. severe toxicity was less frequent. and included neutropenia (56. 127/317 .3 mg/m(2) as a 24-hour continuous intravenous infusion produced very mild toxicity but only some short-term tumor regression. the combined intravenous (IV) administration of fluorouracil. In a trial involving 44 patients with NPC and distant metastasis previously treated with radiation and/or chemotherapy. future studies should address non-cross resistant cisplatin-based neoadjuvant therapy to reduce the distant failure rate [162] b) In a phase II study. Although systemic chemotherapy is usually recommended. Bleomycin was omitted during the last 3 cycles.5%). for an overall response rate of 91. The authors noted that due to the good locoregional control achieved by this chemotherapy regimen.Drug details . Median survival response for the group was 9 months (range. locoregional failures 15% (n=9). No treatment-related deaths occurred. for an overall response rate of 78% (95% confidence interval (CI). thrombocytopenia (17%). and a maximum of 24 cycles. bleomycin.3%). epirubicin (70 mg/m(2) IV on day 1. the median survival is only 8 to 12 months [165]. and 2 cycles in 98% of patients. In group A. Group B patients received the same regimen for 3 cycles. and mucositis (8%). 72 to 99).5%). Grade 3 or 4 toxicities were frequent.5% of patients). The median time to relapse was 17 months. 56 to 92). 63%. and cisplatin 100 mg/m(2) IV on day 5. weekly treatment with fluorouracil 1250 to 1667 milligrams/square meter (mg/m(2)) plus cisplatin 25 to 33. A total of 6 cycles were administered. Three treatment-related deaths were recorded. The authors conclude that this regimen provides good activity against this type of cancer. and cisplatin produced durable responses and manageable toxicities in 49 patients with undifferentiated carcinoma of nasopharyngeal type. 5 patients achieved a complete response (22%) and 16 patients achieved a partial response (69. and the need for insertion of feeding tubes (53%). respectively. 2 to 25 months) with only 40% surviving 1 year. anemia (23%). and mucositis (42. radiation dermatitis. concomitant distant and locoregional failure 12% (n=7). and included neutropenia (84.5 months for partial responses. thrombocytopenia (34. followed by 12 mg/m(2) by continuous IV infusion on days 1 through 4. Completion of all 3 cycles of chemotherapy occurred in 59% of patients. epirubicin. occurring in 39% (n=23) of patients. Of 23 evaluable patients in group A. and weight loss with grade 3/4 incidences of these adverse events of 81%. Patients were mostly male. neutropenic fever (14%). patient refusal.

d) Intraepithelial carcinoma of the vagina was successfully treated with topical fluorouracil 5% cream applied in doses of 2. no Efficacy: Adult. topical fluorouracil was as effective as laser treatment in vaginal intraepithelial neoplasia. Class IIb Strength of Evidence: Adult. 1977). with 3 courses being given 1 week apart.0 was 9 months (range. The periodic regimen produced fewer adverse effects than the continuous regimen [173].25/10/12 Drug details . Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In uncontrolled studies. no Efficacy: Adult. no. Evidence favors efficacy Recommendation: Adult. no. topical fluorouracil has achieved responses (primarily complete) in 75% to 93% of patients with intraepithelial or squamous cell carcinoma of the vagina [171][172] (Sillman et al. There were no systemic side effects [171]. Caglar et al. vaginal application of 1.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. and has been determined to be as effective as laser treatment (Krebs. Pediatric. 2 to 25 months) with only 40% surviving 1 year. 1977).5 grams of 5% fluorouracil cream once weekly at bedtime for 10 consecutive weeks was reported as effective as daily application of 1. 1989). Class IIb Strength of Evidence: Adult. 1981.125 grams vaginally at bedtime for 7 days. In addition. 1981.5 grams twice daily for 2 weeks. treatment was modified to a 5-day course after satisfactory response to a test application. with no serious sequelae [172]. Hull et al. Malignant tumor of vagina 1) Overview FDA Approval: Adult. b) Twelve of 15 patients (80%) had remission of vaginal intraepithelial neoplasia for 2 to 60 months after a 7-day course of intravaginal fluorouracil 5% cream (5 cubic centimeters) twice daily for 7 days. 3) Adult: a) In a retrospective study. The vagina healed normally and cytology remained normal for 3 years (Hull et al. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS thomsonhc. Evidence favors efficacy Recommendation: Adult. c) A 5-day course of topical fluorouracil 20% cream produced an overall response rate of 75% among 8 women with postirradiation squamous cell carcinoma in situ of the vagina.IntermediateToDocumentPrintLink 128/317 . Pediatric. Malignant tumor of vulva 1) Overview FDA Approval: Adult. Because these patients developed severe ulceration of vulvar and vaginal tissue.

Class IIb Strength of Evidence: Adult. alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5). Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Fluorouracil with interleukin-2 produced a response in 17% of patients with metastatic renal cancer [169] 3) Adult: a) In a phase-II study. 4. Pediatric. no. 2. Evidence favors efficacy Recommendation: Adult. Monday to Friday of weeks 2 and 3. no Efficacy: Adult. 6 of week 1. erythema (39%). and anemia (31%) [169].MICROMEDEX® 2. cyclophosphamide.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and longer survival than combination hexamethylmelamine. 3.6 months in Hexa-CAF treated patients (Neijt et al. Complete remission occurred in 40% and 19%. Other toxicities included nausea and vomiting (64%). Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Cyclophosphamide plus hexamethylmelamine. Pancreatic cancer thomsonhc. 1984). no. respectively. of the CHAP-5 and Hexa-CAF treatment groups. Class IIb Strength of Evidence: Adult. produced more complete remissions.7 months in CHAP-5 treated patients and 19. 5.0 2) Summary: Evidence supports the use of fluorouracil in vulvar carcinoma [185][186][187][188] Metastatic renal cell carcinoma 1) Overview FDA Approval: Adult.IntermediateToDocumentPrintLink 129/317 . Pediatric. better overall response. no Efficacy: Adult. Vascular leak syndrome requiring inotropic support was the major toxicity occurring in 6 patients. malaise (35%). Ovarian carcinoma 1) Overview FDA Approval: Adult. 3 partial responses) was observed in 24 patients with metastatic renal cancer who were treated with fluorouracil 200 milligrams/square meter/day combined with subcutaneous interleukin2 9 to 27 x 10(6) international units/day on day 1. Evidence is inconclusive Recommendation: Adult. Overall survival was 30. and fluorouracil (Hexa-CAF) in the treatment of advanced ovarian cancer.25/10/12 Drug details . methotrexate. an overall response rate of 17% (1 complete response.

0 See Drug Consult reference: FOLFIRINOX . Pediatric. intravitreal. no Efficacy: Adult.3%). p=0. placebo controlled trial. preoperative PVR.2% of the placebo-treated patients and combined treatment group patients. which included aphakia.0001). Successful retinal attachment without additional surgery was demonstrated in 71.IntermediateToDocumentPrintLink 130/317 . respectively. infusions of fluorouracil 200 micrograms/milliliter and LMWH 5 international units/milliliter (n=87) or normal saline (n=87). respectively. Psoriasis 1) Overview FDA Approval: Adult. Class IIb Strength of Evidence: Adult. however the visual acuity outcome was significantly worse in those patients developing postoperative PVR (p less than 0. no.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Patients were randomized to receive intraoperative.4% versus 12. anterior uveitis. Pediatric. Evidence favors efficacy Recommendation: Adult. size of retinal detachment.25/10/12 Drug details . no Efficacy: Adult.7%) in the placebo group.MICROMEDEX® 2.5%) and 22 (25. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Adjuvant combination therapy with fluorouracil and low molecular weight heparin significantly reduced the rate of postoperative proliferative vitreoretinopathy after vitrectomy and retinal detachment surgery [166] 3) Adult: a) Adjuvant combination therapy with fluorouracil and low molecular weight heparin (LMWH) significantly reduced the incidence of postoperative proliferative vitreoretinopathy (PVR) in 174 high-risk patients following vitrectomy and retinal reattachment surgery in a randomized. The number of reoperations resulting from PVR in the combined treatment group was nine (52. The total number of one or more reoperations in the combined treatment group and placebo group were 17 (19. Postoperative PVR occurred in 23 of 87 patients in the placebo group compared with 11 of 87 patients in the combined treatment group (26. Complications were limited and not significantly different between the two treatment groups. previous cryotherapy.3% and 78.6%. double blind. respectively. and vitreous hemorrhage. Evidence favors efficacy thomsonhc. The risk of developing PVR was determined by the presence of clinical factors.USED FOR PANCREATIC CANCER Proliferative vitreoretinopathy 1) Overview FDA Approval: Adult. including retinal incarceration and choroidal hemorrhage [166]. The intraoperative infusions were timed from the beginning of the infusion and stopped when air exchange was complete. while two intraoperative complications occurred in the combined treatment group. The final visual acuity outcome was not significantly different between the two treatment groups.9%) compared with 16 (72. no.02). The volume of infusion was determined by weighing the infusion bag at the end of surgery. Postoperative hyphemas were evident in five patients from each treatment group.

Class IIb Strength of Evidence: Adult. no thomsonhc. Remission was maintained in 32% of patients for 3 months or more.25/10/12 Drug details . Pediatric. 3) Adult: a) A case report describes the clinical and functional improvement in psoriatic trachyonychia with topical administration of 5% fluorouracil. Metastatic 1) Overview FDA Approval: Adult. Concomitant medications included glipizide. b) Topical fluorouracil may be useful in treating patients with small patches of psoriasis [168]. No systemic adverse effects were detected. no. once weekly application is preferred because the incidence of ulceration is lower. If effective. When used topically. no Efficacy: Adult. the treatment regimen was changed to every fourth day with resolution of the event. Queyrat's erythroplasia 1) Overview FDA Approval: Adult.MICROMEDEX® 2. Next.IntermediateToDocumentPrintLink 131/317 . albuterol inhaler. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical or intralesional fluorouracil may be useful for small patches of psoriasis [167][168]. localized hyperpigmentation developed [168].com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The response to topical therapy is usually slow. Due to periungual irritation. Eight weeks of topical corticosteroid treatment did not result in any improvement and was therefore discontinued. Evidence favors efficacy Recommendation: Adult. the patient has experienced clinical and functional improvement and is maintained on once weekly administration of 5% fluorouracil cream [167]. the patient was treated with 5% fluorouracil topical cream for 20 minutes every other day for 2 weeks. Class IIb Strength of Evidence: Adult. Pediatric. fluorouracil 5% is usually applied as an ointment 1 to 3 times weekly. c) Intralesional fluorouracil 50 milligrams resulted in complete remission of lesions after 1 to 3 doses in 82% of patients. Following 16 weeks of therapy. and triamcinolone inhaler.0 Recommendation: Adult. however. Medical history included type II diabetes mellitus and asthma. no. A 48-year-old white female with a 12 year history of nail dystrophy was diagnosed with nail psoriasis following physical and clinical examination. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Evidence supports the use of topical fluorouracil in Queyrat's erythroplasia [189][190][191][192] Skin cancer.

Squamous cell carcinoma of conjunctiva 1) Overview FDA Approval: Adult.25/10/12 Drug details . specifically. Class IIb Strength of Evidence: Adult. Pediatric.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. In a prospective.MICROMEDEX® 2. Evidence is inconclusive Recommendation: Adult. Pediatric. no. Disease recurred in 5 of these patients. 2 were disease free for 3 years and one developed new lesions. This treatment regimen was not associated with allergic or irritating adverse reactions [97]. open-label study. Class IIb Strength of Evidence: Adult. no. no Efficacy: Adult.0 Efficacy: Adult. Twelve of 26 patients experienced inactivation of disease and were followed for 33 months. Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: thomsonhc. no Efficacy: Adult. Evidence favors efficacy Recommendation: Adult. Improvement of disease was observed in 24 patients (92%) while no response to treatment was observed in 8% of patients. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: The combination of fluorouracil and cisplatin demonstrated efficacy in a small (n=8) study of patients with locoregional/metastatic metastatic squamous cell carcinoma [184] Squamous cell carcinoma in situ of skin 1) Overview FDA Approval: Adult.IntermediateToDocumentPrintLink 132/317 . 26 women with Bowen's disease of the lower leg were treated with fluorouracil cream in the morning and evening one day per week for a minimum of 3 months. Class IIb Strength of Evidence: Adult. Evidence favors efficacy Recommendation: Adult. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Weekly administration of topical fluorouracil cream was effective in the treatment of Bowen's disease [97] 3) Adult: a) Weekly administration of topical fluorouracil cream was effective in the treatment of Bowen's disease.

The median number of treated lesions per patient was four (range. Evidence favors efficacy Recommendation: Adult. After responding initially. topical 1% fluorouracil was instilled four times daily for 2 to 4 days. no Efficacy: Adult. nonrandomized trial. Post treatment skin biopsies . 3 to 15) and the median duration of treatment was six months (range. One patient required a switch to topical mitomycin-C after fluorouracil failed to alleviate a recurrent tumor. topical 1% fluorouracil therapy was effective and well-tolerated.Xeroderma pigmentosum 1) Overview FDA Approval: Adult. One individual required a second fluorouracil course to attain remission. the topical administration of fluorouracil demonstrated palliative benefit in 10 patients with histologically confirmed multiple facial squamous cell carcinoma associated with xeroderma pigmentosum. pilot study data suggest efficacy and tolerability of fluorouracil 1% ocular drops [110] 3) Adult: a) Topical administration of fluorouracil 1% ocular drops eradicated conjunctival squamous cell carcinoma in 8 of 8 patients in a prospective. fixed tumor facilitated surgical excision. For the initial treatment course. Class IIb Strength of Evidence: Adult. 19. The study sample (mean age: 70) included incompletely excised tumor (n=3). Topical fluorouracil produced skin dryness associated with superficial tumor regression in seven of 10 patients. Three of seven tumors disappeared without additional treatment and no recurrence for 15 to 36 months of followup. Fluorouracil-induced shrinkage of one bulky. b) In a case series of 7 men (mean age: 74 years) with conjunctival and/or corneal intraepithelial neoplasia. Squamous cell carcinoma . Instilled 4 times daily for 4 weeks. Investigators reported no adverse effects [111]. The only adverse effect of local fluorouracil was a transient keratoconjunctivitis during week 3 or 4 in all subjects that was relieved by artificial tears and antibiotics [110]. Pediatric. topical fluorouracil induced complete disappearance of malignant cells as assessed by periodic cytological smears and confirmed by biopsy at the end of follow-up (average: 27 months). recurrent carcinoma (n=3) and untreated disease (n=2). The patients (median age. repeated every 30 to 45 days for two to five cycles. 2 to 36 months).8 years) received topical fluorouracil (Efudex(R).Early. no. Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical fluorouracil may provide palliative treatment in multiple and superficial squamous cell carcinoma of the face secondary to xeroderma pigmentosum [170] 3) Adult: a) In an open study. and good cosmetic outcome with crust disappearance and tumor reduction in eight of 10 patients. Roche Pharmaceutical Laboratories) twice daily to all histologically proven or suspected lesions. two patients experienced recurrence that was successfully eradicated with five and six additional cycles of topical 1% fluorouracil.

4% in basal cell carcinomas treated with topical fluorouracil 5% ointment was the result of a 10-year follow-up study. Pediatric. no Efficacy: Pediatric. 1971. Pediatric.4% (Reymann. 1971). Evidence favors efficacy Recommendation: Adult. Class IIb Strength of Evidence: Adult. b) A recurrence rate of 21. 1997.0 were performed in five patients. Although clinical response was observed within 2 weeks. no Efficacy: Adult. 3) Adult: a) One report described successful treatment of nodular superficial pigmented basal epitheliomas in a patient receiving topical fluorouracil 5% cream applied daily for 9 months. However.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The remaining four patients with biopsies demonstrated persistent carcinoma in the deeper dermal layer. treatment was continued for a full 9 months. accompanied with good cosmetic result. Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical fluorouracil 5% cream was beneficial in patients with basal cell carcinomas and is indicated for multiple and recurrent epitheliomas that have not responded well to surgery or x-ray therapy (Prod Info Efudex(R).IntermediateToDocumentPrintLink 134/317 . 1979). The author concluded that there is hardly any indication for using fluorouracil in local treatment of nodular basal cell carcinoma [88]. yes (Topical). Class IIb Strength of Evidence: Pediatric. Superficial basal cell carcinoma FDA Labeled Indication 1) Overview FDA Approval: Adult. no. early evidence indicated a recurrence rate of 21. Treatment was well tolerated with occasional pruritus and erythema [170]. Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Topical administration of 0. The authors attribute successful therapy to the depth of the lesion [87]. with one patient experiencing tumor necrosis and resolution of epidermal ulceration with superficial fibrosis. Sykes et al. Evidence favors efficacy Recommendation: Pediatric.1% tretinoin and 5% fluorouracil resulted in significant improvement of non-inflamed epidermal verrucous nevus in a pediatric patient [114] thomsonhc. Litwin & Krementz. 1978).MICROMEDEX® 2. Systematized epidermal nevus 1) Overview FDA Approval: Adult.25/10/12 Drug details . and one trial determined that topical fluorouracil may conceal deep foci of invasive basal cell carcinomas with the appearance of complete healing (Mohs et al.

Excellent clearing of the epidermal nevus was evident following 10 weeks of reliable administration. in the international. HER2-negative. which continued to increase in size and darkness. multicenter. Metastatic a) The combination of interleukin-2 with interferon-alfa and 5-fluorouracil (5-FU) has demonstrated significant therapeutic efficacy in patients with metastatic renal cell carcinoma compared to tamoxifen.MICROMEDEX® 2.9% partial response) in the combination therapy group compared to an overall survival of 13 months and no objective remissions in the tamoxifen group (Atzpodien et al. days 1. The choice of thomsonhc. 10 x 10(6) IU/m(2) days 1. 3. The parents stated the first evidence of the nevus occurred at the age of 3 months. placebo-controlled.FU applied once daily under gauze bandage.or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative. The patient was lost to follow-up during a 3-year period in which discontinuation of therapy resulted in recurrence of the nevus. day 1 weeks 5-8). phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). as first-line therapy in combination with capecitabine or taxane. the entire lesion was treated.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. randomized. The tamoxifen group received 80 mg twice daily for 8 weeks. 5 x 10(6) IU/m(2) days 1. 5 weeks 2 and 3.25/10/12 Drug details . The patient resumed therapy at the age of 11 years with a 1:1 combination of topical 0.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane. Following evidence of clinical and histopathologic improvement of the test area. Inadequate patient compliance over subsequent years did not allow for appropriate assessment of treatment. 21. suggesting an indication for maintenance therapy [114]. The patient presented with a large.1% tretinoin cream and 5% 5. Comparative Efficacy / Evaluation With Other Therapies Aldesleukin Renal cell carcinoma.0 3) Pediatric: a) The combination therapy of topical tretinoin and fluorouracil produced significant improvement in a 7-year-old male with non-inflamed linear verrucous epidermal nevus. The treatment was well tolerated with the exception of redness and maceration of the skin during the initial administration phase. patients were treated with interferon-alfa (5 x 10(6) international units/square meter (IU/m(2)). The creams were applied separately and rubbed into the skin sequentially.5 weeks 2 and 3) plus 5-FU (1000 milligrams/square meter (mg/m(2)). In this study (n=78). Following biopsy confirmation of linear verrucous epidermal nevus.. dark-brown linear verrucous epidermal nevus on the right side of his face that extended from the forehead to the base of the neck. 5 weeks 5-8) plus interleukin-2 (10x 10(6) IU/m(2). 2001).05% tretinoin cream once in the morning and 5% fluorouracil once in the evening was applied to a small area of the lesion at the posterior base of the neck and covered with a bandage. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. twice-daily days 3-5 weeks 1 and 4. day 1 weeks 1 and 4. Results of the study showed an overall survival of 24 months and an objective response rate of 39. a test administration of 0.1% (17% complete response. 3. Bevacizumab Metastatic breast cancer.IntermediateToDocumentPrintLink 135/317 .3.

2 months.2 months (95% CI. every 2 weeks in combination with the standard chemotherapy regimen of 5-fluorouracil plus leucovorin (Roswell Park regimen). median age. 17. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161. Among patients with measurable disease at baseline.8.9%).1%.25/10/12 Drug details . 55 years. median age.4 months) vs 7. median age.6 months. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks. 45. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10.6% (95% CI. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. 0. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.or anthracycline-based regimen plus placebo (n=177.5 to 10.56 to 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.2 to 8.52 to 0. 57 years.MICROMEDEX® 2. 0%. range.6%) vs 23. With a median follow-up of 19.0 capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle). p less than 0.8 months)). and the anthracycline arm (34. median PFS was 9. respectively. 0.1 to 9.7%) vs 37. 95% CI.69. 0.7 months with capecitabine plus placebo (n=206. but the majority of patients received additional systemic treatment that might have affected OS. Hypertension.9%.2% to 40. a response rate of 17% (95% CI 7% to 34%) was thomsonhc. 6.5%.2%).4% and 3. 2%). Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35. 55 years. median PFS (primary outcome) was 8. a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). 5. epirubicin 90 to 100 mg/m(2). 30.84.IntermediateToDocumentPrintLink 136/317 . 30.9%. median age. p less than 0.0097) and with a taxane. 0%. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo. After a median follow-up of 15.001). 7.2%.001).or anthracycline-based regimen plus placebo (8.4% vs 21. hazard ratio (HR). HR. 95% confidence interval.2 to 10. range.3%). doxorubicin 50 mg/m(2). 3.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. and the anthracycline arm (10. 35. 5%) [413]. 0%).3 months)) and with a taxane.2 (95% CI.6 months with capecitabine plus bevacizumab (n=409.or anthracycline-based regimen plus bevacizumab (n=415. 51.9% to 56. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9. or an anthracycline-based regimen (fluorouracil 500 mg/m(2). fluorouracil 500 mg/m(2). 2%. 56 years.9% (95% CI.9%. objective responses were seen in 40% (95% CI 24% to 58%) and 24% (95% CI 12% to 43%) of those treated with intravenous bevacizumab 5 milligrams/kilogram (mg/kg) and 10 mg/kg. 8. range 23 to 88 years. p=0. p=0. 0% and 2. 28 to 88 years) compared with 8 months with a taxane. respectively.7%.1 months (95% CI. 28 to 91 years) compared with 5. 8.2 months with a taxane.7% vs 45. 1%.3% vs 15%).6% to 30.3 (95% CI.8% and 2.64. the taxane arm (57. 0%. 0.4% (95% CI.7 months) vs 7. range 29 to 85 years.3% (95% CI. 0%. the taxane arm (8.or anthracycline-based regimen plus placebo (n=207.or anthracycline-based regimen plus bevacizumab compared with a taxane. proteinuria and febrile neutropenia.2% vs 38.0054). Neoplasm of colon a) In a randomized phase II study involving previously untreated patients with metastatic colorectal cancer (n=104).

34.IntermediateToDocumentPrintLink 137/317 . d) Preliminary results from a randomized phase III trial (E3200) indicate that the addition of bevacizumab to FOLFOX4 (5-fluorouracil (5-FU)/leucovorin (LV)) and oxaliplatin) is safe in patients with advanced/metastatic colorectal cancer. p=0.0 observed in patients treated with standard chemotherapy alone. Proteinuria was infrequent (Giantonio et al. Patients (n=925) with untreated.7% (n=70). respectively.005). 37% of patients in the 5-mg/kg arm were alive at 18-months. irinotecan 100 mg/m(2). along with small sample size and chance for the more effective outcome seen with the lower dose bevacizumab (Kabbinavar et al. sex. proteinuria (0. and 13. b) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5.8 months).2 months). All doses of bevacizumab were 5 mg/kilogram IV every two weeks.0014). respectively.fluorouracil (5-FU)/leucovorin (LV) (IFL) therapy resulted in increased survival. Grade 3/4 toxicities included. 5-FU 400 mg/m(2). p=0.217).e.1 months. hypertension (10. Time to progression was similar regardless of IFL regimen used (full IFL group 12. time to progression.8%).1 months. 7. imbalances in randomization (i. response rate (44. metastatic colorectal cancer were randomized to bolus IFL/bevacizumab (n=403).25/10/12 Drug details . 2003).5% of patients respectively (Hurwitz et al.5%). bolus IV 5-FU 500 mg/m(2).2 months (95% CI 3.9. 2004). and LV 20 mg/m(2) repeated every 4 to 6 weeks. LV 500 mg/m(2) repeated every 6 to 8 weeks.5 to 5. pulmonary embolism. and duration of response as compared to bolus IFL alone. bolus IFL/placebo) were as follows: survival (20. The IFL regimen consisted of intravenous (IV) irinotecan 125 milligrams/square meter (mg/m(2)). and gastrointestinal perforation (1.0029). Grade 3/4 adverse events potentially related to bevacizumab included bleeding (3. bolus IV 5-FU 500 mg/m(2).MICROMEDEX® 2.3% and 48. Primary endpoints of the study (response rate. febrile neutropenia. The remaining patients enrolled into the study received REDUCED dose IFL.2 months (95% CI 3.3%.3 vs. neutropenia. p= 0. 6. thromboembolism and hypertensions. or 5-FU/LV/bevacizumab (n=110).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.4 vs.6 months).6). diarrhea. Toxicity data (n=83) showed no statistical difference between grade 3 or 4 toxicities based on the starting dose of IFL (p value not reported). c) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL (bolus irinotecan/5-fluorouracil (5-FU)/leucovorin (LV)) was safe and efficacious in patients with untreated metastatic colorectal cancer.5. Thrombotic events such as deep vein thrombosis. Median survival was 21.9% vs. respectively.9%). and 5. progression-free survival.FU/LV regimen consisted of bolus IV 5-FU 500 mg/m(2). progression-free survival (10. Overall (OR) response rate (based on Response Evaluation Criteria In Solid Tumors (RECIST)) was 45.8 months. 4%. Patients (n=20) received intravenous (IV) bevacizumab 10 milligrams/kilogram every other week.8 to 9. 15. 1. bleeding events. 2003). and duration of response (10. 16.8 to 10. p= 0. and LV 20 mg/m(2) weekly for 4 of 6 weeks. the 5.1. and overall survival) have not yet been determined but are anticipated since the results of a recent study thomsonhc.1%). and myocardial infarction occurred in 9%. Times to disease progression in these three groups were 9 months (95% CI 5. and baseline serum albumin) in this study was a limitation and may be a possible explanation. reduced IFL group 10. The OR obtained in the full and reduced IFL dose groups was 33. and LV 20 mg/m(2).7%.2. irinotecan 125 mg/square meter (mg/m(2)) IV. ECOG performance status. 7.6 vs. Results reported for the primary comparison group (bolus IFL/bevacizumab vs. response rate. bolus IFL/placebo (n=412).

95% CI. 92%. Following the enrollment of 600 patients.17. 33%). 95% CI.001) compared with patients with hormone receptor-negative tumors who received standard therapy. 1. 2.09. 1. Capecitabine Breast cancer. respectively. Standard adjuvant chemotherapy consisted of 4 cycles of AC with cyclophosphamide 600 mg/m(2) intravenously (IV) and doxorubicin 60 mg/m(2) IV given on day 1 every 21 days (n=184) or 6 cycles of CMF with cyclophosphamide 100 mg/m(2)/day orally days 1 to 14 and methotrexate 40 mg/m(2) IV and fluorouracil 600 mg/m(2) IV on days 1 and 8 every 28 days (n=133). Women 65 years (yr) of age or older with operable.7.9 to 6. D'Orazio & Lee.08. and 62% of patients treated with capecitabine.MICROMEDEX® 2. p less than 0.4 yr. At the time of this preplanned interim analysis. 95% confidence interval (CI).001) and overall survival (OS) (HR.76. Adjuvant therapy with capecitabine consisted of 6 cycles of 2000 milligrams/square meter (mg/m(2))/day in 2 divided doses for 14 days every 3 weeks. hormone receptor-negative tumors.23 to 6. 2003). p less than 0. regimen repeated every 2 weeks) were increased bleeding and hypertension. At a median follow-up of 2.02) with capecitabine compared with standard therapy were confirmed. resulting in a hazard ratio (HR) for disease recurrence (standard chemotherapy compared with capecitabine) of 0. 3. 1. After chemotherapy. In multivariate analyses. AC.39. serious bleeding seen in 3% of the bevacizumab patients and none of the FOLFOX patients (Benson et al. p less than 0. 60 patients (20%) in the capecitabine arm and 35 patients (11%) in the standard chemotherapy arm experienced a relapse. Unplanned post hoc analyses demonstrated that patients with hormone receptor-negative tumors who received capecitabine had significantly worse RFS (HR. it appears that the toxicities associated with the addition of bevacizumab to FOLFOX (10 milligrams (mg)/kilogram intravenously (IV) every two weeks plus oxaliplatin 85 mg/square meter (m(2)) IV on day 1/leucovorin 200 mg/m(2) IV and 5-FU 400 mg/m(2) IV followed by 5-FU 600 mg/m(2) IV infused continuously over 22 hours on days 1 and 2.11 to 3.0 (bevacizumab plus IFL) indicate a improvement in survival (20 months) equal to FOLFOX alone. 2. distant metastases. Adjuvant therapy. and CMF. the futility of capecitabine therapy was determined using a Bayesian predictive probability method and the trial was closed. patients with hormone receptorpositive tumors could receive tamoxifen or an aromatase inhibitor.85. noninferiority for relapse-free survival (RFS) was not established between single-agent capecitabine and standard therapy with cyclophosphamide and doxorubicin (AC) or cyclophosphamide. 24 patients in the capecitabine arm and 16 patients in the standard chemotherapy arm had experienced disease recurrence.38 to 3. 32%) or standard chemotherapy (n=326.8046 was 96% which was greater than the limit of 80% predicting futility).25/10/12 Drug details . All scheduled cycles of chemotherapy were received by 80%. p=0. 95% CI.001) and OS (HR. Additionally. hormone receptor-negative tumors.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.53 (probability of HR less than 0. or death from any cause. In abstract form. 2003. and fluorouracil (CMF) as adjuvant therapy in elderly patients with early stage breast cancer. stage I to IIIB breast cancer and a tumor diameter greater than 1 centimeter were randomized to treatment with oral capecitabine (n=307. 2. 18 of 38 deaths (47%) in the capecitabine arm and 8 or 24 deaths (33%) in the standard chemotherapy arm were attributed to breast cancer. One or more serious (grade 3 or higher) hematologic adverse events (AE) occurred less frequently with capecitabine (2%) compared with standard thomsonhc. methotrexate. 4.IntermediateToDocumentPrintLink 138/317 . in women 65 years of age or older a) In a randomized trial (n=633).34. significantly worse RFS (HR.

24%.9 to 7.001). who were chemotherapy-naive other than neoadjuvant induction.03. Gastric cancer.9 mo) and 5 mo (95% CI. randomized. age 56 yr. 95% CI. primary endpoint) of 5. thus meeting the prespecified noninferior margin and revealing statistically significant noninferiority (p less than 0. 4. Adults with advanced gastric cancer.25. Additionally. First-line therapy for advanced or metastatic disease. unadjusted HR. thus demonstrating robustness.02) and mean time to response (3. 1.7 mo vs 3. objective response rate (46% versus (vs) 32%. the XP regimen was noninferior to the FP regimen for overall survival (10. epirubicin 90 to 100 mg/m(2). 4. placebo-controlled. CMF. median age 56 years (yr). in the international.35. yielding a unadjusted PFS hazard ratio (HR) of 0. phase 3 trial (n=316).8 to 6. 0. p=0. 0.8 mo. and CMF.or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative.11 to 2. multicenter. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237).3 mo) for the XP group (n=139) compared with 5 mo (95% CI. 0.63 to 1. 4. 26 to 74 yr)) or 5-fluorouracil 800 mg/m(2)/day continuous infusion on days 1 to 5 every 3 weeks (FP: n=156.64 to 1. respectively. and 40% of patients who received capecitabine. 1.3 mo.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane. grade 3/4 adverse events were neutropenia (16% vs 19%).85.94. or toxicity. odds ratio. randomized.6 mo (95% CI. The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle).5 mo vs 9.25/10/12 Drug details . AC. 0.3 mo) for the FP group (n=137).81 (95% CI. no radiotherapy to target lesions. range. and 139/317 .13.0 therapy (AC. the median PFS was 5. Metastatic breast cancer. unadjusted HR.001). p less than 0.8.6 months (mo) (95% CI.008).2 to 6. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. multicenter.63 to 1. yielding an unadjusted PFS hazard ratio (HR) of 0. 52%) and one or more serious nonhematologic AE occurred in 33%. p=0. 54%. respectively [470]. in combination with chemotherapeutic agents a) First-line therapy with combination capecitabine/cisplatin was significantly noninferior to 5-fluorouracil/cisplatin for the treatment of advanced gastric cancer in an international. Noninferiority of XP to FP was declared if the upper limit of the 95% confidence interval (CI) for the hazard ratio for PFS was less than 1. or an anthracycline-based regimen (fluorouracil 500 mg/m(2). Analysis of the per protocol population revealed a median progression-free survival (PFS. lack of benefit.8 (95% CI. open-label. respectively in the intent-totreat population. HER2-negative. 1.015).9 to 5. vomiting (7% vs 8%) and stomatitis (2% vs 6%) in the XP vs FP groups. Treatment-related death occurred in 2 patients in the capecitabine arm and in no patients in the standard therapy arm [412]. The most common treatment-related.61 to 2. Similarly. as first-line therapy in combination with capecitabine or taxane.04). a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). and a Karnofsky performance status of 70 or greater were randomized to receive cisplatin 80 milligrams/square meter (mg/m(2)) intravenous (IV) infusion over 2 hours on day 1 with hyperhydration plus either capecitabine 1000 mg/m(2) twice daily on days 1 to 14 every 3 weeks (XP: n=160. 22 to 73 yr) until disease progression. 3. p=0. 95% CI.7 mo) in the XP and FP groups.MICROMEDEX® 2. The results for the adjusted analyses were consistent with the results for the unadjusted analyses. range.

0%.3 months.001).5%. 5%) [413]. respectively). respectively).1 to 9.8% and 2. median duration of response (9.or anthracycline-based regimen plus placebo (8. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks. 0%. but the majority of patients received additional systemic treatment that might have affected OS.3 (95% CI. 1%. respectively).7%) vs 37. proteinuria and febrile neutropenia. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9.9% to 56.64. 35.7 months) vs 7.2 months (95% CI.8% was achieved in patients with advanced or metastatic colorectal cancer who received capecitabine compared to a response rate of 11. range. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo. median age.5 months.2% to 40.8 months)).3%).7% vs 45. 28 to 91 years) compared with 5. 5.52 to 0. p=0. 28 to 88 years) compared with 8 months with a taxane. range 29 to 85 years.84.7 months.2 to 8.56 to 0.6%) vs 23.7%. 2%). HR. Among patients with measurable disease at baseline.2 to 10. p=0.2%.9%. 95% CI. fluorouracil 500 mg/m(2). the taxane arm (57. After a median follow-up of 15. 0%. 0. 0% and 2. median PFS (primary outcome) was 8. hazard ratio (HR).cyclophosphamide 500 mg/m(2) IV every 3 weeks.6% (95% CI. There were no significant differences between the capecitabine group and the 5-FU/LV group in overall survival (12. 30.2 (95% CI. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.4% and 3. 55 years. 0%).5 to 10.0054).6% to 30.4% (95% CI. 45. 51. 8. Hypertension. 95% confidence interval. median age.1 months (95% CI.9%. range. 55 years.3 months)) and with a taxane.or anthracycline-based regimen plus bevacizumab compared with a taxane. 30.4 months) vs 7.1 months and 9.or anthracycline-based regimen plus bevacizumab (n=415. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10.1%.5 months and 13. range 23 to 88 years.9% (95% CI.3 months and 4. p less than 0.6 months. 8. 57 years.0001) in a randomized phase III trial (n=605). median PFS was 9.0097) and with a taxane.2% vs 38.7 months with capecitabine plus placebo (n=206.001). 2%. Patients with advanced or metastatic colorectal cancer who had not received prior chemotherapy for metastatic disease were randomized to receive capecitabine orally (1250 milligrams/square meter (mg/m(2)) twice daily for 14 days .6% in patients who received fluorouracil and leucovorin (5-FU/LV) (p=0.3% (95% CI. p less than 0. the taxane arm (8.2 months with a taxane. and median time to disease progression (4. median age. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161. Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35.or anthracycline-based regimen plus placebo (n=207. doxorubicin 50 mg/m(2). 0. 3. 0%.2%).4% vs 21. Neoplasm of colon a) An overall response rate of 24. 0.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane.6 months with capecitabine plus bevacizumab (n=409.2 months.8. 17.9%). 0.or anthracycline-based regimen plus placebo (n=177. median age. 7.69. and the anthracycline arm (34. and the anthracycline arm (10. 56 years. 6.3% vs 15%). respectively.9%. With a median follow-up of 19.

median time to disease progression (5.9%) and hyperbilirubinemia (17. 25. nausea. There were significantly lower incidences of stomatitis. and alopecia occurred in the capecitabine group (p less than 0. neutropenia (2.4%). capecitabine therapy was shown to substantially reduce medical resource use and to improve response rate and tolerability compared to the Mayo Clinic Regimen of 5-fluorouracil (5-FU)/leucovorin (LV) in patients with advanced or metastatic colorectal cancer. 2001).00001). c) In a large multicenter prospective. stomatitis. 5. grade 3/4 stomatitis. and telephone thomsonhc.4%. median duration of response (7. daycare. and uncomplicated grade 3/4 hyperbilirubinemia (p less than 0. b) In another randomized phase III trial (n=602) comparing capecitabine to fluorouracil (5-FU) plus leucovorin in patients with advanced or metastatic colorectal cancer.6%. The authors conclude that capecitabine is an acceptable alternative for the treatment of advanced colorectal cancer based on its response rate.1 months). Chemotherapy-naive patients received either capecitabine 1250 milligrams/square meter (mg/m(2)) orally twice daily for 14 days followed by a 7-day rest period or a rapid intravenous (IV) injection of 20 mg/m(2) of leucovorin followed by an IV bolus of 5-FU 425 mg/m(2) on days 1 to 5 every 4 weeks. A significantly lower incidence of any grade of diarrhea.FU/LV group included diarrhea (15.5% of patients in the capecitabine group (usually hand-foot syndrome or diarrhea) and 49. Dose reduction for adverse reactions was required in 40. Treatment was continued for 30 weeks or until the development of progressive disease or unacceptable toxicity.9%) and improved safety compared to 5FU/LV. Capecitabine treatment resulted in superior response rates (26.7%). Capecitabine patients also required fewer hospital visits for drug administration. grade 3 hand-foot syndrome (p less than 0. favorable toxicity profile.008). every 4 weeks). patients receiving capecitabine needed more frequent unscheduled home.0%. Time to first onset of treatment-related grade 3/4 adverse reaction was significantly later in the capecitabine group (p=0.2 months versus 9.0 followed by a 7-day rest period) or 5-FU/LV (rapid intravenous (IV) injection of 20 mg/m(2) LV followed by an IV bolus of 425 mg/m(2) 5-FU on days 1 to 5 every 4 weeks).2 months versus 4.MICROMEDEX® 2.7%). However.0001) and significantly higher incidences of cutaneous hand.0001) with capecitabine compared with 5-FU/leucovorin.3% of patients in the 5-FU/LV group (usually stomatitis or diarrhea. grade 3/4 neutropenia and alopecia (p less than 0. 2001).00002). A comparison of grade 3/4 toxicity in the capecitabine group and 5. vomiting (3.7 months). an overall response rate of 19% was achieved with capecitabine compared to 15% with fluorouracil/leucovorin.foot syndrome.IntermediateToDocumentPrintLink 141/317 . However.2 months versus 12.0%).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.0 months).1%. No significant differences were seen between the capecitabine group and the 5-FU/leucovorin group in overall survival (13. and had reduced expenses for managing adverse events. hand-foot syndrome (18. a significantly greater incidence of hand-foot syndrome occurred in patients who received capecitabine.25/10/12 Drug details . 0. Oral capecitabine has at least equivalent efficacy compared with intravenous fluorouracil/leucovorin with clinically meaningful safety advantages (Cutsem et al.3%. and time to treatment failure (4.4 months). Patients (n=602) were randomized to receive either capecitabine (1250 mg/m2 orally twice daily for 2 weeks followed by 1 week rest) or 5 FU/LV (20 mg/m2 of LV as a rapid IV injection followed by 425 mg/m2 of 5-FU as an IV bolus given daily for 5 days.2 months versus 4.6% versus 17. stomatitis (3. randomized phase III clinical trial. 4.9%).6%. 13. or for the management of treatment related adverse effects. office. and the convenience of oral therapy (Hoff et al. 16.

median time to progression was not different between the standard.MICROMEDEX® 2. Carboplatin Breast cancer a) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high.0 consultations with physicians (Twelves et al. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414]. All randomized 142/317 . This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. respectively.6 months.and highdose/transplant therapy (38% and 32%. respectively. At 3 years.Drug details .and high-dose chemotherapy were administered according to the following schema: INDUCTION AND HIGH-D0SE (CONTINUOUS MAINTENANCE INFUSION) Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg. mg/m(2)=milligrams/square meter IV=intravenous PO=oral b) Four to six cycles of induction therapy were given every 28 days. Likewise. p=0. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). 2001). Standard. p=0. c) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not.dose/transplant groups (9 and 9. Subgroup analyses (estrogenreceptor status. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. Median follow-up was 37 months. A greater incidence of severe leukopenia. Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. overall survival in this intentionto-treat analysis was not significantly different between standard. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.31).dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone. EPIRUBICIN (120 mg/m(2). thrombocytopenia. Of 553 patients enrolled. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized. mucositis occurred at a similar rate for both groups [414].and high. and anemia was observed in the high-dose/transplant group.23).

0 patients received a fourth course of the up-front chemotherapy regimen. 1998). Toxicities were greater in the high-dose group but both groups experienced nausea. THIOTEPA 480 mg/m(2). 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide). In addition to that. 1998). phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN.MICROMEDEX® 2. vomiting. 2000). fatigue. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support. mucositis. vomiting.dose chemotherapy: 6000 mg/m(2) cyclophosphamide. All subjects underwent post-chemotherapy radiation and tamoxifen therapy. p=NS) favored group 1 over group 2.01) but not overall survival (83% versus 77%. CYCLOPHOSPHAMIDE. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. inoperable breast cancer (Eisen et al. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. diarrhea. alopecia. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. e) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer.143/317 and . All randomized patients received a fourth course of the up-front chemotherapy regimen. EPIRUBICIN (120 mg/m(2). Cisplatin Breast cancer a) A randomized. alopecia. and FLUOROURACIL (5-FU) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion. 1998). Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. radiation therapy and 2 years of TAMOXIFEN therapy. then high. respectively. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). THIOTEPA 480 mg/m(2). and neutropenia. A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al. diarrhea. fatigue. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. d) Following breast cancer surgery. p=0. The estimated 3-year relapse-free survival rate (72% versus 63%. Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0. mucositis. Toxicities were greater in the high-dose group but both groups experienced nausea.0001). with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support. a tailored FEC (fluorouracil (5-FU). those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. and neutropenia. 600 mg/m(2) cyclophosphamide). Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. In addition to that. epirubicin. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. 60 mg/m(2) epirubicin. phlebitis. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al.25/10/12 Drug details . phlebitis. radiation therapy and 2 years of TAMOXIFEN therapy.

Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. inoperable breast cancer (Eisen et al. Stomatitis. CYCLOPHOSPHAMIDE. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. Cisplatin 50 milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation on days 1 and 29. and 33. 30. Patients randomized to oral hydroxyurea received 80 thomsonhc.MICROMEDEX® 2. constipation. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. c) A randomized. By 2 to 1 randomization. ECycloF offers a regimen with comparable efficacy. inoperable breast cancer (Eisen et al. the combination of 5-fluorouracil (5-FU) and cisplatin was superior to hydroxyurea alone as an adjunct to radiation therapy. The overall response rate was 68% and 69% for the ECisF and ECycloF groups. 32. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. The overall response rate was 68% and 69% for the ECisF and ECycloF groups. and greater ease of administration than ECisF (Eisen et al. and thrombosis related to the Hickman catheter occurred more frequently in the ECisF than ECycloF group. 1998). lethargy. By 2 to 1 randomization. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. ECycloF offers a regimen with comparable efficacy. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease.IntermediateToDocumentPrintLink 144/317 . ECycloF offers a regimen with comparable efficacy. epirubicin 60 mg/m(2) every 3 weeks. 1998). The overall survival for ECisF was 10 months compared to 13 months for ECycloF.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. fewer toxicities. fewer toxicities. By 2 to 1 randomization. 1998). Six cycles were planned. while 5-FU was dosed at 1 gram/m(2)/day on days 2. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. lethargy. 5. and greater ease of administration than ECisF. Six cycles were planned. Stomatitis.25/10/12 Drug details . and epirubicin 60 mg/m(2) every 3 weeks. respectively. constipation. CYCLOPHOSPHAMIDE. plantar-palmar syndrome. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. 31. b) A randomized. and thrombosis related to the Hickman catheter occurred more frequently in the ECisF group. plantar-palmar syndrome. The overall survival for ECisF was 10 months compared to 13 months for ECycloF.0 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. fewer toxicities. Six cycles were planned. epirubicin 60 mg/m(2) every 3 weeks. The overall survival for ECisF was 10 months compared to 13 months for ECycloF. plantar-palmar syndrome. Stomatitis. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. lethargy. and greater ease of administration than ECisF Cervical cancer a) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA cervical carcinoma. The overall response rate were 68% and 69% for the ECisF and ECycloF groups. and thrombosis (related to the Hickman catheter) occurred more frequently in the ECisF than ECycloF group. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. respectively. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. constipation. respectively. 4. 3.

The control group received only radiation (85 Gy). Corresponding overall mortality rates were 45% and 57% (p=0. the second study group.25/10/12 Drug details . b) The combination of CISPLATIN and RADIATION therapy or CISPLATIN. multicenter.018). both favoring the 5. There were no treatment-related deaths (Rose et al. open-label. There was no difference in survival between the 2 groups with stage III or IVA disease. again the study group showed better survival (77%) compared to radiation only (58%). III or IVB cancer of the cervix. 64%. Grade 3/4 leukopenia was double the rate in the 3-drug group compared to the other 2 groups. and the control group were 66%. When stratified according to stage IB. The occurrence of grade 3/4 toxicities was greatest in the 3-drug regimen.62 to 0. FLUOROURACIL. PHASE III trial. A total of 388 women were evaluated having STAGE IIB through IVA cancer of the cervix and followed for a median of 43 months.004). or IIB.MICROMEDEX® 2.47) were significantly lower in the study group compared to the radiation-only group (33% and 35% respectively). Relative risks for progression/death and mortality were 0.00001) (Whitney et al.39) locoregional recurrence (19%. relative risk=0. controlled trial. The control group was administered only hydroxyurea 3 grams/square meter orally twice weekly before radiation therapy on weeks 1 through 6. respectively. 1999). The median follow-up was 35 months. The median duration of therapy in both groups was 9 weeks. Progression-free survival relative risk was 0. There were 3 arms in this large (n=526). The first study group received cisplatin 40 milligrams/square meter (mg/m(2)) over 4 hours before radiotherapy at weeks 1 through 6. IIA.FU/cisplatin regimen. 0. the rates of disease progression were 43% and 53% in the 5-FU/cisplatin and hydroxyurea groups. The second study group received cisplatin 50 mg/m(2) on days 1 and 29.7 years.IntermediateToDocumentPrintLink 145/317 . The only statistically significant difference in toxicity was more frequent/severe neutropenia with hydroxyurea (p less than 0.95).79 (90% confidence interval. but was similar in the other 2 groups. randomized. controlled. Disease-free survival at 5 years was also better in the study group (67%) compared to radiation alone (40%).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.57 and 0. fluorouracil 4 grams/square meter as a 96 hour infusion on days 1 and 29. Chemotherapy was given every 3 weeks for a total of 3 cycles. HYDROXYUREA. 67%. The rates of progression-free survival at 24 months for the first and second study group and the control group were 67%.58 to 0. and 49. and hydroxyurea 2 grams/square meter orally twice a week before radiation therapy at weeks 1 through 6. patients receiving CISPLATIN and FLUOROURACIL with RADIATION therapy had significantly better survival (73%) versus patients receiving radiation alone (58%) in the treatment of cervical cancer (p=0. c) In a large. relative risk=0.0 milligrams/kilogram/day twice weekly. Grade 3 and 4 toxicities occurred more frequently with combined therapy but were usually self-limited. multicenter. and 47% respectively.74 (90% CI. The study group was administered cisplatin 75 milligrams/square meter (mg/m(2)) infused over 4 hours followed by fluorouracil 4000 mg/m(2) infused over 96 hours plus a total of 85 Gy radiation.99) and 0. 1999). All groups received radiation at varying doses depending on stage of disease. respectively. Actual survival rates among the first study group.55 for the first and second study groups respectively when compared to the control group. randomized. Hematologic effects were generally moderate thomsonhc. After a median follow-up of 8. and RADIATION therapy produced significantly better survival than a control group receiving hydroxyurea and radiation for the treatment of STAGE IIB. This was also true for the other hematologic effects.7% respectively. Rates of distant relapse and (14%. 0.

IntermediateToDocumentPrintLink 146/317 .9 and 17. Corresponding 1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ statistically. and twice-daily radiation on days 1 through 5. Of the subset (n=14) who attained complete histologic response to the preoperative regimen. tolerable toxicity.9 and 17. respectively (p=NS). cisplatin. The ECF regimen consisted of intravenous (IV) epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) every 3 weeks for up to 8 cycles and a continuous infusion of fluorouracil 200 mg/m(2)/day via a thomsonhc. respectively (median survival: 49. Significant negative independent prognostic factors included tumor size greater than 5 centimeters.0 (Morris et al. 86% and 64% were alive at 1 year and 3 years.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 2001). Of the subset (n=14) who attained complete histologic response to the preoperative regimen. squamous cell histology and age over 70 years. Chemoradiation consisted of CISPLATIN 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5 and days 17 through 21. respectively (p=NS). VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17 through 20. doxorubicin. All patients (n=219) entered into the trial had inoperable adenocarcinoma or undifferentiated carcinoma of the esophagus or stomach. On day 42. b) The addition of a preoperative chemoradiation regimen offered no statistical survival advantage over surgery alone in a randomized trial of 100 patients with previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma (n=25) of the esophagus. and twice-daily radiation on days 1 through 5. and methotrexate (FAMTX regimen).7 months) (Urba et al. The median survival in the preoperative chemoradiation and surgery-only groups were 16. 8 through 12 and 15 through 19 for a total dose of 45 Gy.25/10/12 Drug details .6 months. 8 through 12 and 15 through 19 for a total dose of 45 Gy. Forty-five patients in each arm obtained complete surgical resection of the carcinoma. 2001). Corresponding 1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ statistically. respectively (median survival: 49. VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17 through 20. Esophagogastric cancer a) Combination therapy with epirubicin. Forty-five patients in each arm obtained complete surgical resection of the carcinoma. and fluorouracil (ECF regimen) resulted in longer survival. FLUOROURACIL 300 mg/m(2)/day as a continuous infusion on days 1 through 21. FLUOROURACIL 300 mg/m(2)/day as a continuous infusion on days 1 through 21.6 months. subjects underwent transhiatal esophagectomy. 1999). Esophageal cancer a) The addition of a preoperative chemoradiation regimen offered no statistical survival advantage over surgery alone in a randomized trial of 100 patients with previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma (n=25) of the esophagus.7 months) (Urba et al. The median survival in the preoperative chemoradiation and surgery-only groups were 16.MICROMEDEX® 2. 86% and 64% were alive at 1 year and 3 years. Significant negative independent prognostic factors included tumor size greater than 5 centimeters. subjects underwent transhiatal esophagectomy. squamous cell histology and age over 70 years. Chemoradiation consisted of CISPLATIN 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5 and days 17 through 21. This trial was powered to detect only large overall survival differences. and a better quality of life compared to fluorouracil. On day 42. This trial was powered to detect only large overall survival differences.

median overall survival (OS).7 months) among the 3 groups.106).MICROMEDEX® 2.6 months. and 5fluorouracil (5-FU) combination therapy. 53 years) who had not received chemotherapy and had an Eastern Cooperative Oncology Group performance status of 2 or less were randomized to 1 of 3 groups: docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1 with 5-FU 750 mg/m(2) daily for 5 days every 3 weeks (DCF. n=40). and CF groups received a median of 6. and 18% (p=0. 38% receiving ECF.1 months. Leucovorin rescue 30 mg every 6 hours for 48 hours was started 24 hours after methotrexate. Median survival time was significantly (p=0. The DCF. Advanced a) CISPLATIN 100 mg/m(2) plus FLUOROURACIL 1 gram/m(2) may be superior to SINGLE AGENT FLUOROURACIL or CISPLATIN in patients with advanced HEAD AND NECK CANCER (Jacobs et al. 10. The FAMTX regimen consisted of IV methotrexate 1500 mg/m(2) followed by IV fluorouracil 1500 mg/m(2) on day 1. and 18%. 4. n=36). Patients (median age. Doxorubicin 30 mg/m(2) was administered IV on day 15. 1992).IntermediateToDocumentPrintLink a monthly low-dose leucovorin and 147/317 . Objective response rates in the DCF. the ECF regimen resulted in more alopecia and central venous line complications. ECF.4 months. and hematologic toxicity resulting in infections occurred significantly more often in patients treated with the FAMTX regimen.7 months) [416]. epirubicin 50 mg/m(2) and cisplatin 60 mg/(m2) every 3 weeks plus 5-FU 250 mg/m(2) daily (ECF. nephrotoxicity. the ECF regimen should be offered to all patients with advanced esophagogastric cancer who have an acceptable performance status.8 months.0 portable infusion pump for up to 6 months. cisplatin. Mucositis. However. no complete responses occurred and there was no significant difference in median survival (5.25/10/12 Drug details . The overall response rate with the combination therapy (32%) was superior to that of either single agent cisplatin (17%) or fluorouracil (13%). were 40%. Objective responses including complete and partial responses occurred in 45% (p=0.or 2-year survival rates when docetaxel. 1-year survival was 41%. Two hundred forty-nine patients were randomly assigned to either cisplatin (n=84). complete response plus partial response). Metastatic colorectal cancer a) Bimonthly high-dose leucovorin and bolus fluorouracil plus continuous infusion fluorouracil was more effective and less toxic than thomsonhc. and 5 cycles of chemotherapy. Cycles were repeated every 28 days up to a maximum of 24 weeks. PFS was 5. respectively.054).127). and 5-FU combination therapy. n=40). whereas.0009) longer with ECF (8.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 9 patients underwent complete resections versus 4 patients treated with the FAMTX regimen. cisplatin. and cisplatin/5-FU therapy were compared in patients with advanced stage gastric carcinoma.0002) of patients treated with the ECF regimen compared to 21% of patients treated with the FAMTX regimen. 9%. With the ECF regimen. and 7. 40%. epirubicin.9 months) compared to FAMTX (5. or 1. progression free survival (PFS). or cisplatin 100 mg/m(2)/d on Day 1 with 5-FU 1000 mg/m(2) daily for 5 days every 4 weeks (CF. and 4.3 months (p=0. median OS was 9.4 months (p=0. Head and neck cancer. 5. 30%. and 3%. The DCF group had significantly more cases of neutropenia and neuropathy compared to ECF or CF. Based on this trial. and CF groups. and 2-year survival was 27%. and 39% receiving CF [441]. ECF. Gastric cancer a) There was no statistically significant difference in objective response rate (ORR. fluorouracil (n=84) or cisplatin plus fluorouracil (n=81) for 3 weeks. and dose reductions were required in 50% of patients receiving DCF.

Repeat course at 3. Repeat course at 4. lonidamine.and 5. 9 months). cisplatin 30 mg/m(2) on days 2 and 4. b) In a randomized trial of patients (n=429) with metastatic colorectal cancer. hrs = hours. then every 5 weeks OR Leucovorin 20 mg/m(2)/day IV bolus immediately followed by Fluorouracil 370 mg/m(2)/day IV bolus. CIV = continuous intravenous infusions.2% and 21. Neoplasm of gastrointestinal tract a) In a phase II study (n=65). 8 weeks. then every 5 weeks mg/m(2) = milligrams/square meter.fluorouracil was more effective and less toxic than a monthly low-dose leucovorin and bolus fluorouracil regimen in patients (n=448) with previously untreated metastatic colorectal cancer [425]. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. both administered by intravenous bolus injection. etoposide 100 mg/m(2) on days 1. All repeated days 1 through 5. Neither regimen produced a complete response. Both regimens were repeated every 4 weeks (Barone et al.05) superiority in quality of life. median survival was similar for 5-FU/6S-LV5 (fluorouracil and leucovorin. Repeat cycle every 28 days OR Leucovorin 200 mg/m(2)/day IV bolus followed by Fluorouracil 370 mg/m(2)/day IV bolus.3. Leucovorin 14 mg/m(2) orally every 6 hrs for 8 doses (begin 24 hrs after the start of the methotrexate infusion). the combination of fluorouracil and leucovorin demonstrated a therapeutic advantage (improved tumor response rates and survival) over fluorouracil alone. The following 6 regimens were compared [426]: Fluorouracil 500 mg/m(2)/day IV bolus Days 1 through 5. 8 months) and EEP-L (epirubicin.9% of patients treated with 5FU/6S-LV and EEP-L. partial responses were achieved in 28. Treatment was well tolerated with no treatment-related deaths. 6 weeks and then every 4 weeks OR Methotrexate 40 mg/m(2) IV on days 1 and 8. partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1. respectively. IV = intravenous. Repeat course every 5 weeks OR Methotrexate 200 mg/m(2) IV over 4 hours. etoposide. 1998). The 5-FU/6S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU 370 mg/m(2) daily on days 1 to 5. In both groups. Repeat course at 4. All repeated days 1 through 5. . cisplatin. Only low-dose leucovorin plus fluorouracil was associated with a significant (p less than 0. Fluorouracil 700 mg/m(2) IV bolus 24 hrs after each dose of methotrexate. weight gain. performance status. 8 weeks. and symptomatic relief. and lonidamine 50 mg orally 3 times daily. Repeat course every 5 weeks OR Fluorouracil 325 mg/m(2)/day IV bolus. Cisplatin 20 mg/m(2)/day over 2 hours. continuously. All repeated days 1 through 5. Fluorouracil 900 mg/m(2) bolus IV (7 hrs after the beginning of methotrexate). however.

Five year OS was 53% and 51% in the CEF and EC groups. and FLUOROURACIL (CEF) in women with locally advanced breast cancer. 382 patients had local therapy. Ovarian cancer a) Cyclophosphamide plus hexamethylmelamine.6 months in Hexa-CAF-treated patients [417]. cycled every 28 days. CHAP-5 treatment resulted in more complete remissions. Three patients in the FAMTX experienced complete remissions. The dose intensified EC group (n=224) received epirubicin (120 mg per square meter (mg/m(2))) intravenously (IV) on day 1. A subgroup analysis compared PFS and OS in patients with locally advanced and inflammatory breast cancer. FAMTX. Following chemotherapy. Overall survival duration was 30. EPIRUBICIN. Eligible patients had no evidence of metastasis and no prior treatment for breast cancer.5% for the CEF and EC groups. The median survival in the 2 groups were similar (EAP. and fluorouracil (500 mg/m(2)) IV days 1 and 8. respectively. Patients (n=448) were randomly assigned to receive dose intensified EC plus granulocyte colony-stimulating factor (G-CSF) or standard schedule CEF. Colony Stimulating Factor Breast cancer a) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens demonstrated that dose intensified EPIRUBICIN and CYCLOPHOSPHAMIDE (EC) did not provide improved progression-free survival (PFS). cyclophosphamide. respectively. There were no significant differences in the incidence of grade 3 to 4 toxicity between the CEF and EC groups. fluorouracil 1. cyclophosphamide (830 mg/m(2)) IV on day 1.3 months) [424].3% and 26.b) The FAMTX regimen (methotrexate 1. and 5-fluorouracil (HexaCAF) in the treatment of advanced ovarian carcinoma. 59 had radiotherapy alone. Sixty patients with advanced gastric cancer were randomly assigned to the EAP or FAMTX regimen. With a median follow up of 5. or response rate compared to a standard delivery schedule of CYCLOPHOSPHAMIDE.5 months (p=0.1 months. and G-CSF (5 micrograms per kilogram per day (mcg/kg/day)) subcutaneously (SC) days 2 through 13. methotrexate.7 months in CHAP-5-treated patients and 19. and 34 had radiotherapy then surgery. every 14 days for 6 cycles. but none occurred in the EAP group. Complete clinical response (CR) rates were 31. epirubicin (60 mg/m(2)) IV days 1 and 8. 46 patients had a significant drop in left ventricular ejection fraction (19 . median PFS was 34 months and 33. median PFS was 44 months and 23. and doxorubicin 30 milligrams/m(2) produced comparable results to the EAP regimen with much less toxicity in one study. Objective responses were observed in 20% of the patients in the EAP group and 30% in the FAMTX group. respectively. 7. better overall response and longer survival.0019) and OS was 59% and 44% (p=0. 94 had surgery alone.5 years.5 grams/square meter (g/m(2)).0043) for the locally advanced (n=242) and inflammatory (n=206) subgroups. alternating with doxorubicin and a 5day course of cisplatin (CHAP-5). was reported more effective than the combination of hexamethylmelamine. 6.5 g/m(2). Complete remission occurred in 40% of CHAP-5-treated patients as compared with 19% of HexaCAFtreated patients. overall survival (OS). The CEF group (n=224) received cyclophosphamide (75 mg/m(2)) orally day 1 through 14. respectively.7 months in the CEF and EC groups. all patients received prophylactic therapy with trimethoprim-sulfamethoxazole during treatment and tamoxifen (20 milligrams (mg) per day) following chemotherapy until progression or for 5 years if no progression. 195 had surgery then radiotherapy.

c) In a phase III study of women with metastatic breast cancer (n=151). and fluorouracil 600 mg/m(2) intravenously (IV) on day 1. alopecia (88. and FLUOROURACIL (CEF) with GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) support and a standard CEF regimen showed no significant differences in overall response rate (51% versus 49%).dose chemotherapy: 6000 mg/m(2) cyclophosphamide. a comparison of an accelerated-intensified regimen of CYCLOPHOSPHAMIDE. EPIRUBICIN.01) but not overall survival (83% versus 77%. Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide).3% versus 1. 2001). mucositis (13. b) Following breast cancer surgery. or overall survival (27.3%). were reported in the CEF group (Therasse el al. 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion. 2000).7% versus 0%). A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al.2 versus 32. p=0.7 months). 60 mg/m(2) epirubicin. bone pain (6.3% versus 2. epirubicin 60 mg/m(2). and fluorouracil (CMF) when used in premenopausal. nausea/vomiting (14.0001).8%).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. methotrexate.8 versus 14. node-positive early localized breast thomsonhc. 1 due to congestive heart failure and 1 due to febrile neutropenia. 600 mg/m(2) cyclophosphamide). leukopenia (22. every 14 days.7% versus 2. epirubicin 80 mg/m(2).MICROMEDEX® 2. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support. and asthenia (6. cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer.IntermediateToDocumentPrintLink 150/317 . 2003). The HD-CEF14 regimen consisted of cyclophosphamide 1000 milligrams/square meter (mg/m(2)).6% versus 2. estrogen-receptor (ER) positive. Grade 3/4 toxicity in the HD-CEF14 arm compared with the CEF21 arm included anemia (18. Two toxic deaths. Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0.8%). thrombocytopenia (9. and fluorouracil 600 mg/m(2) IV on day 1.0 CEF. p=NS) favored group 1 over group 2.25/10/12 Drug details . 2 EC). a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support.4%).8%).3 months). G-CSF (lenograstim) 263 micrograms was self-administered subcutaneously on days 4 through 11 after each cycle of HD-CEF14. with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. The authors do not recommend the use of an accelerated-intensified regimen of CEF outside the setting of clinical trials (Del Mastro et al.8%). median time to disease progression (12. The CEF21 regimen consisted of cyclophosphamide 600 mg/m(2).0% versus 95.2%). respectively. every 21 days. epirubicin. The estimated 3-year relapse-free survival rate (72% versus 63%. then high. The complete response rate was slightly higher in the accelerated-intensified CEF regimen (HD-CEF14) compared with the standard CEF regimen (CEF21. Cyclophosphamide Breast cancer a) Goserelin was as effective and well-tolerated as the three-drug cytotoxic combination of cyclophosphamide.7% versus 15. 27 EC) that led to congestive heart failure in 4 patients (2 CEF.7% versus 4. 20% versus 15%) but toxicities were increased. All subjects underwent post-chemotherapy radiation and tamoxifen therapy. a tailored FEC (fluorouracil (5-FU).

and thrombosis related to the Hickman catheter occurred more frequently in the ECisF 151/317 .2 1. data analysis was performed after 684 events.0-1. M=40 mg/m(2) IV days 1 and 8.MICROMEDEX® 2.94 0. Side effect profiles (cytotoxic dominant or endocrinerelated) were reflective of the type of treatment received. constipation. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. 183 of 194 deaths due to breast cancer were recorded among goserelin patients. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks.14 b) From overall survival statistics. After local therapy (surgical with or without radiotherapy). and FLUOROURACIL (5-FU) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced.026 p 0.(n=304) 1. CYCLOPHOSPHAMIDE. Trial design anticipated 688 outcome events.0-1.3 ER. overall approximately 15% of either treatment group reported a serious adverse event.8 1. After adjusting for age. compared to 151 of 165 for CMS patients (overall death rates of 25% verus 20%). Disease-free (DFS) and overall survival (OS) were the primary outcomes. the following hazard ratios (HR).0 0.8 OVERALL SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1.0 0. 797 patients randomized to goserelin (3. By 2 to 1 randomization.6 milligrams (mg) depot subcutaneously every 28 days for 2 years) and 817 randomized to CMF (per cycle: C=500 mg per meter square IV on day 1 and 8 or 100 mg/m(2) orally days 1 through 14.8 1.(n=304) 1.2 1. and number of positive lymph nodes.1 p 0.67 0. as well as those with unknown status.614 premenopausal or perimenopausal women 50 years old or younger with node-positive stage II operable breast cancer without metastasis. The overall survival for ECisF was 10 months compared to 13 months for ECycloF.1-3. c) A randomized.8-1.4 ER unknown (n=121) 2. Stomatitis. tumor size.0 cancer.0043 0.0006 0.2-2. confidence intervals (CI) and statistical significance were calculated (HR ratios less than 1 favor goserelin) for the median follow up time of 6 years: DISEASE-FREE SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1.4 ER+ (n=1189) 1. but leading to treatment withdrawal in fewer than 2% (Jonat et al.6 ER unknown (n=121) 1.8-4.92 0. inoperable breast cancer (Eisen et al. Six cycles were planned.8 0.5 ER+ (n=1189) 1. CMF was preferred in ER-negative patients. 2002).2 ER. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease.3-2.029 0. 1998). lethargy. F 600 mg/m(2) IV days 1 and 8) for 6 28-day cycles became the primary efficacy population cohorts. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomized 1.8-1. The overall response rate was 68% and 69% for the ECisF and ECycloF groups. respectively. plantar-palmar syndrome.0 1. and epirubicin 60 mg/m(2) every 3 weeks. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion.Drug details .

1. A greater incidence of severe leukopenia.dose/transplant groups (9 and 9. At 3 years. PREDNISONE) produced statistically similar survival or disease-free survival rates. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%).or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. thrombocytopenia. Five-year survival was 57% and 62% in the 1and 2-year therapy groups.6 months. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414]. Subgroup analyses (estrogenreceptor status. 1998).3 years) and 445 ER-negative. respectively.6 years (maximum of 11.and highdose/transplant therapy (38% and 32%. Although.0 group.MICROMEDEX® 2. Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. This improvement should be weighed against the difficulty (ie. Standard. Median follow-up was 37 months.23). f) In one study. respectively.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. respectively. VINCRISTINE. median time to progression was not different between the standard. FLUOROURACIL.dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone. and greater ease of administration than ECisF (Eisen et al.31). and anemia was observed in the high-dose/transplant group. d) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high. overall survival in this intentionto-treat analysis was not significantly different between standard. p=0. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized. p=0. toxicity) of thomsonhc. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups.and high.and high-dose chemotherapy were administered according to the following schema: INDUCTION AND HIGH-D0SE (CONTINUOUS MAINTENANCE INFUSION) Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg.25/10/12 Drug details .IntermediateToDocumentPrintLink 152/317 . mg/m(2)=milligrams/square meter IV=intravenous PO=oral e) Four to six cycles of induction therapy were given every 28 days. not statistically different. mucositis occurred at a similar rate for both groups [414]. Median follow-up duration in this study was 8. Likewise. METHOTREXATE. Of 553 patients enrolled. ECycloF offers a regimen with comparable efficacy. node-positive breast cancer patients were enrolled. fewer toxicities.

were reported in the CEF group (Therasse el al. With a median follow up of 5. respectively. cycled every 28 days. a tailored FEC (fluorouracil (5-FU). vomiting. fatigue.7 months in the CEF and EC groups. h) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. In addition to that. overall survival (OS). those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. The dose intensified EC group (n=224) received epirubicin (120 mg per square meter (mg/m(2))) intravenously (IV) on day 1. EPIRUBICIN. 2003). and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. phlebitis. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. respectively. g) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens demonstrated that dose intensified EPIRUBICIN and CYCLOPHOSPHAMIDE (EC) did not provide improved progression-free survival (PFS).IntermediateToDocumentPrintLink 153/317 . 46 patients had a significant drop in left ventricular ejection fraction (19 CEF. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). diarrhea. 27 EC) that led to congestive heart failure in 4 patients (2 CEF. and fluorouracil (500 mg/m(2)) IV days 1 and 8. There were no significant differences in the incidence of grade 3 to 4 toxicity between the CEF and EC groups.3% and 26. respectively. Eligible patients had no evidence of metastasis and no prior treatment for breast cancer. EPIRUBICIN (120 mg/m(2). and FLUOROURACIL (CEF) in women with locally advanced breast cancer. All randomized patients received a fourth course of the up-front chemotherapy regimen.0019) and OS was 59% and 44% (p=0.5% for the CEF and EC groups.5 months (p=0.25/10/12 Drug details .0043) for the locally advanced (n=242) and inflammatory (n=206) subgroups. The CEF group (n=224) received cyclophosphamide (75 mg/m(2)) orally day 1 through 14. 1 due to congestive heart failure and 1 due to febrile neutropenia. and neutropenia. Patients (n=448) were randomly assigned to receive dose intensified EC plus granulocyte colony-stimulating factor (G-CSF) or standard schedule CEF. and 34 had radiotherapy then surgery. epirubicin (60 mg/m(2)) IV days 1 and 8. Following chemotherapy. Toxicities were greater in the high-dose group but both groups experienced nausea.5 years. Two toxic deaths. A subgroup analysis compared PFS and OS in patients with locally advanced and inflammatory breast cancer. Five year OS was 53% and 51% in the CEF and EC groups. 59 had radiotherapy alone. or response rate compared to a standard delivery schedule of CYCLOPHOSPHAMIDE. 382 patients had local therapy. mucositis. cyclophosphamide (830 mg/m(2)) IV on day 1. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. median PFS was 34 months and 33. epirubicin. and G-CSF (5 micrograms per kilogram per day (mcg/kg/day)) subcutaneously (SC) days 2 through 13. THIOTEPA 480 mg/m(2). respectively. all patients received prophylactic therapy with trimethoprim-sulfamethoxazole during treatment and tamoxifen (20 milligrams (mg) per day) following chemotherapy until progression or for 5 years if no progression. i) Following breast cancer surgery. 2 EC). 94 had surgery alone. thomsonhc. median PFS was 44 months and 23. Complete clinical response (CR) rates were 31. 1993). every 14 days for 6 cycles.0 administering 2 years of CMFVP therapy (Rivkin et al. 195 had surgery then radiotherapy.MICROMEDEX® 2. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. 1998). radiation therapy and 2 years of TAMOXIFEN therapy. alopecia.

6 in the FEC 50 group) which included 3 grade 2 conditions requiring treatment interruptions (2 in the FEC 100 group. epirubicin 50 mg/m(2).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.1%). p=NS) favored group 1 over group 2. with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. The estimated 3-year relapse-free survival rate (72% versus 63%. During chemotherapy. EPIRUBICIN. p=0. however the authors note that the difference in 5-year DFS and 5-year OS was significant only in patients with more than three positive nodes (Anon.0 cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer. k) Two doxorubicin-containing regimens were equally effective in the treatment of thomsonhc. Contralateral breast cancer developed in 21 patients (FEC 100.dose chemotherapy: 6000 mg/m(2) cyclophosphamide.3% for FEC 50 (p=0.03). n=14).01) but not overall survival (83% versus 77%.8%. FEC 50. Patients with operable breast cancer with either three positive nodes or between one and three positive nodes with Scarff Bloom Richardson (SBR) grade of 2 or greater and both estrogen and progesterone receptor negativity were enrolled. 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide).007). 0%). respectively. 2000). 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion. n=1). Patients were randomized to receive 6 cycles of FEC 100 (fluorouracil 500 mg/m(2). Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0. n=7. acute leukemia occurred in 2 patients (FEC 100.25/10/12 Drug details . A comparison of grade 3/4 toxicity in the FEC 100 group versus the FEC 50 group included neutropenia (25.MICROMEDEX® 2. A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al. 23.8% with FEC 50 (p=0. This study was not powered for a subset analysis. There were 10 cases of delayed cardiac toxicity (decrease in left ventricular ejection fraction or congestive heart failure and one myocardial infarction) in patients who had received regional radiation. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support. then high. All subjects underwent post-chemotherapy radiation and tamoxifen therapy. 2001). alopecia (78. Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. 60 mg/m(2) epirubicin. 0%).4% for FEC 100 and 65.0001). 5-year OS was 77.8%. FEC 50. anemia (0.7%. Five-year DFS was 66. Tamoxifen (30 mg/day) was prescribed to postmenopausal patients for 3 years starting with the first chemotherapy cycle. j) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were significantly increased in patients with breast cancer and axillary node involvement (n=565) who received ADJUVANT chemotherapy with FLUOROURACIL. epirubicin 100 mg/m(2).8%. n=7). FEC 50. n=7. Treatment was started within 42 days after initial surgery. stomatitis (3.3% with FEC 100 and 54.4%. and infection (3.2%.1%). 0%). and cyclophosphamide 500 mg/m(2) every 21 days) or 6 cycles of FEC 50 (fluorouracil 500 mg/m(2).3%). 1 in the FEC 50 group).IntermediateToDocumentPrintLink 154/317 . and cyclophosphamide 500 mg/m(2) every 21 days). 600 mg/m(2) cyclophosphamide). 20. nausea/vomiting (34. n=1. and CYCLOPHOSPHAMIDE (FEC) with an epirubicin dose of 100 milligrams/square meter (mg/m(2)) (FEC 100) compared to an epirubicin dose of 50 mg/m(2) (FEC 50). and 14 patients developed second malignancies (FEC 100. a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support. 13 cardiac abnormalities were diagnosed (7 in the FEC 100 group. 11.

there were nonsignificant trends toward better disease-free and overall survival rates in the highdose. respectively (p = NS). The FAC regimen consisted of 5fluorouracil (5-FU) 500 milligrams/square meter (mg/m(2)).positive breast cancer patients receiving either 6 cycles of conventional-dose ACMF or 12 cycles of low-dose ACMF (n=93.6 and 4. and decreased hemoglobin (p less than or equal to 0. neuropathy. 1999). A study was conducted in premenopausal.4 years. The overall survival demonstrated no significant difference between the 2 regimens at a median follow up of 4. However. METHOTREXATE. The subset of patients with liver metastases had significantly improved survival with NA as compared to FAC (p = 0. Although both treatment regimens were well tolerated overall.7 years versus 4.25/10/12 advanced breast cancer in a Phase III trial (n=177). and fluorouracil 500 mg/m(2). The overall response rates for FAC and NA were 74% and 75%.3 and 17. respectively. This randomized thomsonhc. p less than 0. doxorubicin 50 mg/m(2) and cyclophosphamide 500 mg/m(2).05).5 years) received CNF.04).5 years (mean survival time of 4. Alopecia occurred in significantly more patients receiving the CNF regimen compared with the CMF regimen (29% versus 17%. m) Escalating doses of ACMF (DOXORUBICIN. Disease-free survival was significantly lower for the CMF regimen compared with the CNF regimen (2. node. were superior to low-dose. The CNF regimen included cyclophosphamide 500 mg/m(2). All patients had undergone either modified radical mastectomy or lumpectomy with axillary lymph node dissection. and fluorouracil 600 mg/m(2).3 years) received CMF and 68 (average age 45. The NA regimen included doxorubicin (same dose and frequency) plus vinorelbine 25 mg/m(2) on days 1 and 8 of a 21-day cycle for a median of 4 cycles. respectively). The only significant differences in toxicity profiles were higher incidences of constipation. respectively (p = NS).001) were reported in significantly more patients treated with the CNF regimen compared with the CMF regimen.04).IntermediateToDocumentPrintLink 155/317 . respectively. and a higher incidence of cardiotoxicity with FAC (Blajman et al. MITOXANTRONE. mitoxantrone 12 mg/m(2).4 years for CMF and CNF regimens. methotrexate 40 mg/m(2). and FLUOROURACIL (CNF) demonstrated an improved disease-free survival compared with cyclophosphamide. prolonged therapy. 2001). l) In a multicenter phase III randomized study. The average dose intensity of doxorubicin was 90% with FAC and 83% with NA. Both chemotherapy regimens were administered every 21 days for 6 courses. six-cycle ACMF group (Fukutomi et al.001). more patients receiving the low-dose 12-cycle refused therapy. and fluorouracil (CMF) as adjuvant therapy for stage II lymph-node positive breast cancer. The CMF regimen included cyclophosphamide 600 milligrams/square meter (mg/m(2)). CYCLOPHOSPHAMIDE. 77 (average age 46. no patient required treatment discontinuation or dose reduction due to toxicity (Ron et al. n=97. n) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.01). Also. respectively. Relapse occurred in 14 and 30 patients treated with the CNF and CMF regimens. CYCLOPHOSPHAMIDE. even with doses within the conventional range. methotrexate. each given intravenously on day 1 of a 21-day cycle for a median duration of 5 cycles. Thrombocytopenia (p less than 0. p = 0. 5-FLUOROURACIL) over a shorter period. Corresponding median overall survival rates were 17. 1995).8 months. leukopenia (p less than or equal to 0. Of the 145 evaluable patients. respectively). phlebitis and cutaneous toxicity with NA.

Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.MICROMEDEX® 2. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.1%). 1998).3%). granulocytopenia (97.and 2-year therapy groups.7%. Median follow-up duration in this study was 8. 4. not statistically different.4%) (Levine et al. EPIRUBICIN (120 mg/m(2).4%.positive breast cancer patients were enrolled.1%). fatigue. Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13. node. METHOTREXATE. This was possibly due to a difference in acute toxicity between the 2 regimens. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. FLUOROURACIL. EPIRUBICIN.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%).9%. 78. toxicity) of administering 2 years of CMFVP therapy. For patients in the CMF group it was 78% and 58% respectively. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. radiation therapy and 2 years of TAMOXIFEN therapy. Toxicities were greater in the high-dose group but both groups experienced nausea. o) The combination regimen CEF (CYCLPHOSPHAMIDE. 1. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0. 60. phlebitis.2%).25/10/12 Drug details . VINCRISTINE.4%. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer.3 years) and 445 ERnegative. METHOTREXATE. stomatitis (12. In addition to that. methotrexate 40 mg/m(2) IV days 1 and 8. however. diarrhea. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter.7%). 3. 1993). p) In one study. Although. 6. leukopenia (94. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. PREDNISONE) produced statistically similar survival or disease-free survival rates (Rivkin et al. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). Greater toxicity was noted in patients receiving the CEF regimen. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. Both regimens were administered for 6 cycles. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. vomiting (11. thrombocytopenia (9. All randomized patients received a fourth course of the up-front chemotherapy regimen. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. alopecia (42. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. diarrhea (0.2%. the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. 2. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0.009). fluorouracil 600 mg/m(2) IV days 1 and 8). Five-year survival was 57% and 62% in the 1. alopecia. respectively.4%. mucositis. and neutropenia. This improvement should be weighed against the difficulty (ie.0 study analyzed 81 patients with extensive axillary lymph-node involvement.IntermediateToDocumentPrintLink 156/317 . 3. vomiting. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. THIOTEPA 480 mg/m(2). METHOTREXATE. 1998).7%).9%). EPIRUBICIN. q) The combination regimen CEF (CYCLOPHOSPHAMIDE.3%. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively. Women thomsonhc. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al.1%.03).6 years (maximum of 11.

2%). methotrexate. VINCRISTINE. Overall survival was 77% and 70% in the CEF and CMF groups. and fluorouracil prolonged time to progression.1%. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%. it was 78% and 58%. and PREDNISONE (CMFVP) produced similar survival/disease-free survival rates.6 years. 2. those with greater than or equal to 4 positive nodes were randomized to 1 of the CMF groups or regional radiotherapy followed by 6 cycles of CMF. CYCLOPHOSPHAMIDE. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. 1and 2-year therapy with CYCLOPHOSPHAMIDE.9%. Both regimens were well tolerated. Greater toxicity was noted in patients receiving the CEF regimen.7%). 78. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. METHOTREXATE.0 previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14. 4. the mean score in the CEF group decreased to a nadir more quickly then in the CMF group. node-positive breast cancer patients (n=190). stomatitis (12. respectively.4%. In another study. was nausea (13. 60.IntermediateToDocumentPrintLink 157/317 .4%. Comparison of grade 3/4 toxicities in the CEF and CMF groups. The 2-year therapy produced a moderate improvement in survival over the 1-year therapy (57% vs 62%). 1991). Patients received either 6 cycles of ACMF or 12 cycles of low-dose ACMF. Both regimens were administered for 6 cycles. thrombocytopenia (9. 1995). leukopenia (94. fluorouracil 600 mg/m(2) IV days 1 and 8). 1992). however. alopecia (42. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. t) In a study of 445 patients with node-positive. but the difficulty (ie.2%. FLUOROURACIL) in the treatment of breast cancer in 622 women with positive axillary nodes. s) Escalating doses of DOXORUBICIN.3%).7%. 1993).4%) (Levine et al. toxicity) of 2-year administration may outweigh the benefit (Rivkin et al. but more patients receiving the low-dose 12-cycle regimen refused therapy. METHOTREXATE. respectively) in a 20-year thomsonhc. n=207. 1998). Also. 3. patients were randomized to CMF for 6 or 12 cycles. respectively (p=0.1%) diarrhea (0. even with conventional doses. 6.MICROMEDEX® 2.9%).03).1%). No difference in survival or disease-free survival was found among the 3 groups at 10 years median follow-up. Median follow-up duration was 8.4%. respectively (p=0. FLUOROURACIL.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. METHOTREXATE. maintenance therapy with cyclophosphamide. u) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE. granulocytopenia (97. respectively. This was possibly due to a difference in acute toxicity between the 2 regimens. 3. 6-cycle ACMF group (Fukutomi et al.7%). METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone in node-positive breast cancer patients (n=179.009). Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group. prolonged therapy in premenopausal. For patients in the CMF group. vomiting (11. there were non-significant trends toward better disease-free and overall survival rates in the high-dose. methotrexate 40 mg/m(2) IV days 1 and 8. receptor-negative breast cancer.25/10/12 Drug details . but did not alter overall survival (Muss et al. The strongest predictors of survival were positive nodes (negative correlation) and ideal or full dose of CMF (positive correlation) (Velez-Garcia et al. were superior to low-dose.3%. 1. respectively. r) No advantage was achieved with 12 versus 6 cycles of CMF (CYCLOPHOSPHAMIDE. Following mastectomy. and FLUOROURACIL (ACMF) over a short period.

the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0.0001. The patients were randomly assigned to receive either the 16-week regimen or six cycles of CAF.25/10/12 Drug details . beginning 24 hours after methotrexate. methotrexate 100 mg/m(2) IV day 1. vincristine 1 mg IV day 1. as well as continuous 5-FU infusion.0001).0001). 20% versus 15%) but toxicities were increased. Due to the complicated schedule and only marginally improved outcomes as compared with CAF.095. 1995). respectively (Bonadonna et al.0001 to 0. EPIRUBICIN.MICROMEDEX® 2. the 16-week regimen should not be substituted for CAF without careful consideration (Fetting et al. 1998). one-sided). granulocytopenia.10.04). Relapse-free and overall survivals in premenopausal patients after 20 years were 26% and 24%.003. Of the 163 patients participating in the quality-of-life study.0003). AND FLUOROURACIL (CAF) with similar toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive.05) and weight loss (P=0. During EVEN-NUMBERED WEEKS.0 follow-up study. respectively. 0.19. Febrile neutropenia hospital admission was not significantly different between the two regimens.0001). a comparison of an accelerated-intensified regimen of CYCLOPHOSPHAMIDE. The estimated 4-year survival rate was 78.7% for CAF (P=0. and for the postmenopausal patients.5% versus 62. two-sided. P=0. with a median follow-up of 3. The 4-year recurrence. nausea (P=0.04). Other significantly worse adverse events in the 16-week regimen were stomatitis (P=0.8 versus 14. 26% and 22%. patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2. doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500 mg/m(2) intravenously (IV) days 1 and 8. but was insignificant by 4 months posttreatment (P=0.2 versus 32. respectively.3 months). The HD-CEF14 regimen consisted of thomsonhc. Dose modification occurred based upon toxicity evaluated and classified by the Common Toxicity Criteria. The 16-week regimen consisted of greater doxorubicin and 5-FU dose intensity than CAF and sequential administration of methotrexate and 5-FU. or overall survival (27. in the CMF-treated group. and FLUOROURACIL (CEF) with GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) support and a standard CEF regimen showed no significant differences in overall response rate (51% versus 49%). median time to disease progression (12. The 16-week regimen involved weekly treatments. DOXORUBICIN. v) A sixteen-week multidrug regimen achieved only marginally better outcomes than CYCLOPHOSPHAMIDE. and thrombocytopenia were significantly worse with CAF than with the 16-week regimen (P=0. 5-FU 600 mg/m(2) IV day 2 at 20 hours after methotrexate.free survival rate for the 16-week regimen was 67. skin toxicity (P=0. doxorubicin 40 mg/m(2) IV day 1. respectively. in the surgery-alone group.9 years.7 months).60). w) In a phase III study of women with metastatic breast cancer (n=151). neurotoxicity (P=0. two-sided. ODD-NUMBERED WEEKS as cyclophosphamide 100 mg/m(2) orally days 1 through 7. and 0.IntermediateToDocumentPrintLink 158/317 .0001 respectively).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Leukopenia. Anemia was significantly higher with the 16-week regimen (P=0. Leucovorin 10 mg/m(2) was administered orally every 6 hours for six doses. The complete response rate was slightly higher in the accelerated-intensified CEF regimen (HD-CEF14) compared with the standard CEF regimen (CEF21. 24% and 22%.4% for CAF (P=0. P=0. one-sided). and for postmenopausal patients. Relapse-free and overall survivals in premenopausal patients after 20 years were 37% and 47%.05.1% for the 16-week regimen and 71. receptor-negative breast cancer patients. Each 28-day cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2)) orally days 1 through 14.

and response rate were significantly increased with DOXORUBICIN and PACLITAXEL (AT) versus FLUOROURACIL. The authors do not recommend the use of an accelerated-intensified regimen of CEF outside the setting of clinical trials (Del Mastro et al.031) as was alopecia (p=0.001).7% versus 4.3% versus 2.26). The CEF21 regimen consisted of cyclophosphamide 600 mg/m(2). diarrhea (2% versus 0%).3%). The FAC regimen consisted of 5. and CYCLOPHOSPHAMIDE (FAC) as first-line therapy for metastatic disease. leukopenia (22. p=0.fluorouracil 500 mg/m(2) IV. infection (2% versus 0%).027).3 months with AT compared with 6. arthralgia/myalgia (10% versus 0%.3 months. Both regimens were administered every 3 weeks for 8 cycles. Patients who had not received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC rather than MV had a higher OR rate (43% versus 35%. a comparison of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL. a longer PFS (8 versus 5 months. p less than 0. mucositis (13. Patients who had received prior neoadjuvant/adjuvant therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a higher OR rate (33% versus 13%.001). thrombocytopenia (2% versus 3%). epirubicin 60 mg/m(2). and a longer OS (22 versus 16 months. Grade 3/4 toxicity in the HD-CEF14 arm compared with the CEF21 arm included anemia (18. thrombocytopenia (9. CYCLOPHOSPHAMIDE.0 cyclophosphamide 1000 milligrams/square meter (mg/m(2)).034) and overall survival was 23. and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed that there was no significant difference in overall response (OR) rate (34.013).001). x) In a phase III trial of women with metastatic breast cancer (n=267).8%). every 21 days.3 months and 18. DOXORUBICIN. overall survival.3%).8%). y) In a phase III trial of women with metastatic breast cancer (n=281). fever (8% versus 4%). nausea/vomiting (14. and fluorouracil 600 mg/m(2) IV on day 1.7% versus 2.25/10/12 Drug details . median time to disease progression. or progression.6% versus 2. and cyclophosphamide 500 mg/m(2) IV.7% versus 15. p=0. Febrile neutropenia and delayed hematological recovery was more frequent in the MV arm (p=0. respectively (p=0. alopecia (88.001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0. every 14 days. and asthenia (6. p=0.014).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.3% versus 1.0001). p less than 0. p less than 0. 2001). The MV regimen consisted of mitoxantrone 12 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and vinorelbine 25 mg/m(2) IV on days 1 and 8. G-CSF (lenograstim) 263 micrograms was self-administered subcutaneously on days 4 through 11 after each cycle of HD-CEF14. bone pain (6.5% versus 33. The AT regimen consisted of doxorubicin 50 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 followed 24 hours later with paclitaxel 220 mg/m(2) administered IV over 3 hours.free survival (PFS. peipheral neuropathy (12% versus 0%. p=0. doxorubicin 50 mg/m(2) IV. 2001). anemia (9% versus 7%).7% versus 0%).8%). The choice of FAC or FEC was decided by participating institution preference with all patients at one institution receiving the thomsonhc.2%). and stomatitis (1% for both)(Jassem et al.IntermediateToDocumentPrintLink 159/317 . p=0.032).25).2 months with FAC (p=0. nausea/vomiting (8% versus 19%.025).8%). and fluorouracil 600 mg/m(2) intravenously (IV) on day 1.028). p=0. and a longer OS (20 versus 16 months. Median time to disease progression was 8.0% versus 95.MICROMEDEX® 2. a longer PFS (9 versus 6 months. Overall response rate was 68% in the AT arm and 55% in the FAC arm (p=0. 7 months for both).0007). p=0.4%). median overall survival (20 versus 17 months). Grade 3/4 toxicity with the AT regimen compared with the FAC regimen included neutropenia (89% versus 65%. epirubicin 80 mg/m(2).

7% PR) (p=0. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. 36. Regimen B (12 cycles with the same doses of fluorouracil and cyclophosphamide. and C. 18.9% CR. The overall survival for ECisF was 10 months compared to 13 months for ECycloF. n=8. 39.3 months. the first 4 cycles with an epirubicin dose of 100 mg/m(2) (FEC 100) followed by 8 cycles of an epirubicin dose of 50 mg/m(2) (FEC 50)) produced a response rate of 64. doxorubicin or epirubicin 50 mg/m(2) on day 1. and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days) produced a response rate of 56. and C included neutropenia (21. respectively (p=0.6% (7.8%. inoperable breast cancer (Eisen et al. Stomatitis.9% CR. randomized trial of patients with metastatic breast cancer (n=417). epirubicin 75 mg/m(2). Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. stomatitis (2. B. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. 1998). p=0. A comparison of grade 3/4 nonhematologic toxicity in the FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%.8% complete response (CR).9%). 19 cardiac abnormalities were diagnosed (regimen A.7%).1% partial response (PR)). constipation.5 months. There were no significant differences in hematologic toxicity among the 3 regimens. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. During chemotherapy. A comparison of grade 3/4 toxicities in regimens A. Six cycles were planned.9 months. Regimen A (11 cycles of fluorouracil 500 milligrams/square meter (mg/m(2)). n=2) which included a decrease in left ventricular ejection fraction (n=12) and lower limb edema (n=1).49).3 months.2%. Six patients (4 who received regimen A and 2 who received regimen C) died of sepsis. 81.2%. The overall response rate was 68% and 69% for the ECisF and ECycloF groups. 39. anemia (3.001)(Namer et al.MICROMEDEX® 2. Although there was 160/317 .001).8%. and thrombosis related to the Hickman catheter occurred more frequently in the ECisF than ECycloF group.1%. CYCLOPHOSPHAMIDE.8%. and greater ease of administration than ECisF. epirubicin 60 mg/m(2) every 3 weeks. lethargy.3%. 15. 81.9% (20.3 months.4%. median duration of response was 8.Drug details . 1. 11. and cyclophosphamide 500 mg/m(2) IV on day 1.2 months. aa) The French Epirubicin Study Group compared varying doses of epirubicin in 3 regimens of FLUOROURACIL.6%.1% PR).0 same regimen. Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the FAC/FEC arm (p=0. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks.9%. plantar-palmar syndrome.2%. and CYCLOPHOSPHAMIDE (FEC) in a phase III.0% (16. For regimens A.3%). 47.5%).001). Regimen C (4 cycles of FEC 100 with the same regimen restarted at disease progression or stabilization) produced a response rate of 47. ECycloF offers a regimen with comparable efficacy.06). The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day 1. 0. respectively (p=0.9 months.8%). and median overall survival was 17. 18. median time to disease progression was 10. and 16. 8. and grade 4 infection (3. 8. regimen B.3 months.031) and alopecia (30% versus 7%. 2001).012). respectively (p less than 0. alopecia (75. nausea/vomiting (24. B. n=9. regimen C. and 6. fewer toxicities. and 6. p=0. By 2 to 1 randomization. 3. 33.0%). there were no cases of congestive heart failure or cardiac deaths.9 months.6%. z) A randomized. EPIRUBICIN. respectively. Cycles of both MV and FAC/FEC were repeated every 21 days. 1. 18.

2000). Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)). Upon crossover to the opposite treatment. Survival rates favored tamoxifen as initial therapy (23 months versus 21 months for CMF).7 months for CEF versus 6.08) in the proportional hazards model.01) but overall survival was not significantly different for CEF and CMF (20. 2%). ab) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of cyclophosphamide. 68%). 14%). nausea/vomiting (21%. methotrexate (40 mg/m(2) IV). response rates were 66% for CEF (n=189) and 52% for CMF (n=200.MICROMEDEX® 2.0 no significant difference in overall survival among the 3 regimens. and fluorouracil (500 mg/m(2) IV on days 1 and 8 of each cycle). 14%).5%. toxicity. respectively. Median time to progression was 8. P=0. 2 patients had significant falls in LVEF as previously described. respectively. or cyclophosphamide (500 mg/m(2) IV).2 months.3 months for CMF (p=0. p=0. and FLUOROURACIL (CEF.01). n=237. 8%). had disease stabalization for at least 2 months. A previous response to CMF tended to be associated with a better chance for tamoxifen response. or patient refusal occurred) or for a total of 9 cycles if complete or partial response occurred. and 3 patients with changes on electrocardiogram (ECG).1 months and 18. methotrexate and 5-fluorouracil (CMF) in the initial treatment of stage IV breast cancer in elderly woman (over the age of 65 years). In an analysis of assessable patients. In the CMF group. 161/317 . and mucositis (12%.25/10/12 Drug details . and alopecia (66%. 3 patients with congestive heart failure (CHF). METHOTREXATE. and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). p=0. and FLUOROURACIL (CMF. In the CEF group. 15%). respectively.23). The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al. which reached a border line level of significance (p=0. the results suggest that epirubicin dose escalation improves the response rate. A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. 1986). respectively). diarrhea (1%. whereas longer treatment improves the duration of responses and the time to disease progression (Anon. epirubicin (50 mg/m(2) IV). 2001). response to either tamoxifen or the CMF regimen was less than that observed when given as initial therapy (29% and 31%. overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE. febrile neutropenia (11%. Response rates were 45% and 38% in tamoxifen and CMF-treated patients. however. Other toxicities in the CEF versus CMF group included grade 4 infections (0. Cycles were repeated every 3 or 4 weeks (depending on toxicity recovery) for a total of 6 cycles (or until disease progression. 58%). 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). Initiation of hormone therapy as opposed to CMF chemotherapy is recommended in most elderly patients (Taylor et al. ac) In an intent-to-treat analysis. a previous response with tamoxifen did not predict CMF response. Additional disease control with hormone withdrawal was observed in 23% of patients. n=223) compared to those who received CYCLOPHOSPHAMIDE. EPIRUBICIN. an additional 33% and 45% of patients treated with tamoxifen and CMF.005). leukopenia (66%. and was correlated highly with prior hormonal response. Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 6 patients with declines in LVEF. 1%).

4%) (Levine et al.4%. 60.7%. methotrexate 40 mg/m(2) IV days 1 and 8. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. respectively.1%.6 months. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively.9%. FEC1 and FEC2) and observed a clinically significant benefit only when FEC2 was compared with CMF2. Relapse-free survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0.3%).7%). af) In premenopausal women with node-positive operable breast cancer. (p=0. Nine of 18 patients receiving mitomycin plus medroxyprogesterone had objective responses. Twelve of the 18 patients receiving CAF had objective responses. 1998).03). ag) The combination regimen CEF (CYCLOPHOSPHAMIDE. n=18. EPIRUBICIN. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy.2%). CMF2 was administered on days 1 and 8 and included methotrexate 40 milligrams/square meter. the other two agents being given without epirubicin on day 8. DOXORUBICIN. median survival was 22. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. METHOTREXATE. granulocytopenia (97. and alopecia were more frequent with either of the two FEC combinations compared with the CMF combinations (Coombes et al. FLUOROURACIL) demonstrated superior survival benefit compared to CMF thomsonhc. Nausea. Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13.9%).4%. and CYCLOPHOSPHAMIDE) provided better overall and relapse-free survival than CMF (FLUOROURACIL.1%). 1. Five-year survival rates among the CMF2 group (n=199) and the FEC2 group (n=200) were 73. median time to treatment failure was 7. alopecia (42. diarrhea (0. stomatitis (12.009). FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE.7%). EPIRUBICIN.2%.7 months. This was possibly due to a difference in acute toxicity between the 2 regimens.4%. 3. For patients in the CMF group it was 78% and 58% respectively. thrombocytopenia (9.1%). however. Greater toxicity was noted in patients receiving the CEF regimen. respectively).3%.25/10/12 ad) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF (CYCLOPHOSPHAMIDE. FEC (FLUOROURACIL. The FEC2 combination included epirubicin 50 milligrams/square meter on day 1. Both schedules included cyclophosphamide and fluorouracil in equivalent doses of 600 milligrams/square meter. ae) The combination regimen CEF (CYCLPHOSPHAMIDE. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0. median time to treatment failure was 5. 4. FLUOROURACIL) in the treatment of metastatic breast cancer. Both regimens were administered for 6 cycles. Objective responses were not significantly different between the 2 regimens (Falkson et al. 34 patients were randomized to either treatment (n=18. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. 6. and fluorouracil 600 mg/m(2) IV days 1 and 8). METHOTREXATE. 3. 1996). the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14. EPIRUBICIN. 1992).5 months. Following first relapse.IntermediateToDocumentPrintLink 162/317 .6%. vomiting (11.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.7 months.8% and 86. 78. median survival was 16. leukopenia (94. vomiting. The authors compared two separate dosing schedules for each adjuvant combination (CMF1 and CMF2. 2.03). and CYCLOPHOSPHAMIDE).

diarrhea (1%.1%). or cyclophosphamide (500 mg/m(2) IV).4%. 58%).3%). Greater toxicity was noted in patients receiving the CEF regimen. respectively (p=0. p=0.2 months. febrile neutropenia (11%. alopecia (42. Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)). granulocytopenia (97. however. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. methotrexate 40 mg/m(2) IV days 1 and 8. Median time to progression was 8. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8.7%). respectively.5%.009). n=223) compared to those who received CYCLOPHOSPHAMIDE. and fluorouracil (500 mg/m(2) IV on days 1 and 8 of each cycle). Both regimens were administered for 6 cycles. This was possibly due to a difference in acute toxicity between the 2 regimens. the mean score in the CEF group decreased to a nadir more quickly then in the CMF group.2%. thomsonhc. and FLUOROURACIL (CEF. it was 78% and 58%. thrombocytopenia (9. Other toxicities in the CEF versus CMF group included grade 4 infections (0. For patients in the CMF group. nausea/vomiting (21%. In the CEF group.0 (CYCLOPHOSPHAMIDE. 68%). respectively.7%). 14%). stomatitis (12. 2. 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). epirubicin (50 mg/m(2) IV). and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). and 3 patients with changes on electrocardiogram (ECG). and mucositis (12%. 1998). 1%). Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14. 14%).1%) diarrhea (0.25/10/12 Drug details .2%). 1. The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al.01). 60.3 months for CMF (p=0. 2 patients had significant falls in LVEF as previously described. 8%). 3 patients with congestive heart failure (CHF). A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. respectively.7%. In the CMF group.4%) (Levine et al. 2001).9%. n=237.3%. respectively (p=0. METHOTREXATE.01) but overall survival was not significantly different for CEF and CMF (20. In an analysis of assessable patients.9%). 3. methotrexate (40 mg/m(2) IV).MICROMEDEX® 2.005). Cycles were repeated every 3 or 4 weeks for a total of 6 cycles or for a total of 9 cycles if complete or partial response occurred. ah) In an intent-to-treat analysis. 4.4%. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group. Comparison of grade 3 and 4 toxicities in the CEF and CMF groups.7 months for CEF versus 6. Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 9 patients with declines in LVEF.4%. p=0. EPIRUBICIN.1 months and 18.IntermediateToDocumentPrintLink 163/317 . 3. p=0. fluorouracil 600 mg/m(2) IV days 1 and 8).23). and alopecia (66%. 2%). METHOTREXATE FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. response rates were 66% for CEF (n=189) and 52% for CMF (n=200. 15%). 78. vomiting (11. and FLUOROURACIL (CMF. 6. leukopenia (66%.03).1%. respectively. Overall survival was 77% and 70% in the CEF and CMF groups. were nausea (13. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%. overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and leukopenia (94.

A complete response was reported in 1 patient in each group.positive breast cancer patients were enrolled. Objective response rates were similar in paclitaxel-treated patients (29%: 2% complete. 5-FLUOROURACIL) over a shorter period. 1993). 27% partial) and in thomsonhc. Also. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. oral cyclophosphamide. more patients receiving the lowdose 12-cycle refused therapy. respectively). node. reduced myleosuppression. methotrexate (40 mg/m(2) intravenously (IV) on days 1 and 8).IntermediateToDocumentPrintLink 164/317 . intravenous fluorouracil) were comparable in efficacy in predominantly pretreated patients with advanced breast cancer. CYCLOPHOSPHAMIDE. six-cycle ACMF group (Fukutomi et al. VINCRISTINE. Although both treatment regimens were well tolerated overall. METHOTREXATE. node-positive breast cancer patients receiving either 6 cycles of ACMF or 12 cycles of low-dose ACMF (n=93. were superior to low-dose. even with doses within the conventional range. 1992).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Median follow-up duration in this study was 8. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al. patients were randomized to CMF for 6 or 12 cycles. Two hundred and nine women (median age 54 years) were randomized to receive paclitaxel (200 milligrams per square meter (mg/m(2)) every 21 days for 8 courses (n=107) or cyclosphosphamide (100 mg/m(2) orally (PO) on days 1 to 14). ak) No advantage was observed with 12 versus 6 cycles of CMF (CYCLOPHOSPHAMIDE. There was no difference in survival or disease-free survival among the 3 groups at approximately 10 years median follow-up. FLUOROURACIL.0 ai) In a randomized comparison (n=78). and prednisone (40 mg/m(2) PO on days 1 to 14) every 28 days for 6 courses (n=102). Durations of partial response were 19 weeks with FPC and 14 weeks in the FAC group. prolonged therapy. an FAC regimen (intravenous doxorubicin. respectively. 5-fluorouracil (600 mg/m(2) IV on days 1 and 8). Following mastectomy. Objective responses (complete or partial) were observed in 30% and 35% of patients. Although. n=97. PREDNISONE) produced statistically similar survival or disease-free survival rates. intravenous fluorouracil) and an FPC regimen (intravenous pirarubicin. 1989). Five-year survival was 57% and 62% in the 1. and prednisone in patients with metastatic breast cancer. METHOTREXATE. The strongest predictors of survival were positive nodes (negative correlation) and ideal or full dose of CMF (positive correlation) (Velez-Garcia et al. al) In one study.MICROMEDEX® 2.3 years) and 445 estrogen receptor (ER)negative. and a slightly higher quality of life rating was observed following first-line treatment with paclitaxel as compared to the combination of cyclophosphamide. there were non-significant trends toward better disease-free and overall survival rates in the high-dose.and 2-year therapy groups. 2 years of therapy produced a moderate improvement in survival (57% vs 62%) over 1 year of therapy. 5-fluorouracil. methotrexate. am) Prolonged survival. This improvement should be weighed against the difficulty (ie. METHOTREXATE.25/10/12 Drug details . aj) Escalating doses of ACMF (DOXORUBICIN. Alopecia was significantly less frequent with the FPC regimen. A study was conducted in premenopausal. respectively. 1995). FLUOROURACIL) in the treatment of breast cancer in 622 women with positive axillary nodes. not statistically different. electrocardiogram abnormalities occurred in 3 of 16 evaluable patients in the FAC group (18%) but in none of 23 evaluated in the FPC group (Tominaga et al. those with greater than or equal to 4 positive nodes were randomized to 1 of the CMF groups or regional radiotherapy followed by 6 cycles of CMF. oral cyclophosphamide.6 years (maximum of 11.

p=0. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. Multivariate analysis revealed a signifcantly improved survival with paclitaxel therapy (17.0006). repeated every 21 days. Patients were randomized to receive C and FU 500 milligrams per square meter (mg/m(2)) on day 1 and E 40 mg/m(2) on days 1 and 8 (n=52) or C and FU (same doses) plus E 80 mg/m(2) on day 1 (n=52) every 21 days for 6 cycles. mucositis.and 3 (Hainsworth et al.IntermediateToDocumentPrintLink 165/317 . paclitaxel caused more alopecia. thrombocytopenia. Febrile neutropenia with or without infection occurred significantly less frequently with paclitaxel as compared to combination therapy (10% versus 27%. 2 and 3. lethargy. Although median survival was similar in both groups. CYCLOPHOSPHAMIDE. (p=0. The regimen was compared to combination (CMF) cyclophosphamide 600 mg/m(2) IV. and peripheral neuropathy than combination therapy. The overall response rate were 68% and 69% for the ECisF and ECycloF groups.0 those treated with combination therapy (35%: 6% complete. 1998). respectively. LEUCOVORIN. Quality of life measures. respectively. but the differences between groups were not statistically significant. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. 29% partial).4 days. and FLUOROURACIL among 31 patients with metastatic breast cancer. Response duration ranged from 3 to 16+ months (Hainsworth et al. including physical wellbeing. which was significantly different. thomsonhc. The NFL and CMF regimens produced a 45% vs 26% response rate. epirubicin 60 mg/m(2) every 3 weeks. The above regimen was tested in another study with the addition of fluorouracil (NFL) 350 mg/m(2) IV bolus on days 1. ao) A randomized. and greater ease of administration than ECisF ap) EPIRUBICIN (E) on days 1 and 8 in combination with 5-FLUOROURACIL (FU) and CYCLOPHOSPHAMIDE (C) provided no advantage in efficacy over epirubicin on day 1 only in a phase II study of 104 patients with metastatic breast cancer. constipation.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details .021). The regimens were repeated at 21-day intervals and given to chemotherapynaive patients with metastatic breast cancer. Stomatitis. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. plantar-palmar syndrome. Leukopenia.06). p=0. and leucovorin 300 milligrams as a 1hour infusion followed by fluorouracil 350 milligrams/square meter IV push on days 1. and appetite were slightly better in paclitaxel-treated patients.025).001) and required fewer hospital days for appropriate treatment (1. 1997). There was no difference between treatment schedules regarding overall response rates (50% versus 52%). and fluorouracil 600 mg/m(2) given on day one. p=0.MICROMEDEX® 2. an) An overall response rate of 65% (2 complete.9 months. and nausea/vomiting were less severe with paclitaxel treatment. 1991). ECycloF offers a regimen with comparable efficacy. The overall survival for ECisF was 10 months compared to 13 months for ECycloF. However. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. 18 partial) was achieved with combination MITOXANTRONE. Six cycles were planned. By 2 to 1 randomization. (p=0.5 days versus 4. fewer toxicities.3 months versus 13.2. the median duration of response was 9 months and 6 months in the NFL and CMF groups respectively. inoperable breast cancer (Eisen et al. and thrombosis (related to the Hickman catheter) occurred more frequently in the ECisF than ECycloF group. methotrexate 40 mg/m(2) IV. mood. Patients received intravenous mitoxantrone 12 milligrams/square meter (mg/m(2)) on day 1. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. myalgia.

international study (n=453) conducted in women with metastatic breast cancer. and 6 cycles were planned. for the FEC-50 regimen. When administered preoperatively as four 21-day cycles. elicited a statistically similar 79% response rate (24% complete plus 55% partial). Complete thomsonhc. 5-FU 500 mg/m(2). The combination regimen. and CYCLOPHOSPHAMIDE (CYC) (FEC-100) had a higher objective response rate (p=0. p=0. versus 9% and 0. respectively. 31%).0037). aq) Patients treated with HIGH-DOSE EPIRUBICIN (EPI). Most dosage reductions and delays in therapy were due to hematologic toxicity (van Toorn et al. With the FEC-100 regimen. respectively. respectively.MICROMEDEX® 2. myalgias and paresthesias were numerically more frequent in the paclitaxel group. many of whom had undergone radical mastectomy with some also receiving adjuvant chemotherapy at the time of initial diagnosis (cumulative anthracycline dose 60 mg/m(2) or less). Patients had not received prior chemotherapy for advanced disease. ar) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of doxorubicin. Toxicities such as neutropenic fever. 1999). 2000). type of surgery and use of irradiation also did not differ significantly between groups. deaths from infectious complications were reported in 2 patients in each arm. Overall response rates were identical with FEC-75 and FEC-50 (45%). 1997). but were not analyzed statistically (Buzdar et al.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.25/10/12 Drug details . and CYC 500 mg/m(2) or EPI 50 mg/m(2) with the same dose of 5-FU and CYC. p=0. FLUOROURACIL (5-FU). consisting of fluorouracil 500 mg/m(2) IV on days 1 and 4. 1991) compared EPIRUBICIN alone (75 milligrams/square meter) with 2 FEC regimens (EPIRUBICIN 75 milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-75) or EPIRUBICIN 50 milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-50)) in a randomized trial involving 412 advanced breast cancer patients. and both combination regimens were statistically superior to EPIRUBICIN alone (overall response rate. respectively (p not significant). if toxicity allowed. Upon study entry patients were randomly assigned to receive EPI 100 mg/m(2). it did NOT increase survival. Other parameters including nodal disease at surgery.0 duration of response (11 months versus 10 months). as) The French Epirubicin Study Group (Anon.intensity for E was observed for the day 1 versus day 1 plus 8 scheduling (89% versus 78%. Significant decreases in left ventricular enddiastolic pressure (LVEF) were noted in 23 and 12 patients receiving FEC-100 and FEC-50. fluorouracil and cyclophosphamide as neoadjuvant therapy of operable (stage IIA to IIIA) breast cancer in a randomized trial (n=174).007) but no difference in duration of response or survival was demonstrated compared to LOW-DOSE EPIRUBICIN (FEC-50).IntermediateToDocumentPrintLink 166/317 . Two patients (1 in each arm) developed congestive heart failure. as well as for C and FU (90% versus 80%. paclitaxel 250 milligrams/square meter (mg/m(2)) as a 24-hour intravenous (IV) infusion resulted in an 80% response rate (27% complete plus 53% partial). While toxicity was acceptable in this study and overall response was greater with FEC-100. Further study of this regimen is needed in the adjuvant setting or of epirubicin in combination with highly active new agents (taxoids) (Brufman et al. cyclophosphamide 500 mg/m(2) IV on day 1 and doxorubicin 50 mg/m(2) as a 72-hour IV infusion. A significantly higher relative dose. or overall survival (16 months versus 14 months).4% of patients. This was a multicenter. Each cycle was repeated every 21 days.0006). The incidences of in situ or no residual disease in the breast at surgery were 14% and 23% in the paclitaxel and combination arms. pathologic stage after neoadjuvant therapy. grade IV neutropenia and infections occurred in 57% and 8% of patients.

patients with hormone receptorpositive tumors could receive tamoxifen or an aromatase inhibitor.09. distant metastases. 24 patients in the capecitabine arm and 16 patients in the standard chemotherapy arm had experienced disease recurrence. 1. hormone receptor-negative tumors. the futility of capecitabine therapy was determined using a Bayesian predictive probability method and the trial was closed.11 to 3.001) and overall survival (OS) (HR. 3.08. significantly worse RFS (HR. stage I to IIIB breast cancer and a tumor diameter greater than 1 centimeter were randomized to treatment with oral capecitabine (n=307.23 to 6.4 yr.8046 was 96% which was greater than the limit of 80% predicting futility). Standard adjuvant chemotherapy consisted of 4 cycles of AC with cyclophosphamide 600 mg/m(2) intravenously (IV) and doxorubicin 60 mg/m(2) IV given on day 1 every 21 days (n=184) or 6 cycles of CMF with cyclophosphamide 100 mg/m(2)/day orally days 1 to 14 and methotrexate 40 mg/m(2) IV and fluorouracil 600 mg/m(2) IV on days 1 and 8 every 28 days (n=133). One or more serious (grade 3 or higher) hematologic adverse events (AE) occurred less frequently with capecitabine (2%) compared with standard therapy (AC.0 responses were more frequent with the FEC-75 regimen (16%) as compared to FEC50 (7%) and EPIRUBICIN alone (4%). Additionally.39. 60 patients (20%) in the capecitabine arm and 35 patients (11%) in the standard chemotherapy arm experienced a relapse. or death from any cause. Treatment-related death occurred in 2 patients in the capecitabine arm thomsonhc. respectively.85. Therapy had to be discontinued due to cardiac toxicity more frequently in the EPIRUBICIN and FEC-75 arms. times to progression and survival were not different among the 3 groups. 52%) and one or more serious nonhematologic AE occurred in 33%. Breast cancer. and CMF. and fluorouracil (CMF) as adjuvant therapy in elderly patients with early stage breast cancer.IntermediateToDocumentPrintLink 167/317 .MICROMEDEX® 2. 1. 92%. 95% CI. although more early relapses occurred in patients receiving EPIRUBICIN alone and FEC-50. and CMF. 1.38 to 3. 24%.53 (probability of HR less than 0.7. resulting in a hazard ratio (HR) for disease recurrence (standard chemotherapy compared with capecitabine) of 0. methotrexate. 95% CI. 2.17. 32%) or standard chemotherapy (n=326. All scheduled cycles of chemotherapy were received by 80%. Women 65 years (yr) of age or older with operable.9 to 6.76.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.02) with capecitabine compared with standard therapy were confirmed. 2. noninferiority for relapse-free survival (RFS) was not established between single-agent capecitabine and standard therapy with cyclophosphamide and doxorubicin (AC) or cyclophosphamide. At a median follow-up of 2. 4. 2. in women 65 years of age or older a) In a randomized trial (n=633). 33%). AC. 95% confidence interval (CI). Adjuvant therapy with capecitabine consisted of 6 cycles of 2000 milligrams/square meter (mg/m(2))/day in 2 divided doses for 14 days every 3 weeks. hormone receptor-negative tumors.001) compared with patients with hormone receptor-negative tumors who received standard therapy. respectively. and 40% of patients who received capecitabine. Following the enrollment of 600 patients. Adjuvant therapy.34. p=0. p less than 0. and 62% of patients treated with capecitabine. At the time of this preplanned interim analysis. AC. CMF.001) and OS (HR.25/10/12 Drug details . After chemotherapy. 18 of 38 deaths (47%) in the capecitabine arm and 8 or 24 deaths (33%) in the standard chemotherapy arm were attributed to breast cancer. 54%. Unplanned post hoc analyses demonstrated that patients with hormone receptor-negative tumors who received capecitabine had significantly worse RFS (HR. 95% CI. p less than 0. In multivariate analyses. p less than 0. Median durations of response were similar with all regimens (315 to 395 days).

3% vs 15%).001). randomized. 7. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks.0097) and with a taxane.9% to 56. 8. 55 years.8.IntermediateToDocumentPrintLink 168/317 . The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle).56 to 0. 0.4% vs 21. 0%.7% vs 45. epirubicin 90 to 100 mg/m(2).or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane. range. the taxane arm (57.or anthracycline-based regimen plus bevacizumab (n=415. median age. proteinuria and febrile neutropenia. the taxane arm (8.3 months)) and with a taxane.25/10/12 Drug details .9%). median age. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10. 28 to 88 years) compared with 8 months with a taxane. Among patients with measurable disease at baseline. and cyclophosphamide 500 mg/m(2) IV every 3 weeks.1%. median age. 35.64.3%).7 months) vs 7.6% to 30.7 months with capecitabine plus placebo (n=206.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). multicenter. 0. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9. hazard ratio (HR). p=0. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. 17. 0. Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35. placebo-controlled. median PFS (primary outcome) was 8. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo.9%. respectively.1 to 9. 0% and 2. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.9% (95% CI. HR.or anthracycline-based regimen plus bevacizumab compared with a taxane.52 to 0.69. or an anthracycline-based regimen (fluorouracil 500 mg/m(2).1 months (95% CI. 5. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161. doxorubicin 50 mg/m(2).3 (95% CI.5 to 10. as first-line therapy in combination with capecitabine or taxane. 2%. p=0. 45. in the international.or anthracycline-based regimen plus placebo (n=177.3% (95% CI. 28 to 91 years) compared with 5. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). 55 years.001). range. fluorouracil 500 mg/m(2). 0. median PFS was 9.7%.or anthracycline-based regimen plus placebo (8.2 months.0 and in no patients in the standard therapy arm [412].84. HER2-negative.2%. p less than 0. 57 years. 95% confidence interval. Metastatic breast cancer.2% vs 38. 1%. but the majority of patients received additional systemic treatment that might have affected OS. 56 years.or anthracycline-based regimen plus placebo (n=207.or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative.6 months. thomsonhc.4 months) vs 7.7%) vs 37.8 months)). and the anthracycline arm (34.2 (95% CI.2% to 40. range 29 to 85 years.6%) vs 23. 30.2 to 8.0054). 95% CI.2 to 10. After a median follow-up of 15.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. With a median follow-up of 19. 30. 6.4% (95% CI.2 months (95% CI.2 months with a taxane. 51. Hypertension. median age.2%).MICROMEDEX® 2. 0%).6 months with capecitabine plus bevacizumab (n=409.6% (95% CI. range 23 to 88 years. p less than 0.

and heparin 50. with or without leucovorin. demonstrated an improved two-year overall survival and decreased rate of recurrence compared with systemic chemotherapy alone.4% and 3. with a median follow-up of 62.2 months in the combination therapy group and 59. After adjustment for the location of primary tumor (rectum versus colon) and largest liver lesions (greater than or equal to 5 centimeters (cm) versus less than 5 cm). a total of 74 patients were randomized to receive six cycles of the combination therapy.25 mg/kilogram (kg)/day. analysis based on carcinoma histology revealed a significant difference in survival rates only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma.8% and 2. fluorouracil. All patients received induction commensurability with intramuscular picibanil plus MFC for 6 weeks following surgery.IntermediateToDocumentPrintLink group was 2.5%.7 months. 8 weeks after surgery. and maintenance therapy was continued until death. If a patient in either study group had previously received 5-FU and leucovorin.minute infusion of leucovorin 200 mg/square meter.03).34 (95% 169/317 .000 units was administered for 14 days. following leucovorin 200 mg/square meter. administered as a intravenous bolus of 5-FU 325 milligrams (mg)/square meter daily for 5 days. Dexamethasone Metastasis from malignant tumor of colon a) In 156 patients who underwent complete resection of hepatic metastases from colorectal cancer. particularly in patients with undifferentiated gastric cancer (Yasue et al. 0%. 5-FU was administered as 370 mg/square meter intravenously for 5 days every four weeks. 3.0 8.25/10/12 Drug details . preceded each day by a 30. dexamethasone 20 mg. and the anthracycline arm (10. 2%).MICROMEDEX® 2. the risk ratio for death at two years in the systemic therapy alone group as compared with the combination therapy thomsonhc. 5-FU alone was administered by continuous infusion at a dose of 850 mg/square meter for 5 days every five weeks in the combination therapy group and 1000 mg/square meter for 5 days every four weeks in the monotherapy group.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. signet-ring cell carcinoma) as compared to those with differentiated histology. further studies are required to confirm these findings. respectively. Beginning four weeks after resection. and cytarabine) in patients with advanced untreated gastric cancer following palliative gastrectomy.9%. However. 0%. 5%) [413]. Based on these results. It is speculated that the MFC regimen may have concealed the immunopotentiating effect of picibanil. followed by a 1-week rest period.3 months in the monotherapy group. patients were randomized to picibanil alone or picibanil plus MFC. However. Survival rates following 8 months of therapy were 81% and 57% in patients receiving maintenance picibanil alone and picibanil plus MFC. picibanil maintenance therapy alone appears preferable to picibanil plus MFC. hepatic arterial infusion of FUDR 0. 0%.9%. The two-year overall actuarial survival rate was 86% in the combination therapy group compared with 72% in the monotherapy group (p=0. Among the 82 patients randomized to receive six cycles of systemic monotherapy beginning 4 weeks after resection. the postoperative combination of hepatic arterial infusion of floxuridine (FUDR) and systemic intravenous fluorouracil (5-FU). 1981). Cytarabine Gastric cancer a) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL alone has been significantly more effective than commensurability with intramuscular picibanil plus MFC (mitomycin. The estimated median survival was 72. accounting for greater benefits with picibanil alone. Two weeks later.

1-year thomsonhc.IntermediateToDocumentPrintLink survival was 41%. p=0. were 40%.2 months in the combination therapy and monotherapy groups. Patients who relapsed on randomized study treatment were encouraged to crossover to the alternate treatment. ECF. and cisplatin/5-FU therapy were compared in patients with advanced stage gastric carcinoma.106). The median duration of progression.4 months. Gastric cancer a) There was no statistically significant difference in objective response rate (ORR. and 5 cycles of chemotherapy. 1999).or 2-year survival rates when docetaxel. 5.127). ECF. 53 years) who had not received chemotherapy and had an Eastern Cooperative Oncology Group performance status of 2 or less were randomized to 1 of 3 groups: docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1 with 5-FU 750 mg/m(2) daily for 5 days every 3 weeks (DCF. and 7. Patients enrolled in this open-label. leukopenia. with the exception of a higher frequency of diarrhea (29% versus 14%) and hepatic effects in the combination therapy group.0 alone group as compared with the combination therapy group was 2. complete response plus partial response). The rate of survival free of hepatic recurrence after two years was 90% in the combination therapy group and 60% in the monotherapy group (p less than 0. The two-year actuarial rates of overall progression-free survival were 57% in the combination therapy group and 42% in the monotherapy group (p=0.001) in patients (n=282) with advanced breast cancer who had failed anthracycline treatment. 1. and CF groups.free survival was 37. The DCF. In the combination therapy group.0 months. 30%. Docetaxel was associated with more toxicity than MF with 3 treatment related deaths in the docetaxel arm and one in the MF arm (Sjostrom et al 1999). 170/317 . Eight percent of docetaxel patients and 3% of MF patients experienced complete response.8 months.98.07). and 18% (p=0. doubling of the serum alkaline phosphatase level occurred in 29%. and 5fluorouracil (5-FU) combination therapy. epirubicin.25/10/12 Drug details .1 months. cisplatin. n=40). Almost twice as many docetaxel patients experienced a partial response (34%) compared to MF (18%). n=40). PFS was 5. and 4.0 mg per deciliter occurred in 18% of patients. 40%. mucositis. Hospitalization for diarrhea. Adverse effects of moderate severity were similar in both groups. respectively. progression free survival (PFS). median OS was 9. n=36).34 (95% confidence interval. respectively (p=0.3 months (p=0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. or cisplatin 100 mg/m(2)/d on Day 1 with 5-FU 1000 mg/m(2) daily for 5 days every 4 weeks (CF. and 18%. median overall survival (OS). Objective response rates in the DCF.027). p less than 0.4 and 17.001). randomized study received docetaxel 100 milligrams/square meter (mg/m(2)) over 1 hour every 3 weeks or sequential methotrexate 200 mg/m(2) and 5-fluorouracil 600 mg/m(2) on days 1 and 8 every 3 weeks. and CF groups received a median of 6. cisplatin.6 months. epirubicin 50 mg/m(2) and cisplatin 60 mg/(m2) every 3 weeks plus 5-FU 250 mg/m(2) daily (ECF. and 5-FU combination therapy.MICROMEDEX® 2. respectively. 10.02) (Kemeny et al. and increased total bilirubin levels to more than 3.3 months) compared to METHOTREXATE and 5-FLUOROURACIL (MF) combination therapy (3. tripling of the serum aspartate aminotransferase level occurred in 65%.10 to 4. Patients (median age. Docetaxel Breast cancer a) DOCETAXEL MONOTHERAPY was associated with a significantly longer time to progression (6. or small bowel obstruction was required in 29 and 18 patients in the combination therapy and monotherapy groups. or 1.4 months (p=0. 4.054).

or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative.1 months (95% CI.2 months (95% CI. and 3%.52 to 0. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks.8. 30. 8. p less than 0.106).69.3 months)) and with a taxane.1 to 9.84.3 (95% CI. p=0. 28 to 91 years) compared with 5.7 months) vs 7.001). 95% CI. 30. and 39% receiving CF [441]. With a median follow-up of 19. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. 9%. 6.56 to 0. 51. 5.6%) vs 23. 0. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161.7%. but the majority of patients received additional systemic treatment that might have affected OS. randomized.4% (95% CI. median PFS was 9. The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle). median age.or anthracycline-based regimen plus bevacizumab compared with a taxane.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. median age. HER2-negative.4 months) vs 7.2 (95% CI. 7. p less than 0. 28 to 88 years) compared with 8 months with a taxane. fluorouracil 500 mg/m(2). 57 years. a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). After a median follow-up of 15.64. 40%. in the international.2%). placebo-controlled. as first-line therapy in combination with capecitabine or taxane. epirubicin 90 to 100 mg/m(2). hazard ratio (HR). HR.or anthracycline-based regimen plus placebo (n=177. median age.25/10/12 Drug details . 1-year survival was 41%.5 to 10. 45. 0. 17.0054).2 months with a taxane.1 months.2 to 8. 35. doxorubicin 50 mg/m(2). and dose reductions were required in 50% of patients receiving DCF. 0. and cyclophosphamide 500 mg/m(2) IV every 3 weeks.8 months)).6 months.7 months with capecitabine plus placebo (n=206. The DCF group had significantly more cases of neutropenia and neuropathy compared to ECF or CF.or anthracycline-based regimen plus placebo (n=207.6% (95% CI.9% to 56. range.or anthracycline-based regimen plus bevacizumab (n=415. Among patients with measurable disease at baseline.6% to 30. multicenter. 55 years.0 10. p=0.2% to 40.0097) and with a taxane.or anthracycline-based regimen plus placebo (8.6 months with capecitabine plus bevacizumab (n=409.3% (95% CI. range. or an anthracycline-based regimen (fluorouracil 500 mg/m(2).MICROMEDEX® 2. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). 56 years. median PFS (primary outcome) was 8. range 29 to 85 years. locally recurrent or metastatic breast cancer previously untreated with chemotherapy.7%) vs 37.7% vs 45. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.9% (95% CI. 95% confidence interval. 38% receiving ECF. 55 years. Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the 171/317 . and 7. Metastatic breast cancer. median age. 0.2 months.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo.2 to 10.4 months (p=0.001). range 23 to 88 years. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9. and 2-year survival was 27%. and 18%.

9% of the 5-FU group. as was median survival time (48 weeks with doxifluridine.9%). and the anthracycline arm (10. toxicity. Median hospital-free survival time and median time to disease progression were 159 and 89 days for 5DFUR.3%). 0% and 2. Grade 3 and higher adverse events occurred in 2. and quality of life when intravenous 172/317 . 8. 39 weeks with 5-fluorouracil).9%. intravenous doxifluridine was similarly as effective as intravenous 5-fluorouracil in the treatment of patients with locally advanced or metastatic colorectal carcinoma. DOXIFLURIDINE (5-DFUR) proved to be as efficacious as 5-FLUOROURACIL (5-FU) in patients with advanced gastric cancer who needed supportive therapy.8% and 2. 1%.MICROMEDEX® 2. proteinuria and febrile neutropenia. leukopenia) compared with 6. the taxane arm (57. Adverse effects profiles favor doxifluridine in some investigations. 5%) [413]. and 111 and 66 days for 5.4% and 3.0 capecitabine arm (35. The median time to progression was. respectively). Response rates of 5% and 0. 0%. 0%.4% vs 21. Enrollees in the 5-DFUR group (n=75) received oral 5-DFUR 800 milligrams (mg)/body/day and those in the 5-FU group (n=75) received oral 5-FU 200 mg/body/day. Doxifluridine 4 grams/square meter/day and 5-fluorouracil 400 milligrams/square meter/day were each given as a 1-hour infusion for 5 days every 28 days. 0%. the small number of patients treated in these studies does not enable an adequate comparison.5%. Neurotoxicity and cardiotoxicity were greater with doxifluridine in the study using intravenous bolus doses [432].1%. b) According to a randomized prospective study. significantly longer in the doxifluridine group (18 weeks versus 13 weeks). were observed (not a significant difference).Drug details . Hypertension. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10. anorexia. however. and the larger trial is more relevant [430]. and greater than that of 5-fluorouracil (leukopenia.2%. Doxifluridine Colorectal cancer a) SUMMARY: Oral DOXIFLURIDINE and 5-FLUOROURACIL have similar efficacy in the treatment of gastric cancer. Adverse drug reactions occurred in 4. the taxane arm (8.9%.2% of 5-FU-treated patients (diarrhea. however. c) In a large randomized study (n=222).4% of 5-DFUR-treated patients (stomatitis. respectively. and the anthracycline arm (34. Toxicity with doxifluridine was significant. gastrointestinal toxicity.9%. but in whom intensive chemotherapy was not an option. 3.2% vs 38.9%.3% vs 15%). but not in others. the adverse effect profile of 5-DFUR was slightly more favorable compared with 5-FU [429]. There were no significant differences between groups in survival time (median survival time 223 and 165 days for 5-DFUR and 5-FU. neurologic toxicity) [430]. and abdominal pain).9% of the 5-DFUR group compared with 9.FU. 2%). respectively. 0%). 0%. Malignant tumor of rectum a) No differences were noted in efficacy. The median duration of response was similar in each group (26 to 27 weeks). d) Smaller comparative studies employing daily intravenous bolus doses or 1-hour infusions of doxifluridine (4 grams/square meter) and 5-fluorouracil (450 milligrams/square meter) for 5 days every 3 to 4 weeks have suggested an advantage of doxifluridine (response rates of 20% versus 7%) [431][432]. 2%. both therapies continuing daily for 4 weeks or more until evidence of disease progression was observed (use of body terminology in dosing not explained).

p=0. a synthetic 5-deoxynucleoside derivative. Complete and partial responses were observed in 21% and 14%. p=0. Toxicities included diarrhea. DOXIFLURIDINE. Mean follow-up period was 15 months with local (oral groups) and 3 systemic failures (1 IV. stomatitis and leukopenia (not different between the 2 groups).307). Patients received either a intravenous bolus infusion of 5-FU 450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years. respectively (p=0. In this small prospective study. toxicity. 50% and 43%. Patients received either a intravenous bolus infusion of 5-FU 450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years.IntermediateToDocumentPrintLink 173/317 .168. n=14)in combination with leucovorin 20 mg/m(2)/d continuously during radiotherapy. offered no significant advantage over intravenous 5-FU in preoperative concurrent chemoradiotherapy (Kim et al. Mean follow-up period was 15 months with 1 local (oral group) and 3 systemic failures (1 IV. Fair and good quality of life scores showed no difference among the 2 groups. stomatitis and leukopenia (no difference between the 2 groups).MICROMEDEX® 2. DOXIFLURIDINE.235). respectively (p=0. 2 oral. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized.dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone. Of 553 patients enrolled. and quality of life when intravenous (IV) fluorouracil (5-FU) and leucovorin were compared to oral DOXIFLURIDINE and leucovorin in 28 patients with advanced rectal cancer. Complete and partial responses were observed in 21% and 14%. Standard. Doxorubicin Breast cancer a) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high. n=14)in combination with leucovorin 20 mg/m(2)/d continuously during radiotherapy. offered no significant advantage over intravenous 5. 50% and 43%.168.0 (IV) fluorouracil (5-FU) and leucovorin were compared to oral DOXIFLURIDINE and leucovorin in 28 patients with advanced rectal cancer. p=0. 2001).235). Fair and good quality of life scores showed no difference between the 2 groups.25/10/12 Drug details .and high-dose chemotherapy were administered according to the following schema: INDUCTION AND HIGH-D0SE (CONTINUOUS MAINTENANCE INFUSION) Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 thomsonhc. In this small prospective study. Neoplasm of rectum a) No differences were noted in efficacy. n=14) in combination with leucovorin 20 mg/ m (2)/d for 5 consecutive days on the first and fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age 52 years. 2 oral. Toxicities included diarrhea.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. a synthetic 5-deoxynucleoside derivative. 2001). p=0.307).FU in preoperative concurrent chemoradiotherapy (Kim et al. n=14) in combination with leucovorin 20 mg/m(2)/d for 5 consecutive days on the first and fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age 52 years.

The subset of patients with liver metastases had significantly improved survival with NA as compared to FAC (p = 0. thrombocytopenia. thomsonhc. p=0. The NA regimen included doxorubicin (same dose and frequency) plus vinorelbine 25 mg/m(2) on days 1 and 8 of a 21-day cycle for a median of 4 cycles. respectively (p = NS). A study was conducted in premenopausal. node. Corresponding median overall survival rates were 17. doxorubicin 50 mg/m(2) and cyclophosphamide 500 mg/m(2).25/10/12 Drug details . Subgroup analyses (estrogenreceptor status. even with doses within the conventional range.8 months. At 3 years.and high.MICROMEDEX® 2. mg/m(2)=milligrams/square meter IV=intravenous PO=oral b) Four to six cycles of induction therapy were given every 28 days. and a higher incidence of cardiotoxicity with FAC (Blajman et al. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414]. n=97. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. 5-FLUOROURACIL) over a shorter period.6 months. respectively (p = NS). median time to progression was not different between the standard. phlebitis and cutaneous toxicity with NA. The average dose intensity of doxorubicin was 90% with FAC and 83% with NA. and anemia was observed in the high-dose/transplant group. each given intravenously on day 1 of a 21-day cycle for a median duration of 5 cycles.31). respectively. there were nonsignificant trends toward better disease-free and overall survival rates in the highdose.IntermediateToDocumentPrintLink 174/317 .23). A greater incidence of severe leukopenia. more patients receiving the low-dose 12-cycle refused therapy.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. mucositis occurred at a similar rate for both groups [414].04). The only significant differences in toxicity profiles were higher incidences of constipation.and highdose/transplant therapy (38% and 32%. 1999).positive breast cancer patients receiving either 6 cycles of conventional-dose ACMF or 12 cycles of low-dose ACMF (n=93. Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. Also. 1995). neuropathy. six-cycle ACMF group (Fukutomi et al. respectively). prolonged therapy. c) Two doxorubicin-containing regimens were equally effective in the treatment of advanced breast cancer in a Phase III trial (n=177).3 and 17. respectively. CYCLOPHOSPHAMIDE. Likewise.0 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg. The overall response rates for FAC and NA were 74% and 75%. were superior to low-dose. p=0. Median follow-up was 37 months. Although both treatment regimens were well tolerated overall. d) Escalating doses of ACMF (DOXORUBICIN. overall survival in this intentionto-treat analysis was not significantly different between standard. METHOTREXATE.dose/transplant groups (9 and 9. The FAC regimen consisted of 5fluorouracil (5-FU) 500 milligrams/square meter (mg/m(2)).

Other significantly worse adverse events in the 16-week regimen were stomatitis (P=0. AND FLUOROURACIL (CAF) with similar toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive. two-sided.0001). The patients were randomly assigned to receive either the 16-week regimen or six cycles of CAF. The 4-year recurrence. skin toxicity (P=0.013). Patients received either 6 cycles of ACMF or 12 cycles of low-dose ACMF.003. Both regimens were well tolerated.0001 respectively). f) A sixteen-week multidrug regimen achieved only marginally better outcomes than CYCLOPHOSPHAMIDE.IntermediateToDocumentPrintLink 175/317 .1% for the 16-week regimen and 71.095. patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2. METHOTREXATE. doxorubicin 40 mg/m(2) IV day 1. nausea (P=0. the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0. doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500 mg/m(2) intravenously (IV) days 1 and 8. with a median follow-up of 3. Due to the complicated schedule and only marginally improved outcomes as compared with CAF. even with conventional doses. Of the 163 patients participating in the quality-of-life study.25/10/12 Drug details .9 years. and response rate were significantly increased with DOXORUBICIN and PACLITAXEL (AT) versus FLUOROURACIL. 0.10. Dose modification occurred based upon toxicity evaluated and classified by the Common Toxicity Criteria.04). 1998).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. one-sided). 5-FU 600 mg/m(2) IV day 2 at 20 hours after methotrexate. the 16-week regimen should not be substituted for CAF without careful consideration (Fetting et al. and FLUOROURACIL (ACMF) over a short period. two-sided.4% for CAF (P=0. vincristine 1 mg IV day 1. receptor-negative breast cancer patients. Also.7% for CAF (P=0.0001 to 0.60). 1995). respectively (p=0. and CYCLOPHOSPHAMIDE (FAC) as first-line therapy for metastatic disease. The 16-week regimen involved weekly treatments.0001. methotrexate 100 mg/m(2) IV day 1. but more patients receiving the low-dose 12-cycle regimen refused therapy. and thrombocytopenia were significantly worse with CAF than with the 16-week regimen (P=0. Febrile neutropenia hospital admission was not significantly different between the two regimens.free survival rate for the 16-week regimen was 67. as well as continuous 5-FU infusion. beginning 24 hours after methotrexate. DOXORUBICIN.MICROMEDEX® 2. node-positive breast cancer patients (n=190).0001). Each 28-day cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2)) orally days 1 through 14. and 0.034) and overall survival was 23.05) and weight loss (P=0. Overall response rate was 68% in the AT arm and 55% in the FAC arm thomsonhc. overall survival. granulocytopenia.3 months and 18.0 e) Escalating doses of DOXORUBICIN. Leucovorin 10 mg/m(2) was administered orally every 6 hours for six doses. neurotoxicity (P=0. Median time to disease progression was 8. ODD-NUMBERED WEEKS as cyclophosphamide 100 mg/m(2) orally days 1 through 7.0001). but was insignificant by 4 months posttreatment (P=0. During EVEN-NUMBERED WEEKS.2 months with FAC (p=0.19. The estimated 4-year survival rate was 78. Leukopenia.3 months with AT compared with 6. one-sided).05.04). Anemia was significantly higher with the 16-week regimen (P=0.5% versus 62. median time to disease progression. prolonged therapy in premenopausal. P=0.0003). DOXORUBICIN. 6-cycle ACMF group (Fukutomi et al.3 months. P=0. g) In a phase III trial of women with metastatic breast cancer (n=267). The 16-week regimen consisted of greater doxorubicin and 5-FU dose intensity than CAF and sequential administration of methotrexate and 5-FU. were superior to low-dose. CYCLOPHOSPHAMIDE. there were non-significant trends toward better disease-free and overall survival rates in the high-dose.

Nine of 18 patients receiving mitomycin plus medroxyprogesterone had objective responses. median survival was 16. p=0. an FAC regimen (intravenous doxorubicin. Grade 3/4 toxicity with the AT regimen compared with the FAC regimen included neutropenia (89% versus 65%. The choice of FAC or FEC was decided by participating institution preference with all patients at one institution receiving the same regimen.001).001)(Namer et al. peipheral neuropathy (12% versus 0%.fluorouracil 500 mg/m(2) IV. The FAC regimen consisted of 5. Cycles of both MV and FAC/FEC were repeated every 21 days.Drug details . DOXORUBICIN.027). i) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF (CYCLOPHOSPHAMIDE. fever (8% versus 4%). p=0. median time to treatment failure was 7.025).MICROMEDEX® 2. p=0. Both regimens were administered every 3 weeks for 8 cycles.free survival (PFS. p=0. a longer PFS (9 versus 6 months.001). The MV regimen consisted of mitoxantrone 12 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and vinorelbine 25 mg/m(2) IV on days 1 and 8.031) and alopecia (30% versus 7%. A comparison of grade 3/4 nonhematologic toxicity in the FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%. Objective responses were not significantly different between the 2 regimens (Falkson et al. diarrhea (2% versus 0%). p=0. doxorubicin 50 mg/m(2) IV.5% versus 33. The AT regimen consisted of doxorubicin 50 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 followed 24 hours later with paclitaxel 220 mg/m(2) administered IV over 3 hours. and cyclophosphamide 500 mg/m(2) IV. p less than 0. and stomatitis (1% for both)(Jassem et al. Patients who had received prior neoadjuvant/adjuvant therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a higher OR rate (33% versus 13%. 2001).26). thrombocytopenia (2% versus 3%). Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the FAC/FEC arm (p=0. anemia (9% versus 7%). and a longer OS (20 versus 16 months. Twelve of the 18 patients receiving CAF had objective responses.0007). 2001). The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day 1. doxorubicin or epirubicin 50 mg/m(2) on day 1. arthralgia/myalgia (10% versus 0%.032).014). Following first relapse. a longer PFS (8 versus 5 months.25). a comparison of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL. 7 months for both). oral cyclophosphamide. 34 patients were randomized to either treatment (n=18. and a longer OS (22 versus 16 months. p=0. FLUOROURACIL) in the treatment of metastatic breast cancer. and cyclophosphamide 500 mg/m(2) IV on day 1. median survival was 22.001).5 months. p=0.028). Patients who had not received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC rather than MV had a higher OR rate (43% versus 35%. p less than 0. respectively).031) as was alopecia (p=0.6 months. median overall survival (20 versus 17 months). median time to treatment failure was 5. intravenous fluorouracil) and an FPC regimen (intravenous 176/317 . CYCLOPHOSPHAMIDE.001).3%). n=18. 1992). j) In a randomized comparison (n=78). p less than 0.0001). p=0. and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed that there was no significant difference in overall response (OR) rate (34.7 months.0 (p=0. infection (2% versus 0%).001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0. p=0. nausea/vomiting (8% versus 19%.7 months. h) In a phase III trial of women with metastatic breast cancer (n=281). or progression. Febrile neutropenia and delayed hematological recovery was more frequent in the MV arm (p=0.

there were non-significant trends toward better disease-free and overall survival rates in the high-dose. were superior to low-dose. and a better quality of life compared with fluorouracil. pathologic stage after neoadjuvant therapy. l) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of doxorubicin. The ECF regimen consisted of intravenous (IV) epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) every 3 weeks for up to 8 cycles and a continuous infusion of fluorouracil 200 mg/m(2)/day via a portable infusion pump for up to 6 months. tolerable toxicity. Although both treatment regimens were well tolerated overall. six-cycle ACMF group (Fukutomi et al. myalgias and paresthesias were numerically more frequent in the paclitaxel group. Objective responses (complete or partial) were observed in 30% and 35% of patients. Other parameters including nodal disease at surgery. respectively (p not significant). even with doses within the conventional range. 1995).MICROMEDEX® 2. more patients receiving the lowdose 12-cycle refused therapy. respectively. but were not analyzed statistically (Buzdar et al. cisplatin. prolonged therapy.0 pirarubicin. respectively). Also. consisting of fluorouracil 500 mg/m(2) IV on days 1 and 4. All patients (n=219) entered into the trial had inoperable adenocarcinoma or undifferentiated carcinoma of the esophagus or stomach. and methotrexate (FAMTX regimen). When administered preoperatively as four 21-day cycles. Doxorubicin 30 mg/m(2) was administered IV on day 15. elicited a statistically similar 79% response rate (24% complete plus 55% partial). k) Escalating doses of ACMF (DOXORUBICIN. With the ECF regimen. Alopecia was significantly less frequent with the FPC regimen. The combination regimen.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. intravenous fluorouracil) were comparable in efficacy in predominantly pretreated patients with advanced breast cancer. Leucovorin rescue 30 mg every 6 hours for 48 hours was started 24 hours after methotrexate. Cycles were repeated every 28 days up to a maximum of 24 weeks. type of surgery and use of irradiation also did not differ significantly between groups. Toxicities such as neutropenic fever. 5-FLUOROURACIL) over a shorter period. The incidences of in situ or no residual disease in the breast at surgery were 14% and 23% in the paclitaxel and combination arms.0002) of patients treated with the ECF regimen compared with 21% of patients treated with the FAMTX regimen. n=97. A study was conducted in premenopausal. paclitaxel 250 milligrams/square meter (mg/m(2)) as a 24-hour intravenous (IV) infusion resulted in an 80% response rate (27% complete plus 53% partial). Durations of partial response were 19 weeks with FPC and 14 weeks in the FAC group. cyclophosphamide 500 mg/m(2) IV on day 1 and doxorubicin 50 mg/m(2) as a 72-hour IV infusion. A complete response was reported in 1 patient in each group. electrocardiogram abnormalities occurred in 3 of 16 evaluable patients in the FAC group (18%) but in none of 23 evaluated in the FPC group (Tominaga et al.IntermediateToDocumentPrintLink and hematologic toxicity 177/317 . 9 patients underwent complete resections versus 4 patients treated with the FAMTX regimen. METHOTREXATE. node-positive breast cancer patients receiving either 6 cycles of ACMF or 12 cycles of low-dose ACMF (n=93. Esophagogastric cancer a) Combination therapy with epirubicin. and fluorouracil (ECF regimen) resulted in longer survival. fluorouracil and cyclophosphamide as neoadjuvant therapy of operable (stage IIA to IIIA) breast cancer in a randomized trial (n=174). nephrotoxicity. doxorubicin. 1999). The FAMTX regimen consisted of IV methotrexate 1500 mg/m(2) followed by IV fluorouracil 1500 mg/m(2) on day 1. thomsonhc. Mucositis. CYCLOPHOSPHAMIDE.25/10/12 Drug details . 1989). Objective responses including complete and partial responses occurred in 45% (p=0. oral cyclophosphamide.

whereas. The dose of streptozocin was 500 milligrams/square meter (mg/m(2))/day given every 6 weeks. Chlorozotocin alone produced a 30% regression rate with length of time to tumor progression and survival time equivalent to the streptozocin plus 5fluorouracil group (Moertel et al.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Except for diarrhea and stomatitis.0 treated with the FAMTX regimen. respectively. The authors indicate that. and every 5 weeks thereafter. Single-agent fluorouracil was administered as 500 milligrams/square meter per day for 5 days. the ECF regimen should be offered to all patients with advanced esophagogastric cancer who have an acceptable performance status. 1985).9 months) compared with FAMTX (5. and hematologic toxicity resulting in infections occurred significantly more often in patients treated with the FAMTX regimen. the authors advocate FLUOROURACIL monotherapy in advanced pancreatic or gastric cancer (Cullinan et al. due to failure to induce improved survival or palliation combined with excessive cost of combination therapy and greater toxicity. Survival was also extended in the streptozocin plus doxorubicin group. 1985). Mucositis. neither combination is indicated over fluorouracil alone in advanced pancreatic or gastric cancer (Cullinan et al. Due to the greater cost and toxicity of combination therapy. Doxorubicin was administered at 50 mg/m(2) on day 1 of streptozocin and for day 22 of each 6-week cycle. respectively. both stomatitis and diarrhea occurred more frequently in patients receiving fluorouracil alone. respectively. with regard to patient survival in the treatment of advanced pancreatic and gastric carcinoma in a study involving 305 patients with advanced disease. Proposed reasons for this discrepancy are that previous trials have accepted a so-called "biologic response" and the clinical measurement of hepatomegaly on physical examination or measurement on radionuclide liver-spleen scan as indicators of a major objective response. Based on this trial. b) A later retrospective analysis of 16 patients receiving the previously described regimen of streptozocin and doxorubicin revealed only a 6% (ie. 2.2 versus 1. repeated at 4 and 8 weeks. repeated at 4 and 8 weeks and every 5 weeks thereafter) was as effective as a combination of fluorouracil plus doxorubicin. nephrotoxicity. alopecia) were greater with the combination regimens.9 months.IntermediateToDocumentPrintLink 178/317 . time to tumor progression was 20 versus 6. Gastric cancer a) Survival rates with FLUOROURACIL ALONE were similar to those observed with FLUOROURACIL plus DOXORUBICIN with or without MITOMYCIN in patients with advanced pancreatic and gastric carcinoma (n=305). or a combination of fluorouracil plus doxorubicin plus mitomycin C.MICROMEDEX® 2. 1 of 16) response rate to therapy. and 6 patients (38%) showed disease progression. 1992).0009) longer with ECF (8. The authors conclude that an expectation of frequent major tumor regressions after treatment with this regimen thomsonhc. Malignant tumor of Islets of Langerhans a) The combination of STREPTOZOCIN plus DOXORUBICIN was superior to STREPTOZOCIN plus 5-FLUOROURACIL or CHLOROZOTOCIN alone in the treatment of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients. Nine patients (56%) had stable disease.25/10/12 Drug details . the ECF regimen resulted in more alopecia and central venous line complications.7 months) [438]. blood dyscrasias and nonhematologic toxicity (GI disturbances. Tumor regression occurred in 69% and 45% of patients receiving streptozocin plus doxorubicin and streptozocin plus 5-fluorouracil. b) Fluorouracil alone (500 milligrams/square meter (mg/m(2)) daily for 5 days per course.4 years. Median survival time was significantly (p=0.

3 months) [424].com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Single-agent fluorouracil was administered as 500 milligrams/square meter per day for 5 days. and CMF. The median survival in the 2 groups were similar (EAP. Following the enrollment of 600 patients. 18 of thomsonhc. the futility of capecitabine therapy was determined using a Bayesian predictive probability method and the trial was closed. and 62% of patients treated with capecitabine. or death from any cause. resulting in a hazard ratio (HR) for disease recurrence (standard chemotherapy compared with capecitabine) of 0. noninferiority for relapse-free survival (RFS) was not established between single-agent capecitabine and standard therapy with cyclophosphamide and doxorubicin (AC) or cyclophosphamide. 24 patients in the capecitabine arm and 16 patients in the standard chemotherapy arm had experienced disease recurrence. Due to the greater cost and toxicity of combination therapy. and every 5 weeks thereafter. respectively. the authors advocate FLUOROURACIL monotherapy in advanced pancreatic or gastric cancer (Cullinan et al. 60 patients (20%) in the capecitabine arm and 35 patients (11%) in the standard chemotherapy arm experienced a relapse. stage I to IIIB breast cancer and a tumor diameter greater than 1 centimeter were randomized to treatment with oral capecitabine (n=307. Sixty patients with advanced gastric cancer were randomly assigned to the EAP or FAMTX regimen. Additionally. patients with hormone receptorpositive tumors could receive tamoxifen or an aromatase inhibitor. Pancreatic cancer a) Survival rates with FLUOROURACIL ALONE were similar to those observed with FLUOROURACIL plus DOXORUBICIN with or without MITOMYCIN in patients with advanced pancreatic and gastric carcinoma (n=305). and fluorouracil (CMF) as adjuvant therapy in elderly patients with early stage breast cancer. AC. After chemotherapy. 32%) or standard chemotherapy (n=326. in women 65 years of age or older a) In a randomized trial (n=633). 1999).0 may be overly optimistic (Cheng & Saltz.4 yr. repeated at 4 and 8 weeks.IntermediateToDocumentPrintLink 179/317 . 1985). fluorouracil 1.5 grams/square meter (g/m(2)).25/10/12 Drug details . 7. Neoplasm of gastrointestinal tract a) The FAMTX regimen (methotrexate 1. hormone receptor-negative tumors. Doxorubicin Hydrochloride Breast cancer. Standard adjuvant chemotherapy consisted of 4 cycles of AC with cyclophosphamide 600 mg/m(2) intravenously (IV) and doxorubicin 60 mg/m(2) IV given on day 1 every 21 days (n=184) or 6 cycles of CMF with cyclophosphamide 100 mg/m(2)/day orally days 1 to 14 and methotrexate 40 mg/m(2) IV and fluorouracil 600 mg/m(2) IV on days 1 and 8 every 28 days (n=133). Adjuvant therapy. All scheduled cycles of chemotherapy were received by 80%. At a median follow-up of 2. methotrexate. but none occurred in the EAP group. hormone receptor-negative tumors.8046 was 96% which was greater than the limit of 80% predicting futility). 6. At the time of this preplanned interim analysis. 92%. distant metastases. Three patients in the FAMTX experienced complete remissions. and doxorubicin 30 milligrams/m(2) produced comparable results to the EAP regimen with much less toxicity in one study.1 months. Adjuvant therapy with capecitabine consisted of 6 cycles of 2000 milligrams/square meter (mg/m(2))/day in 2 divided doses for 14 days every 3 weeks. Objective responses were observed in 20% of the patients in the EAP group and 30% in the FAMTX group.MICROMEDEX® 2. Women 65 years (yr) of age or older with operable.5 g/m(2). 33%). FAMTX.53 (probability of HR less than 0.

hazard ratio (HR). range 29 to 85 years. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks.7%. 2. 55 years. 1.6% to 30.38 to 3. a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks).8. Metastatic breast cancer.52 to 0. median age.001) and OS (HR. or an anthracycline-based regimen (fluorouracil 500 mg/m(2). 17.6% (95% CI. respectively. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). range. p=0. multicenter.4% (95% CI.08. 55 years.7 months with capecitabine plus placebo (n=206. 0. 54%.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. doxorubicin 50 mg/m(2).IntermediateToDocumentPrintLink 180/317 .or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative.64. 52%) and one or more serious nonhematologic AE occurred in 33%. 3. Among patients with measurable disease at baseline.0097) and with a taxane. p less than 0.001) compared with patients with hormone receptor-negative tumors who received standard therapy. HER2-negative.02) with capecitabine compared with standard therapy were confirmed. 95% CI.6%) vs 23. 35. as first-line therapy in combination with capecitabine or taxane. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. 95% CI.56 to 0.or anthracycline-based regimen plus thomsonhc. epirubicin 90 to 100 mg/m(2). 4.6 months. One or more serious (grade 3 or higher) hematologic adverse events (AE) occurred less frequently with capecitabine (2%) compared with standard therapy (AC. randomized. After a median follow-up of 15. significantly worse RFS (HR.2% to 40. 1.2 months with a taxane.7. median age. in the international. p less than 0.17. and CMF.25/10/12 38 deaths (47%) in the capecitabine arm and 8 or 24 deaths (33%) in the standard chemotherapy arm were attributed to breast cancer. fluorouracil 500 mg/m(2). and 40% of patients who received capecitabine. median age. With a median follow-up of 19. 2. 1. 30. range 23 to 88 years.39. Treatment-related death occurred in 2 patients in the capecitabine arm and in no patients in the standard therapy arm [412].84.11 to 3. 28 to 91 years) compared with 5.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane. placebo-controlled.001) and overall survival (OS) (HR.23 to 6.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.or anthracycline-based regimen plus bevacizumab (n=415. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo. 95% CI. 0. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. p=0. 24%. p less than 0. HR.69.001). 0. AC.2 months.6 months with capecitabine plus bevacizumab (n=409. Unplanned post hoc analyses demonstrated that patients with hormone receptor-negative tumors who received capecitabine had significantly worse RFS (HR. 95% confidence interval (CI). 57 years. 28 to 88 years) compared with 8 months with a taxane.85. 56 years. 0. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161.76. and cyclophosphamide 500 mg/m(2) IV every 3 weeks.or anthracycline-based regimen plus placebo (n=207. p less than 0. In multivariate analyses.9 to 6.001). range. median age. median PFS (primary outcome) was 8. 2.34. The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle). 95% CI. CMF.09. p less than 0. median PFS was 9. 95% confidence interval.

inoperable breast cancer (Eisen et al. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion.2 to 8.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 0% and 2. 1998). respectively. every 14 days for 6 cycles. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. 6. the taxane arm (8. 0%. 5%) [413]. b) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens demonstrated that dose intensified EPIRUBICIN and CYCLOPHOSPHAMIDE (EC) did not provide improved progression-free survival (PFS). and greater ease of administration than ECisF (Eisen et al. and epirubicin 60 mg/m(2) every 3 weeks.8% and 2.1 months (95% CI.3 (95% CI. constipation. 51.5%. overall survival (OS).9% to 56. 0%. Hypertension.4% vs 21. 8. respectively. By 2 to 1 randomization.2 months (95% CI.3% vs 15%). The CEF group (n=224) received cyclophosphamide (75 mg/m(2)) orally day 1 thomsonhc.3%). 0%. The overall response rate was 68% and 69% for the ECisF and ECycloF groups. p=0. Epirubicin Breast cancer a) A randomized. 2%.4% and 3.9%. the taxane arm (57. and the anthracycline arm (34.4 months) vs 7.7%) vs 37.2% vs 38.5 to 10.9% (95% CI. 7.IntermediateToDocumentPrintLink 181/317 .1%. 30.3% (95% CI. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease.0054). Eligible patients had no evidence of metastasis and no prior treatment for breast cancer. and the anthracycline arm (10. and G-CSF (5 micrograms per kilogram per day (mcg/kg/day)) subcutaneously (SC) days 2 through 13. 1%. cyclophosphamide (830 mg/m(2)) IV on day 1.9%).7% vs 45. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10. CYCLOPHOSPHAMIDE. 1998).25/10/12 Drug details . lethargy.MICROMEDEX® 2. 0%. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. and thrombosis related to the Hickman catheter occurred more frequently in the ECisF group. The overall survival for ECisF was 10 months compared to 13 months for ECycloF. 2%). The dose intensified EC group (n=224) received epirubicin (120 mg per square meter (mg/m(2))) intravenously (IV) on day 1.2%). EPIRUBICIN.or anthracycline-based regimen plus placebo (8. ECycloF offers a regimen with comparable efficacy. Six cycles were planned.9%. 8.2%. fewer toxicities.7 months) vs 7. 3.0 placebo (n=177. plantar-palmar syndrome.1 to 9.3 months)) and with a taxane. and FLUOROURACIL (CEF) in women with locally advanced breast cancer.9%.or anthracycline-based regimen plus bevacizumab compared with a taxane. Stomatitis. 0%). but the majority of patients received additional systemic treatment that might have affected OS. Patients (n=448) were randomly assigned to receive dose intensified EC plus granulocyte colony-stimulating factor (G-CSF) or standard schedule CEF. and FLUOROURACIL (5-FU) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced.2 (95% CI. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9. proteinuria and febrile neutropenia.2 to 10. 45. all patients received prophylactic therapy with trimethoprim-sulfamethoxazole during treatment and tamoxifen (20 milligrams (mg) per day) following chemotherapy until progression or for 5 years if no progression.8 months)). or response rate compared to a standard delivery schedule of CYCLOPHOSPHAMIDE. Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35. 5.

01) but not overall survival (83% versus 77%. Complete clinical response (CR) rates were 31. a tailored FEC (fluorouracil (5-FU). p=0. 2003). 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion.3% and 26. respectively. All subjects underwent post-chemotherapy radiation and tamoxifen therapy.Drug details . phlebitis. 60 mg/m(2) epirubicin. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide). The estimated 3-year relapse-free survival rate (72% versus 63%. A subgroup analysis compared PFS and OS in patients with locally advanced and inflammatory breast cancer. epirubicin (60 mg/m(2)) IV days 1 and 8. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al.0001). mucositis.7 months in the CEF and EC groups. median PFS was 34 months and 33.dose chemotherapy: 6000 mg/m(2) cyclophosphamide. were reported in the CEF group (Therasse el al. and neutropenia.0043) for the locally advanced (n=242) and inflammatory (n=206) subgroups. median PFS was 44 months and 23. 1998). Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. 59 had radiotherapy alone. In addition to that. THIOTEPA 480 mg/m(2). respectively. cycled every 28 days. Toxicities were greater in the high-dose group but both groups experienced nausea. respectively. All randomized patients received a fourth course of the up-front chemotherapy regimen. radiation therapy and 2 years of TAMOXIFEN therapy. c) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support. Following chemotherapy. cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer. fatigue. 27 EC) that led to congestive heart failure in 4 patients (2 CEF.0 through 14. a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support. EPIRUBICIN (120 mg/m(2). With a median follow up of 5. respectively. 94 had surgery alone. 182/317 . then high. Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0. and fluorouracil (500 mg/m(2)) IV days 1 and 8. 1 due to congestive heart failure and 1 due to febrile neutropenia. Five year OS was 53% and 51% in the CEF and EC groups. 382 patients had local therapy. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. epirubicin. diarrhea. 46 patients had a significant drop in left ventricular ejection fraction (19 CEF.5% for the CEF and EC groups. 2 EC).5 months (p=0. with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. and 34 had radiotherapy then surgery. alopecia. 600 mg/m(2) cyclophosphamide). Two toxic deaths. p=NS) favored group 1 over group 2. d) Following breast cancer surgery. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.MICROMEDEX® 2. There were no significant differences in the incidence of grade 3 to 4 toxicity between the CEF and EC groups.5 years.0019) and OS was 59% and 44% (p=0. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. 195 had surgery then radiotherapy. vomiting. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement.

0 respectively. There were 10 cases of delayed cardiac toxicity (decrease in left ventricular ejection fraction or congestive heart failure and one myocardial infarction) in patients who had received regional radiation. 6 in the FEC 50 group) which included 3 grade 2 conditions requiring treatment interruptions (2 in the FEC 100 group. 0%). 23.25/10/12 Drug details . Patients with operable breast cancer with either three positive nodes or between one and three positive nodes with Scarff Bloom Richardson (SBR) grade of 2 or greater and both estrogen and progesterone receptor negativity were enrolled. n=14).4% for FEC 100 and 65. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. FEC 50. 11. 0%). epirubicin 100 mg/m(2). EPIRUBICIN. Toxicities were greater in the high-dose group but both groups experienced nausea.7%. During chemotherapy.IntermediateToDocumentPrintLink 183/317 . 1998). radiation therapy and 2 years of TAMOXIFEN therapy. 13 cardiac abnormalities were diagnosed (7 in the FEC 100 group. Contralateral breast cancer developed in 21 patients (FEC 100. however the authors note that the difference in 5-year DFS and 5-year OS was significant only in patients with more than three positive nodes (Anon. 20. A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al. n=7.2%. e) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were significantly increased in patients with breast cancer and axillary node involvement (n=565) who received ADJUVANT chemotherapy with FLUOROURACIL. n=1. and cyclophosphamide 500 mg/m(2) every 21 days). This study was not powered for a subset analysis. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. vomiting. acute leukemia occurred in 2 patients (FEC 100. Treatment was started within 42 days after initial surgery. All randomized patients received a fourth course of the up-front chemotherapy regimen. 5-year OS was 77.8% with FEC 50 (p=0. nausea/vomiting (34. A comparison of grade 3/4 toxicity in the FEC 100 group versus the FEC 50 group included neutropenia (25.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. THIOTEPA 480 mg/m(2). EPIRUBICIN (120 mg/m(2). FEC 50. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. g) The combination regimen CEF (CYCLPHOSPHAMIDE.MICROMEDEX® 2. anemia (0. and CYCLOPHOSPHAMIDE (FEC) with an epirubicin dose of 100 milligrams/square meter (mg/m(2)) (FEC 100) compared to an epirubicin dose of 50 mg/m(2) (FEC 50). Patients were randomized to receive 6 cycles of FEC 100 (fluorouracil 500 mg/m(2). This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. FLUOROURACIL) demonstrated superior survival benefit compared to CMF thomsonhc. 1 in the FEC 50 group). 2000). and 14 patients developed second malignancies (FEC 100. 2001).4%.3%).03). 0%). n=7). alopecia (78. n=7. and neutropenia. and cyclophosphamide 500 mg/m(2) every 21 days) or 6 cycles of FEC 50 (fluorouracil 500 mg/m(2).007). diarrhea. epirubicin 50 mg/m(2). fatigue. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. Tamoxifen (30 mg/day) was prescribed to postmenopausal patients for 3 years starting with the first chemotherapy cycle.8%. mucositis. Five-year DFS was 66. In addition to that. and infection (3.1%). f) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not.8%. EPIRUBICIN. stomatitis (3. phlebitis. FEC 50.1%).3% with FEC 100 and 54. n=1). alopecia.3% for FEC 50 (p=0.8%. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))).

respectively. it was 78% and 58%.03). 1998).2%.7%).1%. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. thrombocytopenia (9.2%. leukopenia (94. h) The combination regimen CEF (CYCLOPHOSPHAMIDE. 2. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0. 3. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0. Both regimens were administered for 6 cycles. 60. For patients in the CMF group. 6. 3.3%. Comparison of grade 3/4 toxicities in the CEF and CMF groups. 1998).9%. Overall survival was 77% and 70% in the CEF and CMF groups.7%). For patients in the CMF group it was 78% and 58% respectively. 60.4%. 1.4%) (Levine et al.7%.009).1%). Greater toxicity was noted in patients receiving the CEF regimen. stomatitis (12. alopecia (42.7%). the mean score in the CEF group decreased to a nadir more quickly then in the CMF group. the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. however. however. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. a comparison of an accelerated-intensified regimen of CYCLOPHOSPHAMIDE. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. 3. thrombocytopenia (9.1%) diarrhea (0.4%. Both regimens were administered for 6 cycles. This was possibly due to a difference in acute toxicity between the 2 regimens. METHOTREXATE. alopecia (42. 4. 78. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. 78. 4.4%) (Levine et al. This was possibly due to a difference in acute toxicity between the 2 regimens.7%).9%). respectively (p=0.4%. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. 3. diarrhea (0.2%).3%).4%. 6.9%. respectively.9%). Greater toxicity was noted in patients receiving the CEF regimen.3%).1%). Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14. EPIRUBICIN.1%). fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. vomiting (11. stomatitis (12.7%. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively. respectively (p=0. 1. EPIRUBICIN. and FLUOROURACIL (CEF) with GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) support and a standard CEF regimen showed no significant .2%). epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8.(CYCLOPHOSPHAMIDE.009). fluorouracil 600 mg/m(2) IV days 1 and 8). FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. 2.1%.4%. i) In a phase III study of women with metastatic breast cancer (n=151). respectively.03). methotrexate 40 mg/m(2) IV days 1 and 8. METHOTREXATE. was nausea (13. methotrexate 40 mg/m(2) IV days 1 and 8.3%. granulocytopenia (97. granulocytopenia (97. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%. fluorouracil 600 mg/m(2) IV days 1 and 8).4%. leukopenia (94. vomiting (11. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.

epirubicin 80 mg/m(2).0% versus 95. CYCLOPHOSPHAMIDE.014). Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the FAC/FEC arm (p=0.8%). p=0. Cycles of both MV and FAC/FEC were repeated every 21 days.6% versus 2. G-CSF (lenograstim) 263 micrograms was self-administered subcutaneously on days 4 through 11 after each cycle of HD-CEF14.2 versus 32. and cyclophosphamide 500 mg/m(2) IV on day 1. 20% versus 15%) but toxicities were increased. Febrile neutropenia and delayed hematological recovery was more frequent in the MV arm (p=0. A comparison of grade 3/4 nonhematologic toxicity in the FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%. The choice of FAC or FEC was decided by participating institution preference with all patients at one institution receiving the same regimen. 2001). 7 months for both). p=0.7% versus 15.025).7 months).3 months). CYCLOPHOSPHAMIDE. The HD-CEF14 regimen consisted of cyclophosphamide 1000 milligrams/square meter (mg/m(2)). j) In a phase III trial of women with metastatic breast cancer (n=281). and fluorouracil 600 mg/m(2) intravenously (IV) on day 1. Patients who had not received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC rather than MV had a higher OR rate (43% versus 35%. median overall survival (20 versus 17 months). p=0. and asthenia (6.027).7% versus 0%). p=0. 2001).001)(Namer et al.8%).7% versus 2.5% versus 33.031) and alopecia (30% versus 7%.001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0. or progression. mucositis (13. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. a longer PFS (9 versus 6 months.3%). a longer PFS (8 versus 5 months. and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed that there was no significant difference in overall response (OR) rate (34.0001).0007). p=0. nausea/vomiting (14.3% versus 2. Grade 3/4 toxicity in the HD-CEF14 arm compared with the CEF21 arm included anemia (18.free survival (PFS. The authors do not recommend the use of an accelerated-intensified regimen of CEF outside the setting of clinical trials (Del Mastro et al. inoperable breast cancer (Eisen et al. Patients who had received prior neoadjuvant/adjuvant therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a higher OR rate (33% versus 13%. p=0. The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day 1. p=0. The CEF21 regimen consisted of cyclophosphamide 600 mg/m(2).26).8%).8 versus 14. .4%).7% versus 4. alopecia (88.differences in overall response rate (51% versus 49%). The complete response rate was slightly higher in the accelerated-intensified CEF regimen (HD-CEF14) compared with the standard CEF regimen (CEF21. thrombocytopenia (9.3% versus 1. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. and fluorouracil 600 mg/m(2) IV on day 1. p=0. epirubicin 60 mg/m(2). every 21 days. and a longer OS (20 versus 16 months. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. 1998).8%).25).031) as was alopecia (p=0. and a longer OS (22 versus 16 months. k) A randomized.2%).001). median time to disease progression (12. leukopenia (22. The MV regimen consisted of mitoxantrone 12 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and vinorelbine 25 mg/m(2) IV on days 1 and 8.3%). a comparison of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL. or overall survival (27. every 14 days. bone pain (6. doxorubicin or epirubicin 50 mg/m(2) on day 1.

36. 11. n=223) compared to those who received CYCLOPHOSPHAMIDE.3 months for CMF (p=0.0% (16. 3. EPIRUBICIN.9 months.01) but overall survival was not significantly different for CEF and CMF (20. regimen C.25/10/12 Drug details . there were no cases of congestive heart failure or cardiac deaths.9% (20. In an analysis of assessable patients. randomized trial of patients with metastatic breast cancer (n=417). median duration of response was 8. 39. 15. n=9. 18. respectively (p less than 0. and C.2%. 1. respectively (p=0. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. There were no significant differences in hematologic toxicity among the 3 regimens. epirubicin 75 mg/m(2). fewer toxicities. Although there was no significant difference in overall survival among the 3 regimens.8% complete response (CR). The overall response rate was 68% and 69% for the ECisF and ECycloF groups. METHOTREXATE. 0. 81.6% (7. 1. n=8.2 months. respectively (p=0.9 months.5%).MICROMEDEX® 2.49). respectively. alopecia (75. and C included neutropenia (21. Median time to progression was 8. Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)). and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days) produced a response rate of 56. ECycloF offers a regimen with comparable efficacy.3 months. and greater ease of administration than ECisF.1% partial response (PR)). n=2) which included a decrease in left ventricular ejection fraction (n=12) and lower limb edema (n=1). By 2 to 1 randomization. 81.6%.8%.3 months.3%). The overall survival for ECisF was 10 months compared to 13 months for ECycloF.06).012).7% PR) (p=0. and FLUOROURACIL (CEF.01). and FLUOROURACIL (CMF. the first 4 cycles with an epirubicin dose of 100 mg/m(2) (FEC 100) followed by 8 cycles of an epirubicin dose of 50 mg/m(2) (FEC 50)) produced a response rate of 64.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. During chemotherapy. and grade 4 infection (3. P=0.7 months for CEF versus 6.IntermediateToDocumentPrintLink 186/317 .0 epirubicin 60 mg/m(2) every 3 weeks. epirubicin (50 mg/m(2) IV). Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. Regimen C (4 cycles of FEC 100 with the same regimen restarted at disease progression or stabilization) produced a response rate of 47.9%. 18.2%. and 16.23). and CYCLOPHOSPHAMIDE (FEC) in a phase III. and median overall survival was 17.1% PR).1 months and 18.6%.1%. and 6.005).5 months.0%).8%. Stomatitis. 33.3 months. For regimens A. EPIRUBICIN. p=0. Six cycles were planned. 19 cardiac abnormalities were diagnosed (regimen A. Regimen A (11 cycles of fluorouracil 500 milligrams/square meter (mg/m(2)). B.4%.2%. Six patients (4 who received regimen A and 2 who received regimen C) died of sepsis.2 months. response rates were 66% for CEF (n=189) and 52% for CMF (n=200.9% CR. 39. overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE. 2000). and thrombosis related to the Hickman catheter occurred more frequently in the ECisF than ECycloF group. Regimen B (12 cycles with the same doses of fluorouracil and cyclophosphamide.8%. whereas longer treatment improves the duration of responses and the time to disease progression (Anon. regimen B. n=237. l) The French Epirubicin Study Group compared varying doses of epirubicin in 3 regimens of FLUOROURACIL. 47. lethargy. and fluorouracil (500 thomsonhc.8%). plantar-palmar syndrome. B. nausea/vomiting (24.3%. stomatitis (2. constipation. 8. respectively.9 months.9%). m) In an intent-to-treat analysis. A comparison of grade 3/4 toxicities in regimens A. 8.3 months. the results suggest that epirubicin dose escalation improves the response rate.001). p=0.7%).9% CR. anemia (3. median time to disease progression was 10. and 6. 18.

alopecia (42. thrombocytopenia (9. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.mg/m(2) IV on days 1 and 8 of each cycle). In the CEF group. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. o) In premenopausal women with node-positive operable breast cancer. 2 patients had significant falls in LVEF as previously described. toxicity. or patient refusal occurred) or for a total of 9 cycles if complete or partial response occurred.1%). and 3 patients with changes on electrocardiogram (ECG). however. vomiting (11. 78. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively. Cycles were repeated every 3 or 4 weeks (depending on toxicity recovery) for a total of 6 cycles (or until disease progression. METHOTREXATE. 1998). Other toxicities in the CEF versus CMF group included grade 4 infections (0.3%. Greater toxicity was noted in patients receiving the CEF regimen. The authors compared two separate dosing schedules for each adjuvant combination (CMF1 and CMF2. and CYCLOPHOSPHAMIDE). 60. Both schedules . epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. and mucositis (12%. nausea/vomiting (21%. or cyclophosphamide (500 mg/m(2) IV).9%). 6.7%.3%).7%). granulocytopenia (97. n) The combination regimen CEF (CYCLPHOSPHAMIDE.03). fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. Both regimens were administered for 6 cycles. and CYCLOPHOSPHAMIDE) provided better overall and relapse-free survival than CMF (FLUOROURACIL. 15%). 2001). 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2).5%. 2%). A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. METHOTREXATE. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. and fluorouracil 600 mg/m(2) IV days 1 and 8).7%).2%). leukopenia (94. This was possibly due to a difference in acute toxicity between the 2 regimens. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0.009). 3. FEC1 and FEC2) and observed a clinically significant benefit only when FEC2 was compared with CMF2. FEC (FLUOROURACIL. diarrhea (1%. methotrexate 40 mg/m(2) IV days 1 and 8. and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). leukopenia (66%. stomatitis (12. 1. 58%). Relapse-free survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0. Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13. The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al. 14%). methotrexate (40 mg/m(2) IV). EPIRUBICIN. diarrhea (0. 3 patients with congestive heart failure (CHF). 1%).4%) (Levine et al. 3. EPIRUBICIN. Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 6 patients with declines in LVEF.4%. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer.2%. the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. febrile neutropenia (11%. 8%). 4.4%. and alopecia (66%. 14%). For patients in the CMF group it was 78% and 58% respectively. In the CMF group.9%.1%.4%. 2. 68%).1%).

2%. methotrexate (40 mg/m(2) IV). 1. the other two agents being given without epirubicin on day 8. 14%).4%. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. Comparison of grade 3 and 4 toxicities in the CEF and CMF groups. CMF2 was administered on days 1 and 8 and included methotrexate 40 milligrams/square meter. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE.2 months.25/10/12 included cyclophosphamide and fluorouracil in equivalent doses of 600 milligrams/square meter.7 months for CEF versus 6.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. alopecia (42. The FEC2 combination included epirubicin 50 milligrams/square meter on day 1. n=237. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group.1 months and 18. 78. and FLUOROURACIL (CEF. thrombocytopenia (9.03). 68%).23).6%. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. Both regimens were administered for 6 cycles. diarrhea (1%. Median time to progression was 8. fluorouracil 600 mg/m(2) IV days 1 and 8). fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. EPIRUBICIN.1%. respectively (p=0. epirubicin (50 mg/m(2) IV). Cycles were repeated every 3 or 4 weeks for a total of 6 cycles or for a total of 9 cycles if complete or partial response occurred.1%).009). and fluorouracil (500 mg/m(2) IV on days 1 and 8 of each cycle). however. p=0.005). METHOTREXATE.2%). Other toxicities in the CEF versus CMF group included grade 4 thomsonhc. 4.1%) diarrhea (0.9%.7%). 3. and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. and mucositis (12%. 6. 15%). response rates were 66% for CEF (n=189) and 52% for CMF (n=200.4%) (Levine et al. 3. and leukopenia (94. 60. respectively.7%. stomatitis (12. respectively. methotrexate 40 mg/m(2) IV days 1 and 8. overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE. 58%). leukopenia (66%. (p=0. granulocytopenia (97.IntermediateToDocumentPrintLink 188/317 . were nausea (13. it was 78% and 58%. p) The combination regimen CEF (CYCLOPHOSPHAMIDE.4%.3%). For patients in the CMF group. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%.01). respectively. This was possibly due to a difference in acute toxicity between the 2 regimens. n=223) compared to those who received CYCLOPHOSPHAMIDE. respectively (p=0.4%.8% and 86. vomiting. p=0. or cyclophosphamide (500 mg/m(2) IV). the mean score in the CEF group decreased to a nadir more quickly then in the CMF group.01) but overall survival was not significantly different for CEF and CMF (20. p=0. 2%). In an analysis of assessable patients. 2. q) In an intent-to-treat analysis.9%).3 months for CMF (p=0. Overall survival was 77% and 70% in the CEF and CMF groups. respectively.3%. EPIRUBICIN. respectively. nausea/vomiting (21%. vomiting (11. METHOTREXATE FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. 1996).03). Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)). Nausea. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14. and alopecia were more frequent with either of the two FEC combinations compared with the CMF combinations (Coombes et al. Greater toxicity was noted in patients receiving the CEF regimen.7%). Five-year survival rates among the CMF2 group (n=199) and the FEC2 group (n=200) were 73. 1998). and FLUOROURACIL (CMF.

CYCLOPHOSPHAMIDE. lethargy. constipation.007) but no difference in duration of response or survival was demonstrated compared to LOW-DOSE EPIRUBICIN (FEC-50).0006). The overall survival for ECisF was 10 months compared to 13 months for ECycloF. phase II study demonstrated comparable efficacy between ECycloF (EPIRUBICIN. Upon study entry patients were randomly assigned to receive EPI 100 mg/m(2). 2 patients had significant falls in LVEF as previously described. patients were allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks. p=0. 14%). A significantly higher relative dose. FLUOROURACIL (5-FU). and thrombosis (related to the Hickman catheter) occurred more frequently in the ECisF than ECycloF group. inoperable breast cancer (Eisen et al. plantar-palmar syndrome. Stomatitis.MICROMEDEX® 2.intensity for E was observed for the day 1 versus day 1 plus 8 scheduling (89% versus 78%.0 infections (0. Six cycles were planned. In the CMF group. In the CEF group. 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 9 patients with declines in LVEF. Patients were randomized to receive C and FU 500 milligrams per square meter (mg/m(2)) on day 1 and E 40 mg/m(2) on days 1 and 8 (n=52) or C and FU (same doses) plus E 80 mg/m(2) on day 1 (n=52) every 21 days for 6 cycles. 8%). many of whom had undergone radical mastectomy with some also receiving adjuvant chemotherapy at the time of initial diagnosis (cumulative anthracycline dose 60 mg/m(2) or less). 2001).5%. 5-FU 500 mg/m(2). and CYCLOPHOSPHAMIDE (CYC) (FEC-100) had a higher objective response rate (p=0. t) Patients treated with HIGH-DOSE EPIRUBICIN (EPI). and CYC 500 mg/m(2) or EPI 50 mg/m(2) with the same dose of 5-FU and CYC. and 6 cycles were planned. With the FEC-100 regimen. The overall response rate were 68% and 69% for the ECisF and ECycloF groups. There was no difference between treatment schedules regarding overall response rates (50% versus 52%). epirubicin 60 mg/m(2) every 3 weeks. Patients with locally advanced disease had higher response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients with metastatic disease. grade IV neutropenia and infections 189/317 . Each cycle was repeated every 21 days. and 3 patients with changes on electrocardiogram (ECG). 3 patients with congestive heart failure (CHF). p=0. 1998). febrile neutropenia (11%. respectively. 2000). fewer toxicities. or overall survival (16 months versus 14 months). Most dosage reductions and delays in therapy were due to hematologic toxicity (van Toorn et al. if toxicity allowed. r) A randomized.Drug details .0037). duration of response (11 months versus 10 months). and greater ease of administration than ECisF s) EPIRUBICIN (E) on days 1 and 8 in combination with 5-FLUOROURACIL (FU) and CYCLOPHOSPHAMIDE (C) provided no advantage in efficacy over epirubicin on day 1 only in a phase II study of 104 patients with metastatic breast cancer. 1%). This was a multicenter. By 2 to 1 randomization. international study (n=453) conducted in women with metastatic breast cancer. Patients in both groups received 5-FU 200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion. and FLUOROURACIL (5-FU)) and ECisF (CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced. The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al. ECycloF offers a regimen with comparable efficacy. as well as for C and FU (90% versus 80%. and alopecia (66%.

1991) compared EPIRUBICIN alone (75 milligrams/square meter) with 2 FEC regimens (EPIRUBICIN 75 milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-75) or EPIRUBICIN 50 milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-50)) in a randomized trial involving 412 advanced breast cancer patients. u) The French Epirubicin Study Group (Anon. whereas. Gastric cancer a) MITOMYCIN.0002) of patients treated with the ECF regimen compared with 21% of patients treated with the FAMTX regimen. and methotrexate (FAMTX regimen). and a better quality of life compared with fluorouracil. Two patients (1 in each arm) developed congestive heart failure. Complete responses were more frequent with the FEC-75 regimen (16%) as compared to FEC50 (7%) and EPIRUBICIN alone (4%). respectively. versus 9% and 0. Objective responses including complete and partial responses occurred in 45% (p=0. the ECF regimen should be offered to all patients with advanced esophagogastric cancer who have an acceptable performance status. Esophagogastric cancer a) Combination therapy with epirubicin. although more early relapses occurred in patients receiving EPIRUBICIN alone and FEC-50. Therapy had to be discontinued due to cardiac toxicity more frequently in the EPIRUBICIN and FEC-75 arms. and both combination regimens were statistically superior to EPIRUBICIN alone (overall response rate. tolerable toxicity. Based on this trial. The ECF regimen consisted of intravenous (IV) epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) every 3 weeks for up to 8 cycles and a continuous infusion of fluorouracil 200 mg/m(2)/day via a portable infusion pump for up to 6 months. The FAMTX regimen consisted of IV methotrexate 1500 mg/m(2) followed by IV fluorouracil 1500 mg/m(2) on day 1.MICROMEDEX® 2. respectively. respectively.4% of patients.25/10/12 Drug details . and FLUOROURACIL did NOT produce a statistically thomsonhc. 31%). Significant decreases in left ventricular enddiastolic pressure (LVEF) were noted in 23 and 12 patients receiving FEC-100 and FEC-50. nephrotoxicity. Further study of this regimen is needed in the adjuvant setting or of epirubicin in combination with highly active new agents (taxoids) (Brufman et al. the ECF regimen resulted in more alopecia and central venous line complications. 1997).9 months) compared to FAMTX (5. Overall response rates were identical with FEC-75 and FEC-50 (45%). deaths from infectious complications were reported in 2 patients in each arm.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink 190/317 .0009) longer with ECF (8.0 occurred in 57% and 8% of patients. Median durations of response were similar with all regimens (315 to 395 days). Doxorubicin 30 mg/m(2) was administered IV on day 15. Cycles were repeated every 28 days up to a maximum of 24 weeks. Patients had not received prior chemotherapy for advanced disease. All patients (n=219) entered into the trial had inoperable adenocarcinoma or undifferentiated carcinoma of the esophagus or stomach. and hematologic toxicity resulting in infections occurred significantly more often in patients treated with the FAMTX regimen. for the FEC-50 regimen. With the ECF regimen. While toxicity was acceptable in this study and overall response was greater with FEC-100. cisplatin. it did NOT increase survival. and fluorouracil (ECF regimen) resulted in longer survival. times to progression and survival were not different among the 3 groups. EPIRUBICIN. Leucovorin rescue 30 mg every 6 hours for 48 hours was started 24 hours after methotrexate. Median survival time was significantly (p=0. Mucositis. doxorubicin.7 months) [420]. 9 patients underwent complete resections versus 4 patients treated with the FAMTX regimen.

respectively. In both groups.2% and 21. Toxicity was manageable and included neutropenia (eg. 1998).3. or cisplatin 100 mg/m(2)/d on Day 1 with 5-FU 1000 mg/m(2) daily for 5 days every 4 weeks (CF. etoposide 100 mg/m(2) on days 1. 1-year survival was 41%. Objective response rates in the DCF. This 8-week chemotherapy cycle was repeated three times. PFS was 5.0 significant difference (p=0. epirubicin 45 mg/m(2) (days 1 and 29). and CF groups. and lonidamine 50 mg orally 3 times daily. 38% receiving ECF. and dose reductions were required in 50% of patients receiving DCF. and 4. or 1. cisplatin 30 mg/m(2) on days 2 and 4. were 40%. and 18% (p=0. and 2-year survival was 27%. and 5-FU combination therapy. Patients were followed for a median of 5 years (Tsavaris et al. and 5fluorouracil (5-FU) combination therapy. and 5 cycles of chemotherapy. cisplatin. progression free survival (PFS).1 months. ECF. The 5-FU/6S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU 370 mg/m(2) daily on days 1 to 5. The DCF. 53 years) who had not received chemotherapy and had an Eastern Cooperative Oncology Group performance status of 2 or less were randomized to 1 of 3 groups: docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1 with 5-FU 750 mg/m(2) daily for 5 days every 3 weeks (DCF. 8 months) and EEP-L (epirubicin.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 9%. 29.3 months (p=0. This study enrolled 92 patients with STAGE I to III disease who had complete resection of the tumor and lymph nodes or who had poorly differentiated tumors. and 39% thomsonhc. 40%. diarrhea. Both regimens were repeated every 4 weeks (Barone et al. and mitomycin 10 mg/m(2) (day 1).or 2-year survival rates when docetaxel. 1996).and 5.IntermediateToDocumentPrintLink 191/317 . 30%.127). n=40). cisplatin. 5. partial responses were achieved in 28.106).6 months. epirubicin. eight treatment. Epirubicin Hydrochloride Gastric cancer a) There was no statistically significant difference in objective response rate (ORR. mucositis. and cisplatin/5-FU therapy were compared in patients with advanced stage gastric carcinoma.8 months. both administered by intravenous bolus injection. patients with lymph node metastases or low grade differentiation of the tumor showed a trend toward longer overall survival. 8. patients were randomly assigned to treatment with 5-FU 600 milligrams/square meter (mg/m(2)) (days 1. and 18%. epirubicin 50 mg/m(2) and cisplatin 60 mg/(m2) every 3 weeks plus 5-FU 250 mg/m(2) daily (ECF. 9 months). and CF groups received a median of 6. median survival was similar for 5-FU/6S-LV5 (fluorouracil and leucovorin. Neoplasm of gastrointestinal tract a) In a phase II study (n=65).MICROMEDEX® 2.25/10/12 Drug details . complete response plus partial response). Within two weeks of surgery. n=36). median overall survival (OS). and 3%. 4.related infectious episodes). and 7.054). and alopecia. median OS was 9. Neither regimen produced a complete response. 10. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. 36).9% of patients treated with 5FU/6S-LV and EEP-L. respectively. n=40). Patients (median age.310) in disease-free survival compared to NO chemotherapy in patients with operable gastric cancer. ECF.4 months (p=0. Treatment was well tolerated with no treatment-related deaths. The DCF group had significantly more cases of neutropenia and neuropathy compared to ECF or CF. however. etoposide.4 months. continuously. lonidamine. However. partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1. nausea/vomiting. although not statistically significant. cisplatin.

8. median age. 2%. 0% and 2. 6.64. range. 55 years.or anthracycline-based regimen plus placebo (n=207. 28 to 91 years) compared with 5. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo. 56 years. 0. fluorouracil 500 mg/m(2). range.1 months (95% CI.1 to 9.1%. 55 years.9% (95% CI.7%) vs 37.0097) and with a taxane.6% (95% CI. p less than 0. median PFS (primary outcome) was 8.7%.6 months. p=0. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. median age.7 months) vs 7.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 35.2% to 40.6 months with capecitabine plus bevacizumab (n=409. 0%).56 to 0. 1%.2 (95% CI.69.or anthracycline-based regimen plus placebo (8. and cyclophosphamide 500 mg/m(2) IV every 3 weeks.3 months)) and with a taxane.84.or anthracycline-based regimen plus placebo (n=177.4% vs 21. as first-line therapy in combination with capecitabine or taxane.IntermediateToDocumentPrintLink 192/317 . With a median follow-up of 19. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). 51.0054).6%) vs 23. range 29 to 85 years. but the majority of patients received additional systemic treatment that might have affected OS. a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). 8. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10. 57 years.or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative.MICROMEDEX® 2. Among patients with measurable disease at baseline. HR. multicenter.2 to 10. 0.3 (95% CI. 28 to 88 years) compared with 8 months with a taxane. range 23 to 88 years. in the international. randomized.7 months with capecitabine plus placebo (n=206. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.4% (95% CI.2%).52 to 0. median PFS was 9. 45.9%. proteinuria and febrile neutropenia.7% vs 45. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. respectively. 0.2 months (95% CI. 0.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane.25/10/12 Drug details .3%). thomsonhc. 17. 30. epirubicin 90 to 100 mg/m(2). the taxane arm (8. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161. the taxane arm (57.0 receiving CF [441].4 months) vs 7. HER2-negative. p less than 0.001).9% to 56.2 to 8. 5.or anthracycline-based regimen plus bevacizumab compared with a taxane. doxorubicin 50 mg/m(2). 7. 95% CI.2 months. Metastatic breast cancer.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. After a median follow-up of 15. The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle). The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9.6% to 30.5 to 10. p=0.2 months with a taxane. 95% confidence interval.001). 30. 0%. Hypertension.8 months)). doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks. or an anthracycline-based regimen (fluorouracil 500 mg/m(2). hazard ratio (HR).3% vs 15%). Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35. median age.9%).3% (95% CI. placebo-controlled. and the anthracycline arm (34.2% vs 38.or anthracycline-based regimen plus bevacizumab (n=415. median age.2%.

2%).5 cycles resulted in a statistically similar 15% response rate. cisplatin 30 mg/m(2) on days 2 and 4. corresponding overall survival was 6 and 5 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. partial responses were achieved in 28. Treatment was well tolerated with no treatment-related deaths.310) in disease-free survival compared to NO chemotherapy in patients with operable gastric cancer.8% and 2.2% and 21.IntermediateToDocumentPrintLink 193/317 .3. This 8-week chemotherapy cycle was repeated three times. epirubicin 60 mg/m(2) and cisplatin 80 mg/m(2) on day 1 every 4 weeks for a median 2. Floxuridine Metastasis from malignant tumor of colon thomsonhc. both administered by intravenous bolus injection. Median progression-free survival was 6 months with the etoposide regimen versus 7 months with the 5-FU regimen. mucositis. eight treatment. The 5-FU/6S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU 370 mg/m(2) daily on days 1 to 5. Neoplasm of gastrointestinal tract a) In a phase II study (n=65). 0%. 8. Etoposide Gastric cancer a) The combination of etoposide 120 milligrams/square meter (mg/m(2)). continuously. patients with lymph node metastases or low grade differentiation of the tumor showed a trend toward longer overall survival. respectively (p = NS). and alopecia. Substitution of etoposide in a regimen consisting of 5-fluorouracil 600 mg/m(2). 29.5%. epirubicin 45 mg/m(2) (days 1 and 29). Patients were followed for a median of 5 years (Tsavaris et al. however. etoposide 100 mg/m(2) on days 1. epirubicin 30 mg/m(2) and cisplatin 40 mg/m(2) on days 1 and 8 every 4 weeks for a median 3 cycles achieved a disappointing 20% overall response rate in the treatment of advanced gastric cancer in a Phase III trial (n=131). This study enrolled 92 patients with STAGE I to III disease who had complete resection of the tumor and lymph nodes or who had poorly differentiated tumors.and 5. 1996). and FLUOROURACIL did NOT produce a statistically significant difference (p=0. 1998). Within two weeks of surgery. although not statistically significant. and the anthracycline arm (10. and mitomycin 10 mg/m(2) (day 1). Toxicity was manageable and included neutropenia (eg. 5%) [413]. nausea/vomiting. Excision of tumor of stomach Gastric cancer a) MITOMYCIN. etoposide.0 8.9% of patients treated with 5FU/6S-LV and EEP-L. Neither regimen can be recommended for advanced gastric carcinoma [471].9%. 0%.related infectious episodes). The regimens were generally well-tolerated with no major differences in toxicity.25/10/12 Drug details .MICROMEDEX® 2. In both groups. and lonidamine 50 mg orally 3 times daily. Neither regimen produced a complete response.9%. 3. Both regimens were repeated every 4 weeks (Barone et al. median survival was similar for 5-FU/6S-LV5 (fluorouracil and leucovorin. lonidamine. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. respectively. patients were randomly assigned to treatment with 5-FU 600 milligrams/square meter (mg/m(2)) (days 1.4% and 3. partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1. However. diarrhea. 8 months) and EEP-L (epirubicin. 36). EPIRUBICIN. 9 months). 0%. cisplatin.

followed by a 1-week rest period. In the combination therapy group. with the exception of a higher frequency of diarrhea (29% versus 14%) and hepatic effects in the combination therapy group.002) and 2 (p=0.10 to 4.027). following leucovorin 200 mg/square meter. the postoperative combination of hepatic arterial infusion of floxuridine (FUDR) and systemic intravenous fluorouracil (5-FU). Adverse effects of moderate severity were similar in both groups.free survival was 37.34 (95% confidence interval. 1. with or without leucovorin. if studies permitting cross-over to regional therapy after disease progression were excluded.5% or 8. the survival advantage increased to 19.0 mg per deciliter occurred in 18% of patients.2 months in the combination therapy group and 59.02) (Kemeny et al. the risk ratio for death at two years in the systemic therapy alone group as compared with the combination therapy group was 2. The estimated median survival was 72. preceded each day by a 30.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and increased total bilirubin levels to more than 3.6% if cross-over studies were excluded.25/10/12 Drug details . demonstrated an improved two-year overall survival and decreased rate of recurrence compared with systemic chemotherapy alone. If a patient in either study group had previously received 5-FU and leucovorin. The two-year overall actuarial survival rate was 86% in the combination therapy group compared with 72% in the monotherapy group (p=0. The median duration of progression.1%. a 1-year survival advantage of 12. mucositis. Beginning four weeks after resection. leukopenia. When all studies were included.IntermediateToDocumentPrintLink 194/317 . The 2-year survival advantage was 7. Metastatic colorectal cancer a) Meta-analysis of 6 studies showed significantly better 1 (p=0. After adjustment for the location of primary tumor (rectum versus colon) and largest liver lesions (greater than or equal to 5 centimeters (cm) versus less than 5 cm).026) year survival in patients with colorectal cancer and metastases to the liver who were treated with hepatic regional floxuridine (FUDR) infusion versus systemic FUDR or fluorouracil (5-FU).MICROMEDEX® 2.4 and 17. respectively (p=0.98. Hospitalization for diarrhea.25 mg/kilogram (kg)/day. 5-FU was administered as 370 mg/square meter intravenously for 5 days every four weeks. or small bowel obstruction was required in 29 and 18 patients in the combination therapy and monotherapy groups. a total of 74 patients were randomized to receive six cycles of the combination therapy. tripling of the serum aspartate aminotransferase level occurred in 65%. dexamethasone 20 mg.2 months in the combination therapy and monotherapy groups. The rate of survival free of hepatic recurrence after two years was 90% in the combination therapy group and 60% in the monotherapy group (p less than 0. 1999).9% was noted.000 units was administered for 14 days. p=0.03). Two weeks later. hepatic arterial infusion of FUDR 0. The two-year actuarial rates of overall progression-free survival were 57% in the combination therapy group and 42% in the monotherapy group (p=0.minute infusion of leucovorin 200 mg/square meter.7 months. however. Among the 82 patients randomized to receive six cycles of systemic monotherapy beginning 4 weeks after resection.3 months in the monotherapy group. and heparin 50. doubling of the serum alkaline phosphatase level occurred in 29%.07). 5-FU alone was administered by continuous infusion at a dose of 850 mg/square meter for 5 days every five weeks in the combination therapy group and 1000 mg/square meter for 5 days every four weeks in the monotherapy group.0 a) In 156 patients who underwent complete resection of hepatic metastases from colorectal cancer. with a median follow-up of 62.001). respectively. thomsonhc. administered as a intravenous bolus of 5-FU 325 milligrams (mg)/square meter daily for 5 days.

001). Before regional chemotherapy is considered the treatment of choice for liver metastases associated with colorectal cancer. single.6 months) in the gemcitabine group (HR. 9 to 13. followed by 1 week of rest.3 months with the combination regimen (oxaliplatin.IntermediateToDocumentPrintLink 195/317 .4 g/m(2) IV over 46 hours continuous infusion repeated every 2 weeks (n=171) or gemcitabine 1000 mg/m(2) IV over 30 minutes once weekly for 7 consecutive weeks.57 (95% CI. p=0.0 While regional chemotherapy offers the benefit of relatively few systemic adverse effects. then resumed for 3 consecutive weeks thomsonhc.6% (95% CI. p less than 0. sensory neuropathy (9% vs 0%. First-line therapy a) The overall survival was increased by 4.6% vs 6% at 18 months. Grade 3 or 4 adverse events and corresponding rates for the FOLFIRINOX and gemcitabine groups.1 months) and 6. after 30 minutes. p less than 0.6% at 6 months. followed by one week off treatment.4% to 14.2 months) in the FOLFIRINOX group and 3. diarrhea (12. Pancreatic cancer a) Gemcitabine demonstrated superior efficacy to 5-fluorouracil (5.6%.03). respectively. p less than 0.001) in the gemcitabine group.001). 24. the median overall survival (primary endpoint for phase 3) was 11. irinotecan.5 to 7.6% at 12 months. was 31. with the addition.FU) in the treatment of chemotherapy-naive patients (n=126) with advanced.73. The gemcitabine regimen consisted of 1000 milligrams/square meter as a 30-minute intravenous infusion once weekly for 7 weeks.25/10/12 Drug details . 5. 0. phase 2/3 trial (n=342).7% vs 1.001).45 to 9. respectively.5 to 44.7%. The adjusted HR for death in the FOLFIRINOX was 0.blind study.001).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.4% vs 1. 2. febrile neutropenia (5. p less than 0.57 (95% CI.59. were neutropenia (45.MICROMEDEX® 2. At a median duration of follow-up of 26.4% vs 20.37 to 0. 48.2 to 3. followed by one week off treatment (n=171).4 months (95% CI.9% vs 57. immediately followed by fluorouracil 400 mg/m(2) IV bolus followed by fluorouracil 2. 20. The overall survival rates for the FOLFIRINOX group and gemcitabine group.04). of irinotecan 180 mg/m(2) IV over 90 minutes through a Yconnector.8 months (95% CI. p less than 0. 61 years) were randomized to the FOLFIRINOX group (oxaliplatin 85 mg/m(2) IV over 2 hours. 0. 5.3 months (95% CI. 0.3% vs 20.8%. immediately followed by leucovorin 400 mg/m(2) IV over 2 hours. additional study is needed to answer questions concerning quality of life [469]. p less than 0. The median progression-free survival was 6. 5.001) [442]. and 18.47 (95% CI. were 75. 0.2%. fluorouracil (FOLFIRINOX)) treatment compared with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma who had not received prior chemotherapy for advanced disease in a multicenter.7% to 39.001. Patients (median age. Gemcitabine Carcinoma of pancreas.7% vs 21%.6 months) for the FOLFIRINOX and gemcitabine groups (hazard ratio (HR) was 0. p=0. p less than 0. subsequent cycles were administered once weekly for 3 weeks. The recommended duration of chemotherapy was 6 months. nonresectable pancreas cancer in a randomized. complications associated with hepatic artery cannulation and hepatic toxicity are possible. and elevated level of alanine aminotransferase (7.45 to 0.001). The objective response (complete + partial response) rate. leucovorin. the primary endpoint for phase 2.1%) in the FOLFIRINOX group and 9.73.8%.4% (95% CI. randomized.1 months (95% confidence interval (CI).6 months (95% confidence interval (CI). p less than 0.1% vs 3.5 to 7. respectively.9 months). thrombocytopenia (9.

0 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. estrogen-receptor (ER) positive.MICROMEDEX® 2. and number of positive lymph nodes.3 ER. 24% of gemcitabine-treated patients and 5% of 5-FU-treated patients were classified as responders (p=0.8-4. 183 of 194 deaths due to breast cancer were recorded among goserelin patients. Disease-free (DFS) and overall survival (OS) were the primary outcomes. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomized 1.92 0. data analysis was performed after 684 events. the following hazard ratios (HR).1 p 0. Goserelin Breast cancer a) Goserelin was as effective and well-tolerated as the three-drug cytotoxic combination of cyclophosphamide.41 months) and 12-month survival probabilities (18% versus 2%) increased significantly with gemcitabine compared to 5.0022). confidence intervals (CI) and statistical significance were calculated (HR ratios less than 1 favor goserelin) for the median follow up time of 6 years: DISEASE-FREE SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1.0-1. 797 patients randomized to goserelin (3. compared to 151 of 165 for CMS patients (overall death rates of 25% verus 20%).0 1.(n=304) 1.8 1. F 600 mg/m(2) IV days 1 and 8) for 6 28-day cycles became the primary efficacy population cohorts. and fluorouracil (CMF) when used in premenopausal.8-1. For the primary outcome measure of clinical benefit. as well as those with unknown status.8 1. Median survival (5.25/10/12 Drug details . 5-FU was administered as 600 milligrams/square meter as a 30minute intravenous infusion once weekly.026 p 0. Side effect profiles (cytotoxic dominant or endocrinerelated) were reflective of the type of treatment received.IntermediateToDocumentPrintLink 196/317 .14 b) From overall survival statistics.0043 0. node-positive early localized breast cancer.0006 0.3-2. but leading to treatment withdrawal in fewer than 2% (Jonat et al. Trial design anticipated 688 outcome events.5 ER+ (n=1189) 1. thomsonhc. methotrexate.8-1.94 0. After local therapy (surgical with or without radiotherapy).0 out of every 4 weeks. functional impairment and weight for at least 4 weeks.6 milligrams (mg) depot subcutaneously every 28 days for 2 years) and 817 randomized to CMF (per cycle: C=500 mg per meter square IV on day 1 and 8 or 100 mg/m(2) orally days 1 through 14. overall approximately 15% of either treatment group reported a serious adverse event.029 0. defined as sustained improvement in a composite of pain.FU [421][421].6 ER unknown (n=121) 1.614 premenopausal or perimenopausal women 50 years old or younger with node-positive stage II operable breast cancer without metastasis.(n=304) 1. CMF was preferred in ER-negative patients.2 ER. M=40 mg/m(2) IV days 1 and 8.2-2.4 ER unknown (n=121) 2. 2002).4 ER+ (n=1189) 1.67 0.2 1.8 0.0-1.65 months versus 4. After adjusting for age.2 1.1-3.8 OVERALL SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1. tumor size.0 0.

This randomized study analyzed 81 patients with extensive axillary lymph-node involvement.31). and anemia was observed in the high-dose/transplant group. Likewise. overall survival in this intentionto-treat analysis was not significantly different between standard. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. Of 553 patients enrolled. respectively. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized.MICROMEDEX® 2. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414].dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone.IntermediateToDocumentPrintLink 197/317 . Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. mucositis occurred at a similar rate for both groups [414]. p=0.and high-dose chemotherapy were administered according to the following schema: INDUCTION AND HIGH-D0SE (CONTINUOUS MAINTENANCE INFUSION) Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg.23). median time to progression was not different between the standard. respectively. At 3 years. thrombocytopenia. c) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). Standard. radiation thomsonhc.and high. All randomized patients received a fourth course of the up-front chemotherapy regimen.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. mg/m(2)=milligrams/square meter IV=intravenous PO=oral b) Four to six cycles of induction therapy were given every 28 days. Subgroup analyses (estrogenreceptor status. EPIRUBICIN (120 mg/m(2).6 months. p=0.25/10/12 Drug details .and highdose/transplant therapy (38% and 32%. A greater incidence of severe leukopenia.dose/transplant groups (9 and 9.0 Hemopoietic stem cell transplant Breast cancer a) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high. Median follow-up was 37 months. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.

If a patient in either study group had previously received 5-FU and leucovorin.0 patients received a fourth course of the up-front chemotherapy regimen. p=0. 60 mg/m(2) epirubicin. Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0. with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. with or without leucovorin.25/10/12 Drug details . diarrhea. radiation therapy and 2 years of TAMOXIFEN therapy.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. fatigue. administered as a intravenous bolus of 5-FU 325 milligrams (mg)/square meter daily for 5 days. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. Beginning four weeks after resection.25 mg/kilogram (kg)/day. a total of 74 patients were randomized to receive six cycles of the combination therapy. mucositis.0001). a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support. the postoperative combination of hepatic arterial infusion of floxuridine (FUDR) and systemic intravenous fluorouracil (5-FU). 5-FU was administered as 370 mg/square meter intravenously for 5 days every four weeks. epirubicin. phlebitis. cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer. Two weeks later. Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. dexamethasone 20 mg.000 units was administered for 14 days.dose chemotherapy: 6000 mg/m(2) cyclophosphamide. respectively. and heparin 50. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. Among the 82 patients randomized to receive six cycles of systemic monotherapy beginning 4 weeks after resection. 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion. THIOTEPA 480 mg/m(2). preceded each day by a 30. The two-year overall actuarial survival rate was 86% in the combination therapy group compared with 72% in the thomsonhc. a tailored FEC (fluorouracil (5-FU).MICROMEDEX® 2. Toxicities were greater in the high-dose group but both groups experienced nausea. followed by a 1-week rest period. then high. The estimated 3-year relapse-free survival rate (72% versus 63%. and neutropenia. 5-FU alone was administered by continuous infusion at a dose of 850 mg/square meter for 5 days every five weeks in the combination therapy group and 1000 mg/square meter for 5 days every four weeks in the monotherapy group. 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide). A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al. demonstrated an improved two-year overall survival and decreased rate of recurrence compared with systemic chemotherapy alone. In addition to that. following leucovorin 200 mg/square meter. p=NS) favored group 1 over group 2.minute infusion of leucovorin 200 mg/square meter. 1998). Heparin Metastasis from malignant tumor of colon a) In 156 patients who underwent complete resection of hepatic metastases from colorectal cancer. alopecia. d) Following breast cancer surgery. 600 mg/m(2) cyclophosphamide). CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.IntermediateToDocumentPrintLink 198/317 .01) but not overall survival (83% versus 77%. All subjects underwent post-chemotherapy radiation and tamoxifen therapy. vomiting. hepatic arterial infusion of FUDR 0. 2000).

The two-year actuarial rates of overall progression-free survival were 57% in the combination therapy group and 42% in the monotherapy group (p=0. After adjustment for the location of primary tumor (rectum versus colon) and largest liver lesions (greater than or equal to 5 centimeters (cm) versus less than 5 cm). Relative risks for progression/death and mortality were 0. respectively.07). The median duration of therapy in both groups was 9 weeks.free survival was 37.34 (95% confidence interval. Cisplatin 50 milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation on days 1 and 29. 31.4 and 17.2 months in the combination therapy group and 59. and 33.98. b) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA cervical carcinoma. 1.99) thomsonhc. Cisplatin 50 milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation on days 1 and 29. The only statistically significant difference in toxicity was more frequent/severe neutropenia with hydroxyurea (p less than 0. The rate of survival free of hepatic recurrence after two years was 90% in the combination therapy group and 60% in the monotherapy group (p less than 0.62 to 0. the combination of 5-fluorouracil (5-FU) and cisplatin was superior to hydroxyurea alone as an adjunct to radiation therapy.62 to 0. 3. respectively.3 months in the monotherapy group. Relative risks for progression/death and mortality were 0. and 33.7 years.00001) [423]. respectively. or small bowel obstruction was required in 29 and 18 patients in the combination therapy and monotherapy groups.7 months.018).58 to 0. while 5-FU was dosed at 1 gram/m(2)/day on days 2. Patients randomized to oral hydroxyurea received 80 milligrams/kilogram/day twice weekly. Corresponding overall mortality rates were 45% and 57% (p=0.02) (Kemeny et al. leukopenia.001).2 months in the combination therapy and monotherapy groups.99) and 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 30.79 (90% confidence interval. respectively. After a median follow-up of 8. 30. After a median follow-up of 8.0 mg per deciliter occurred in 18% of patients.79 (90% confidence interval. with a median follow-up of 62.03). while 5-FU was dosed at 1 gram/m(2)/day on days 2. mucositis.027). The median duration of therapy in both groups was 9 weeks. Adverse effects of moderate severity were similar in both groups. 32. the rates of disease progression were 43% and 53% in the 5FU/cisplatin and hydroxyurea groups. 3. with the exception of a higher frequency of diarrhea (29% versus 14%) and hepatic effects in the combination therapy group. the rates of disease progression were 43% and 53% in the 5-FU/cisplatin and hydroxyurea groups. the risk ratio for death at two years in the systemic therapy alone group as compared with the combination therapy group was 2. 5. Patients randomized to oral hydroxyurea received 80 milligrams/kilogram/day twice weekly. tripling of the serum aspartate aminotransferase level occurred in 65%. 5. 4. 1999). Hydroxyurea Cervical cancer a) In a Phase III trial of 388 subjects with locally advanced stage IIB to IVA cervical carcinoma.95). and increased total bilirubin levels to more than 3.10 to 4. In the combination therapy group.018).MICROMEDEX® 2. 0. Hospitalization for diarrhea.IntermediateToDocumentPrintLink 199/317 . Corresponding overall mortality rates were 45% and 57% (p=0. p=0. respectively (p=0. 0.7 years. both favoring the 5-FU/cisplatin regimen. 32. The estimated median survival was 72.25/10/12 Drug details .74 (90% CI. 31. The median duration of progression. the combination of 5-fluorouracil (5-FU) and cisplatin was superior to hydroxyurea alone as an adjunct to radiation therapy. doubling of the serum alkaline phosphatase level occurred in 29%.0 monotherapy group (p=0. 0. 4.

respectively. III or IVB cancer of the cervix. the second study group. Drug-related toxicity was minimal in patients treated with 5-FU alone but was rated moderate in patients treated with the combination.7% for 5-FU plus IFN. Patients were randomly assigned to receive 5-FU 500 milligrams (mg) on days 1 to 5 followed by 5-FU 500 mg weekly starting on day 15 or the same dose and schedule of 5-FU plus IFN 1. fluorouracil 4 grams/square meter as a 96 hour infusion on days 1 and 29. Interferon Alfa Colon cancer a) After enrolling 142 patients with advanced colorectal cancer.FU/cisplatin regimen. There were no treatment-related deaths (Rose et al. c) The combination of CISPLATIN and RADIATION therapy or CISPLATIN. Grade 3/4 leukopenia was double the rate in the 3-drug group compared to the other 2 groups.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. the median time to progression and median survival were the same for both treatments.0 and 0.00001) (Whitney et al. but was similar in the other 2 groups. The overall response (complete and partial) for 5-FU alone was 12. and 47% respectively. and the control group were 66%. The control group was administered only hydroxyurea 3 grams/square meter orally twice weekly before radiation therapy on weeks 1 through 6. The median follow-up was 35 months.IntermediateToDocumentPrintLink 200/317 . and 49. This was also true for the other hematologic effects. The occurrence of grade 3/4 toxicities was greatest in the 3-drug regimen. and the combination offered no clinical advantage in the treatment of metastatic colorectal carcinoma in 50 patients. HYDROXYUREA. 1999). 1999).5% compared to 8.58 to 0. The rates of progression-free survival at 24 months for the first and second study group and the control group were 67%. Actual survival rates among the first study group. This phase II regimen consisted of a 2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) on 2 consecutive days. The combination regimen is NOT recommended for routine use in clinical practice since it does NOT improve survival. The second study group received cisplatin 50 mg/m(2) on days 1 and 29. 67%.95).25/10/12 Drug details . controlled trial.MICROMEDEX® 2.7% respectively. both favoring the 5. especially hematologic.55 for the first and second study groups respectively when compared to the control group. randomized.74 (90% CI. multicenter. Neoplasm of colon a) The addition of interferon-alfa to FLUOROURACIL and leucovorin was associated with higher toxicity. 0.5 million units (mU) on days 6 to 12 followed by 3 mU/day thereafter. There were 3 arms in this large (n=526). every two weeks thomsonhc.57 and 0. and hydroxyurea 2 grams/square meter orally twice a week before radiation therapy at weeks 1 through 6. and RADIATION therapy produced significantly better survival than a control group receiving hydroxyurea and radiation for the treatment of STAGE IIB. and a 48-hour infusion of FLUOROURACIL 1. The first study group received cisplatin 40 milligrams/square meter (mg/m(2)) over 4 hours before radiotherapy at weeks 1 through 6. All groups received radiation at varying doses depending on stage of disease. a study comparing fluorouracil (5-FU) to 5-FU plus interferon alpha-2a (IFN) was stopped due to a lower than expected response to 5-FU plus IFN [458].5 to 2 grams/m(2) per 24 hours starting the day after leucovorin. FLUOROURACIL. Progression-free survival relative risk was 0. 64%. The only statistically significant difference in toxicity was more frequent/severe neutropenia with hydroxyurea (p less than 0.

Results of the study showed an overall survival of 24 months and an objective response rate of 39. a longer disease-free interval. 3. Patients were randomly assigned to receive 5-FU 500 milligrams (mg) on days 1 to 5 followed by 5-FU 500 mg weekly starting on day 15 or the same dose and schedule of 5-FU plus IFN 1. 5 weeks 5-8) plus interleukin-2 (10x 10(6) IU/m(2). Subcutaneous interferon-alfa was given 3 times weekly: 3 million units for a body surface area (BSA) less than 1. and a longer duration of survival than FLUOROURACIL and leucovorin plus interferon alfa-2B in patients with advanced colorectal cancer. FLUOROURACIL plus leucovorin resulted in a higher initial response rate. One hundred patients were randomly assigned to receive racemic leucovorin 200 milligrams/square meter (mg/m(2)) and FLUOROURACIL 370 mg/m(2) for 5 consecutive days. In this study (n=78).7% for 5FU plus IFN. The median progression-free survival was 9 months and the median survival was 25 months (Tournigand et al.3. Interferon Alfa-2b Neoplasm of colon a) A phase III randomized study demonstrated that combination interferon alfa-2a and FLUOROURACIL did not significantly improve response rates or offer a survival advantage in 245 advanced colorectal cancer patients in comparison with FLUOROURACIL alone. and the authors discourage further study of this combination in advanced colorectal cancer patients (Greco et al.75 m(2). or 4.1% (17% complete response. Metastatic a) The combination of interleukin-2 with interferon-alfa and 5-fluorouracil (5-FU) has demonstrated significant therapeutic efficacy in patients with metastatic renal cell carcinoma compared to tamoxifen. Renal cell carcinoma. 5 x 10(6) IU/m(2) days 1. The overall response (complete and partial) for 5-FU alone was 12. b) In a comparative trial.75 m(2) or more. The combination was associated with greater toxicity resulting in treatment withdrawal. 5 weeks 2 and 3. day 1 weeks 1 and 4.IntermediateToDocumentPrintLink weekly from days 6 through 27.5 weeks 2 and 3) plus 5-FU (1000 milligrams/square meter (mg/m(2)).5 million units for a BSA of 1. Interferon Alfa-2a Colon cancer a) After enrolling 142 patients with advanced colorectal cancer. 3.0 until disease progression.MICROMEDEX® 2. 21. a study comparing fluorouracil (5-FU) to 5-FU plus interferon alpha-2a (IFN) was stopped due to a lower than expected response to 5-FU plus IFN [464]. or the same regimen plus subcutaneous interferon alfa-2b 3 x 10(6) international units subcutaneously 3 times thomsonhc. The combination regimen is NOT recommended for routine use in clinical practice since it does NOT improve survival. 1996).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5% compared to 8.. 1997). day 1 weeks 5-8).9% partial response) in the combination therapy group compared to an overall survival of 13 months and no objective remissions in the tamoxifen group (Atzpodien et al. Overall response rate was 44% with 21 patients experiencing Grade 3 to 4 toxicity. Drug-related toxicity was minimal in patients treated with 5-FU alone but was rated moderate in patients treated with the combination. patients were treated with interferon-alfa (5 x 10(6) international units/square meter (IU/m(2)).5 million international units (mU) on days 6 to 12 followed by 3 mU/day thereafter. days 1. 2001). 10 x 10(6) IU/m(2) days 1. The tamoxifen group received 80 mg twice daily for 8 weeks.25/10/12 Drug details . the median time to progression and median survival were the same for both treatments. twice-daily days 3-5 weeks 1 and 4. 201/317 .

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10(6) international units subcutaneously 3 times weekly from days 6 through 27.
Severe toxicity (hematologic, gastrointestinal) was more prevalent in the group
receiving interferon (Recchia et al, 1996).
c) Leucovorin (LV) plus 5-fluorouracil (5-FU) increased the objective response rate
and increased time to progression compared to interferon alfa-2b (IFN) plus 5-FU or
LV plus IFN plus 5-FU in patients with metastatic colorectal cancer. Median survival
was 16.2 months (p=0.02) for the 5-FU/LV arm versus 12.7 months for the 5-FU/IFN
arm. Patients (n=236) were randomly assigned to 3 treatment regimens of which all
included a weekly 24-hour continuous intravenous infusion (CI) of 5-FU 2600
milligrams/square meter (mg/m(2)) for 6 weeks with a 2-week rest modulated by: (1)
LV 500 mg/m(2) as a 2-hour infusion before 5-FU, (2) IFN 3 million units 3 times per
week before 5-FU, or (3) LV and IFN at the same doses. Due to toxicity (primarily
diarrhea, mucositis), the 5-FU dose was reduced by 20% in all treatment arms within
the first or second cycle. At an interim analysis, accrual to the 5-FU/LV/IFN arm was
stopped due to 3 toxic deaths (Kohne et al, 1998).
Irinotecan
Colorectal cancer
a) Based on results from a PHASE III trial (n=267) demonstrating improved survival
with irinotecan over high-dose 5-fluorouracil (5-FU) infusion regimens, investigators
recommend irinotecan as the standard second- line therapy for advanced colorectal
cancer resistant to first-line 5- FU. Irinotecan was dosed at 350 milligrams/square
meter (mg/m(2)) as a 90-minute intravenous infusion every 3 weeks for a median
duration of 4.2 months. The dose was reduced to 300 mg/m(2) in subjects over 70
years and those with a performance status of 2. Patients randomized to 5-FU received
one of 3 different regimens at the discretion of the investigator for a median duration
of 2.8 months. Despite these differences, all 5-FU-treated patients were grouped
together for outcome assessment. Median survival was significantly longer in the
irinotecan arm than in the 5-FU arm (10.8 versus 8.5 months, p = 0.04), with 45%
and 32% alive at 1 year, respectively. The only secondary survival endpoint to reach
statistical significance was median progression-free survival, which favored irinotecan
(4.2 versus 2.9 months, p = 0.03). Quality of life measures were statistically
equivalent between groups, with no unexpected toxicities reported [459][460].
Neoplasm of colon
a) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5- fluorouracil
(5-FU)/leucovorin (LV) (IFL) therapy resulted in increased survival, progression-free
survival, response rate, and duration of response as compared to bolus IFL alone.
Patients (n=925) with untreated, metastatic colorectal cancer were randomized to
bolus IFL/bevacizumab (n=403), bolus IFL/placebo (n=412), or 5-FU/LV/bevacizumab
(n=110). The IFL regimen consisted of intravenous (IV) irinotecan 125
milligrams/square meter (mg/m(2)), bolus IV 5-FU 500 mg/m(2), and LV 20 mg/m(2)
repeated every 4 to 6 weeks; the 5- FU/LV regimen consisted of bolus IV 5-FU 500
mg/m(2), LV 500 mg/m(2) repeated every 6 to 8 weeks. All doses of bevacizumab
were 5 mg/kilogram IV every two weeks. Results reported for the primary comparison
group (bolus IFL/bevacizumab vs. bolus IFL/placebo) were as follows: survival (20.3
vs. 15.6 months), progression-free survival (10.6 vs. 6.2 months), response rate
(44.9% vs. 34.7%; p=0.0029), and duration of response (10.4 vs. 7.1 months;
p=0.0014). Grade 3/4 adverse events potentially related to bevacizumab included
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bleeding (3.1%), hypertension (10.9%), proteinuria (0.8%), and gastrointestinal
perforation (1.5%). Thrombotic events such as deep vein thrombosis, pulmonary
embolism, and myocardial infarction occurred in 9%, 4%, 1.5% of patients
respectively (Hurwitz et al, 2003).
b) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL
(bolus irinotecan/5-fluorouracil (5-FU)/leucovorin (LV)) was safe and efficacious in
patients with untreated metastatic colorectal cancer. Patients (n=20) received
intravenous (IV) bevacizumab 10 milligrams/kilogram every other week, irinotecan
125 mg/square meter (mg/m(2)) IV, bolus IV 5-FU 500 mg/m(2), and LV 20 mg/m(2)
weekly for 4 of 6 weeks. The remaining patients enrolled into the study received
REDUCED dose IFL; irinotecan 100 mg/m(2), 5-FU 400 mg/m(2), and LV 20 mg/m(2).
Overall (OR) response rate (based on Response Evaluation Criteria In Solid Tumors
(RECIST)) was 45.7% (n=70). The OR obtained in the full and reduced IFL dose
groups was 33.3% and 48.3%, respectively. Time to progression was similar
regardless of IFL regimen used (full IFL group 12.1 months, reduced IFL group 10.8
months). Toxicity data (n=83) showed no statistical difference between grade 3 or 4
toxicities based on the starting dose of IFL (p value not reported). Grade 3/4 toxicities
included; diarrhea, neutropenia, febrile neutropenia, bleeding events,
thromboembolism and hypertensions. Proteinuria was infrequent (Giantonio et al,
2003).
c) Based on results from a PHASE III trial (n=267) demonstrating improved survival
with irinotecan over high-dose 5-fluorouracil (5-FU) infusion regimens, investigators
recommend irinotecan as the standard second-line therapy for advanced colorectal
cancer resistant to first- line 5-FU. Irinotecan was dosed at 350 milligrams/square
meter (mg/m(2)) as a 90-minute intravenous infusion every 3 weeks for a median
duration of 4.2 months. The dose was reduced to 300 mg/m(2) in subjects over 70
years and those with a performance status of 2. Patients randomized to 5-FU received
one of 3 different regimens at the discretion of the investigator for a median duration
of 2.8 months. Despite these differences, all 5-FU-treated patients were grouped
together for outcome assessment. Median survival was significantly longer in the
irinotecan arm than in the 5-FU arm (10.8 versus 8.5 months, p=0.04), with 45% and
32% alive at 1 year, respectively. The only secondary survival endpoint to reach
statistical significance was median progression-free survival, which favored irinotecan
(4.2 versus 2.9 months, p=0.03). Quality of life measures were statistically equivalent
between groups, with no unexpected toxicities reported (Van Cutsem & Blijham, 1999;
Rougier et al, 1998).
d) Treatment with IRINOTECAN, FLUOROURACIL, and LEUCOVORIN increased
progression-free survival and median survival compared to fluorouracil, and leucovorin
in patients with metastatic colorectal cancer (Saltz et al, 2000). However, subsequent
studies using this regimen were associated with unexpectedly higher death rates
(Sargent et al, 2001). In the phase III, open-label, multicenter trial (Saltz et al, 2000),
683 treatment-naive (for metastatic disease) patients were assigned via random
allocation to one of the following regimens:
e) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square
meter (mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus
Fluorouracil 500 mg/m(2) as an IV bolus All given weekly for 4 weeks every 6 weeks
or Double therapy - Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500
mg/m(2) as an IV bolus Both given daily on days 1 to 5 every 4 weeks or - Irinotecan
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125 mg/m(2) IV over 90 minutes Given weekly for 4 weeks every 6 weeks
f) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
double therapy, respectively (p=0.004); median survival was also extended from 12.6
to 14.8 months with triple therapy (p=0.04). The objective response rate (defined as
a 50% reduction in measurable lesions) increased from 28% to 50% in patients
receiving triple therapy (p less than 0.001). Irinotecan alone was generally
comparable to double therapy. Grade III or IV diarrhea (22.7%) and vomiting (9.7%)
occurred at a higher incidence with triple therapy; whereas, mucositis (16.9%),
neutropenia (66.2%), and neutropenic fever (14.6%) were more common after double
therapy. Results of this study suggest that triple therapy may become a new standard
of care (Mayer, 2000).
g) Treatment with irinotecan, fluorouracil, and leucovorin increased progression-free
survival and median survival compared to fluorouracil, and leucovorin in patients with
metastatic colorectal cancer (Saltz et al, 2000). However, subsequent studies using
this regimen were associated with unexpectedly higher death rates (Sargent et al,
2001). In this phase III, open-label, multicenter trial (Saltz et al, 2000), 683
treatment-naive (for metastatic disease) patients were assigned via random
allocation to one of the following regimens:
h) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square
meter (mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus
Fluorouracil 500 mg/m(2) as an IV bolus All given weekly for 4 weeks every 6 weeks
or Double therapy - Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500
mg/m(2) as an IV bolus Both given daily on days 1 to 5 every 4 weeks or - Irinotecan
125 mg/m(2) IV over 90 minutes Given weekly for 4 weeks every 6 weeks
i) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
double therapy, respectively (p=0.004); median survival was also extended from 12.6
to 14.8 months with triple therapy (p=0.04). The objective response rate (defined as
a 50% reduction in measurable lesions) increased from 28% to 50% in patients
receiving triple therapy (p less than 0.001). Irinotecan alone was generally
comparable to double therapy. Grade III or IV diarrhea (22.7%) and vomiting (9.7%)
occurred at a higher incidence with triple therapy; whereas, mucositis (16.9%),
neutropenia (66.2%), and neutropenic fever (14.6%) were more common after double
therapy.
Irinotecan Hydrochloride
Carcinoma of pancreas, First-line therapy
a) The overall survival was increased by 4.3 months with the combination regimen
(oxaliplatin, leucovorin, irinotecan, fluorouracil (FOLFIRINOX)) treatment compared
with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma who
had not received prior chemotherapy for advanced disease in a multicenter,
randomized, phase 2/3 trial (n=342). Patients (median age, 61 years) were
randomized to the FOLFIRINOX group (oxaliplatin 85 mg/m(2) IV over 2 hours,
immediately followed by leucovorin 400 mg/m(2) IV over 2 hours, with the addition,
after 30 minutes, of irinotecan 180 mg/m(2) IV over 90 minutes through a Yconnector, immediately followed by fluorouracil 400 mg/m(2) IV bolus followed by
fluorouracil 2.4 g/m(2) IV over 46 hours continuous infusion repeated every 2 weeks
(n=171) or gemcitabine 1000 mg/m(2) IV over 30 minutes once weekly for 7
consecutive weeks, followed by one week off treatment; subsequent cycles were
administered once weekly for 3 weeks, followed by one week off treatment (n=171).
The recommended duration of chemotherapy was 6 months. At a median duration
of
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The recommended duration of chemotherapy was 6 months. At a median duration of
follow-up of 26.6 months (95% confidence interval (CI), 20.5 to 44.9 months), the
median overall survival (primary endpoint for phase 3) was 11.1 months (95%
confidence interval (CI), 9 to 13.1 months) and 6.8 months (95% CI, 5.5 to 7.6
months) for the FOLFIRINOX and gemcitabine groups (hazard ratio (HR) was 0.57
(95% CI, 0.45 to 9.73; p less than 0.001), respectively. The overall survival rates for
the FOLFIRINOX group and gemcitabine group, respectively, were 75.9% vs 57.6% at
6 months, 48.4% vs 20.6% at 12 months, and 18.6% vs 6% at 18 months. The
adjusted HR for death in the FOLFIRINOX was 0.57 (95% CI, 0.45 to 0.73; p less than
0.001. The objective response (complete + partial response) rate, the primary
endpoint for phase 2, was 31.6% (95% CI, 24.7% to 39.1%) in the FOLFIRINOX
group and 9.4% (95% CI, 5.4% to 14.7%; p less than 0.001) in the gemcitabine
group. The median progression-free survival was 6.4 months (95% CI, 5.5 to 7.2
months) in the FOLFIRINOX group and 3.3 months (95% CI, 2.2 to 3.6 months) in the
gemcitabine group (HR, 0.47 (95% CI, 0.37 to 0.59; p less than 0.001). Grade 3 or 4
adverse events and corresponding rates for the FOLFIRINOX and gemcitabine groups,
respectively, were neutropenia (45.7% vs 21%; p less than 0.001), febrile
neutropenia (5.4% vs 1.2%; p=0.03), thrombocytopenia (9.1% vs 3.6%; p=0.04),
diarrhea (12.7% vs 1.8%; p less than 0.001). sensory neuropathy (9% vs 0%; p less
than 0.001), and elevated level of alanine aminotransferase (7.3% vs 20.8%; p less
than 0.001) [442].
Metastasis from malignant tumor of colon
a) In a randomized, multicenter, phase 3, noninferiority trial (n=491), second-line
treatment of metastatic colorectal cancer with irinotecan was noninferior in overall
survival (OS) compared with infusional fluorouracil, leucovorin, and oxaliplatin
(FOLFOX4). Patients (median age, 63 yr; range, 25 to 86 yr) refractory to a
fluorouracil-based regimen (or within 6 months of adjuvant fluorouracil) were
randomized to irinotecan 350 mg/m(2) IV on day 1, given every 3 wk (for patients
with an Eastern Cooperative Oncology group performance score of 2, age greater than
or equal to 70 yr, or a history of pelvic radiotherapy, 300 mg/m(2) IV on day 1, given
every 3 wk) or oxaliplatin 85 mg/m(2) IV on day 1, fluorouracil 400 mg/m(2) plus
leucovorin 200 mg/m(2) IV bolus followed by fluorouracil 600 mg/m(2) in 22-hr IV
infusions on days 1 and 2 (FOLFOX4). Median OS, the primary endpoint, in the intentto-treat population was 14.3 months (mo) (95% confidence interval (CI), 12 to 15.9
mo) for the irinotecan arm and 13.8 mo (95% CI, 12.2 to 15 mo) for the FOLFOX4
arm (p=0.38; hazard ratio (HR)=0.92; 95% CI, 0.8 to 1.1), demonstrating
noninferiority. With respect to the secondary endpoints, the tumor response rate (RR)
in the FOLFOX4 arm was significantly better compared with irinotecan (28% vs 15.5%
respectively; p=0.0009), and time to progression (TTP), was significantly better with
FOLFOX4, median 6.2 mo (95% CI, 5.3 to 7.4 mo) compared with a median of 4.4 mo
(95% CI, 3.3 to 5.5 mo) in the irinotecan arm (HR=0.73; 95% CI, 0.6 to 0.9;
p=0.0009). Significantly more patients discontinued the FOLFOX4 regimen due to
adverse reactions (17% vs 5% for irinotecan; p less than or equal 0.0001) while
irinotecan was discontinued more often due to disease progression (67% vs 57% for
FOLFOX4; p=0.027). Grade 3 or worse nausea, diarrhea, and febrile neutropenia were
statistically significantly more common in the irinotecan arm, while grade 3 or worse
neutropenia and paresthesias were statistically more common in the FOLFOX4 arm.
Crossover to the other treatment arm was required if disease progressed during
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second-line therapy; consequently 227 patients (46%) also received third-line
therapy. A significantly better RR was observed in the FOLFOX4 crossover arm
compared with irinotecan (13.6% vs 5.2%, respectively; p=0.039). FOLFOX4
crossover patients also had a significantly longer TTP (median 5.8 mo, 95% CI; 4.9 to
6.7 mo; p=0.0022), compared with the irinotecan arm (median 3.3 mo, 95% CI; 2.6
to 4.1 mo; HR=0.65; 95% CI; 0.5 to 0.9). For the entire study period, OS was not
significantly different in those patients who continued on to third-line therapy whether
the original treatment assignment was FOLFOX4 with subsequent irinotecan therapy
(median 15.9 mo; 95% CI; 14.3 to 17.5 mo), or was initially irinotecan followed by
FOLFOX4 (median 14.9 mo; 95% CI; 13.2 to 17.5 mo) [462].
b) A randomized multicenter trial demonstrated that a regimen of infused
FLUOROURACIL/LEUCOVORIN and OXALIPLATIN (FOLFOX) was more effective and
better tolerated than either IRINOTECAN and OXALIPLATIN (IROX) or IRINOTECAN
and bolus FLUOROURACIL/LEUCOVORIN (IFL) in patients with previously untreated
metastatic colorectal cancer. The IFL regimen (control regimen; n=264) was
intravenous (IV) irinotecan 125 milligrams per square meter (mg/m(2)) and
fluorouracil 500 mg/m(2) plus leucovorin 20 mg/m(2) as an IV bolus on days 1, 8, 15,
and 22 every 6 weeks. This IFL regimen (described by Saltz et al., 2000) led to a
higher death rate within the first 60 days of treatment in this IFL group; the patients
described in this study received the full dose regimen, but doses of irinotecan and
fluorouracil were subsequently reduced in that study arm. The FOLFOX regimen
(n=267) consisted of IV oxaliplatin 85 mg/m(2) on day 1 and fluorouracil 400
mg/m(2) plus leucovorin 200 mg/m(2) as an IV bolus followed by fluorouracil 600
mg/m(2) in 22 hour infusions on days 1 and 2 every 2 weeks. The IROX regimen
(n=264) was IV oxaliplatin 85 mg/m(2) and IV irinotecan 200 mg/m(2) every 3
weeks. Median time to disease progression was superior in the FOLFOX group (8.7
months) compared to either the IROX group (6.5 months, p=0.001) or the IFL group
(6.9 months, p=0.0014); no significant difference was found between the IROX and
IFL groups (p greater than 0.5). Median survival for the FOLFOX, IROX, and IFL
groups was 19.5 months, 17.4 months, and 15 months, respectively. The median
survival in the FOLFOX and IROX groups was significantly better than the IFL group
(p=0.0001 for FOLFOX, p=0.04 for IROX); survival in the FOLFOX and IROX groups
was not significantly different (p=0.09). Response rate in the FOLFOX group (45%)
was also significantly higher than either the IROX (35%, p=0.03) or the IFL groups
(31%, p=0.002). In addition, the adverse event profile was more favorable in the
FOLFOX group than the other groups. In the IFL and IROX groups, patients had higher
rates of diarrhea, nausea, vomiting, febrile neutropenia, and dehydration while
patients in the FOLFOX groups had higher rates of paresthesias and neutropenia. The
authors conclude that the results of this study support FOLFOX as a first-line standard
of care for patients with advanced colorectal cancer (Goldberg et al, 2004).
c) In a phase III study comparing two sequential therapies in metastatic colorectal
cancer patients, FOLFIRI then FOLFOX6 (upon disease progression or unacceptable
toxicity) and FOLFOX6 then FOLFIRI (upon disease progression or unacceptable
toxicity), no difference was found in survival and efficacy between the two arms. Two
hundred and twenty patients were randomized to either arm A (n=109), FOLFIRI then
to FOLFOX6, or arm B (n=111), FOLFOX6 then to FOLFIRI. Each FOLFIRI cycle
consisted of a 2-hour infusion of l- or dl-leucovorin (LV) (200 or 400 milligrams per
square meter (mg/m(2)), respectively) and irinotecan 180 mg/m(2) given as a 90thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink

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minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour
infusion of fluorouracil 2,400 mg/m(2) for 2 cycles, increased to 3,000 mg/m(2) from
cycle 3 in cases where toxicities greater than grade 1 did not occur during the first
two cycles. Each FOLFOX6 consisted of the same LV + FU regimen, with the addition
of a 2-hour infusion of oxaliplatin 100 mg/m(2) on day 1. Arm A offered a median
survival of 21.5 months compared to 20.6 months in patients treated with arm B
(p=0.99). Likewise, when response rate (RR) was compared in the first-line
therapies, FOLFIRI resulted in a 56% RR when compared to a 54% RR in the
FOLFOX6 group (p= NS); median progression-free survival (PFS) was found to be 8.5
months and 8.0 months (p=0.26), respectively. In second-line therapy, FOLFIRI when
compared to FOLFOX6 resulted in a 4% RR versus 15% RR (p= 0.05), respectively,
and 2.5 months versus 4.2 months median PFS (p=0.003), respectively. As first-line
therapy, gastrointestinal (except for diarrhea), alopecia, and fatigue were more
frequent with FOLFIRI and hematologic toxicities were more frequent with FOLFOX6.
Grade 3 oxaliplatin- induced neurotoxicity was reported at a high rate (34%) [463].
Lentinan
Gastric cancer
a) A combination of intraarterial lentinan, 5-fluorouracil, and mitomycin-C (FML) has
been superior to a regimen of intraarterial 5-fluorouracil plus mitomycin-C (FM), each
following gastrectomy and hepatectomy, in improving the prognosis of gastric cancer
patients with liver metastases [461].
Leucovorin
Breast cancer
a) A sixteen-week multidrug regimen achieved only marginally better outcomes than
CYCLOPHOSPHAMIDE, DOXORUBICIN, AND FLUOROURACIL (CAF) with similar
toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive, receptor-negative breast cancer patients. The patients were randomly
assigned to receive either the 16-week regimen or six cycles of CAF. Each 28-day
cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2))
orally days 1 through 14, doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500
mg/m(2) intravenously (IV) days 1 and 8. The 16-week regimen consisted of greater
doxorubicin and 5-FU dose intensity than CAF and sequential administration of
methotrexate and 5-FU, as well as continuous 5-FU infusion. The 16-week regimen
involved weekly treatments, ODD-NUMBERED WEEKS as cyclophosphamide 100
mg/m(2) orally days 1 through 7, doxorubicin 40 mg/m(2) IV day 1, methotrexate 100
mg/m(2) IV day 1, vincristine 1 mg IV day 1, 5-FU 600 mg/m(2) IV day 2 at 20 hours
after methotrexate. Leucovorin 10 mg/m(2) was administered orally every 6 hours for
six doses, beginning 24 hours after methotrexate. During EVEN-NUMBERED WEEKS,
patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2. Dose
modification occurred based upon toxicity evaluated and classified by the Common
Toxicity Criteria. The 4-year recurrence- free survival rate for the 16-week regimen
was 67.5% versus 62.7% for CAF (P=0.19, two-sided; P=0.095, one-sided), with a
median follow-up of 3.9 years. The estimated 4-year survival rate was 78.1% for the
16-week regimen and 71.4% for CAF (P=0.10, two-sided; P=0.05, one-sided).
Leukopenia, granulocytopenia, and thrombocytopenia were significantly worse with
CAF than with the 16-week regimen (P=0.0001, 0.003, and 0.0001 respectively).
Anemia was significantly higher with the 16-week regimen (P=0.0001). Febrile
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different between the two 207/317

0001 to 0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. neurotoxicity (P=0.0001). (p=0.04). skin toxicity (P=0. The regimen was compared to combination (CMF) cyclophosphamide 600 mg/m(2) IV. The calculated hazard ratio for death was 1. the median duration of response was 9 months and 6 months in the NFL and CMF groups respectively.0001).99 to 1. and leucovorin 300 milligrams as a 1hour infusion followed by fluorouracil 350 milligrams/square meter IV push on days 1. repeated after a 2-week break. Although median survival was similar in both groups.92. Patients received intravenous mitoxantrone 12 milligrams/square meter (mg/m(2)) on day 1. methotrexate 40 mg/m(2) IV. However limitations in the trial design. p=0.009).021). Carcinoma of pancreas a) Results from a randomized controlled trial of patients with resectable pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1) suggest that postoperative chemotherapy with fluorouracil and leucovorin improves survival whereas postoperative chemoradiotherapy negatively affects survival. chemoradiotherapy (n=73).MICROMEDEX® 2.04). The above regimen was tested in another study with the addition of fluorouracil (NFL) 350 mg/m(2) IV bolus on days 1. which was significantly different. Of the 163 patients participating in the quality-of-life study. Chemoradiotherapy was administered as a 20 Gray dose to the previous tumor bed in 10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 through 3.06). 1991). large drop out rates and potential bias hamper the interpretation of these results. b) An overall response rate of 65% (2 complete. 1997). and FLUOROURACIL among 31 patients with metastatic breast cancer. chemotherapy (n=75). LEUCOVORIN.and 3 (Hainsworth et al. Intent-to-treat analysis was used to conduct 2 comparisons: patients who received chemotherapy with patients who did not receive chemotherapy and patients who received chemoradiotherapy with patients who did not receive chemoradiotherapy. 2 and 3.05) for patients who received chemoradiotherapy. The NFL and CMF regimens produced a 45% vs 26% response rate. respectively. 18 partial) was achieved with combination MITOXANTRONE.28 (95% confidence interval (CI) 0.05) and weight loss (P=0. or combination chemoradiotherapy and chemotherapy (n=72). (p=0. nausea (P=0. Due to the complicated schedule and only marginally improved outcomes as compared with CAF.0 neutropenia hospital admission was not significantly different between the two regimens. p=0. Median survival did not significantly differ between those who received chemotherapy and those who did not. Chemotherapy was associated with a 0. The regimens were repeated at 21-day intervals and given to chemotherapynaive patients with metastatic breast cancer. The same regimens of chemoradiotherapy followed by chemotherapy were used for the combination therapy.0003). Median survival times also did not significantly differ between patients who received chemotherapy and thomsonhc.IntermediateToDocumentPrintLink 208/317 . but was insignificant by 4 months posttreatment (P=0. A total of 289 patients were randomized in a 2-by-2 factorial design to receive no treatment (n=69). Response duration ranged from 3 to 16+ months (Hainsworth et al.2. the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0. 1998). Chemotherapy consisted of leucovorin 20 mg/m(2) as an IV bolus followed by an IV bolus of fluorouracil 425 mg/m(2) on days 1 through 5 every 28 days for 6 cycles.55 to 0.66.71 hazard ratio for death (95% CI 0.25/10/12 Drug details . Other significantly worse adverse events in the 16-week regimen were stomatitis (P=0. repeated every 21 days.60). the 16-week regimen should not be substituted for CAF without careful consideration (Fetting et al. and fluorouracil 600 mg/m(2) given on day one.

2 to 3.57 (95% CI. The objective response (complete + partial response) rate.MICROMEDEX® 2.4% vs 20.3 months with the combination regimen (oxaliplatin.9 months).5 to 44.4 months (95% CI. p less than 0. respectively. phase 2/3 trial (n=342). respectively.001. 9 to 13. However only 70% of patients assigned to receive chemoradiotherapy received a total of 40 Gray according to the protocol and only 50% of patients assigned to receive chemotherapy received all 6 cycles of therapy. all subjects thomsonhc. the primary endpoint for phase 2. the median overall survival (primary endpoint for phase 3) was 11.03). Although these results are suggestive.1 months (95% confidence interval (CI). the ESPAC-3 trial and the Radiation Therapy Oncology Group trial 97-04 will shed further light on the role of chemoradiotherapy and chemotherapy in this patient population [439].37 to 0. were neutropenia (45. 5.1% vs 3.6 months) for the FOLFIRINOX and gemcitabine groups (hazard ratio (HR) was 0.04).6 months) in the gemcitabine group (HR. 0.6%. Patients (median age.59.001).0 those who did not.4% to 14.3% vs 20.45 to 9.6% at 6 months.8 months (95% CI.2%. Malignant tumor of rectum a) A 12-month course of fluorouracil (5-FU) plus leucovorin offered no significant advantage over a 6-month course in the postoperative treatment of patients with stage II or III RECTAL cancer (n=263).5 to 7.7% vs 1.4 g/m(2) IV over 46 hours continuous infusion repeated every 2 weeks (n=171) or gemcitabine 1000 mg/m(2) IV over 30 minutes once weekly for 7 consecutive weeks. immediately followed by fluorouracil 400 mg/m(2) IV bolus followed by fluorouracil 2. followed by one week off treatment. First-line therapy a) The overall survival was increased by 4.4% vs 1.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.57 (95% CI. 5. 24.6 months (95% confidence interval (CI). febrile neutropenia (5.7% vs 21%.6% at 12 months. p=0. sensory neuropathy (9% vs 0%. thrombocytopenia (9. p less than 0. 0.9% vs 57. 2.45 to 0. 48. The median progression-free survival was 6.3 months (95% CI.7%.1 months) and 6. immediately followed by leucovorin 400 mg/m(2) IV over 2 hours.8%.8%. fluorouracil (FOLFIRINOX)) treatment compared with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma who had not received prior chemotherapy for advanced disease in a multicenter.001). 20. leucovorin. p less than 0.6% (95% CI. Dosing consisted of leucovorin 100 milligrams/square meter (mg/m(2)) over 15-30 minutes then 5-FU 450 mg/m(2) over 60 minutes on days 1 to 5 of a 4-week cycle. p less than 0. irinotecan. and 18.IntermediateToDocumentPrintLink 209/317 . subsequent cycles were administered once weekly for 3 weeks. after 30 minutes.47 (95% CI. The overall survival rates for the FOLFIRINOX group and gemcitabine group. with the addition. p less than 0. Grade 3 or 4 adverse events and corresponding rates for the FOLFIRINOX and gemcitabine groups.6% vs 6% at 18 months. The adjusted HR for death in the FOLFIRINOX was 0. randomized. 0. The recommended duration of chemotherapy was 6 months. During the second cycle only.73. Analysis of patient drop out was not presented. 0.001). respectively.001). Carcinoma of pancreas.001). At a median duration of follow-up of 26.5 to 7. and elevated level of alanine aminotransferase (7.2 months) in the FOLFIRINOX group and 3. 61 years) were randomized to the FOLFIRINOX group (oxaliplatin 85 mg/m(2) IV over 2 hours.1%) in the FOLFIRINOX group and 9. was 31.001) in the gemcitabine group. p less than 0. were 75.7% to 39. 5.25/10/12 Drug details . followed by one week off treatment (n=171). p less than 0. of irinotecan 180 mg/m(2) IV over 90 minutes through a Yconnector.001) [442]. p=0. diarrhea (12.4% (95% CI.73. p less than 0.

b) In a randomized study enrolling 208 patients. Results of this study confirm that 5-FU plus LV provides a survival advantage for patients with advanced colorectal cancer. Interval to tumor progression. toxicity. metastatic colorectal cancer. with acceptable toxicity (Borner et al. Corresponding 3-year mortality rates were 20.9 months. overall survival (12.0002) compared to 5-FU alone for measurable.5% and 23. Metastasis from malignant tumor of colon a) Monthly low dose LEUCOVORIN (LV) plus 5 FLUOROURACIL (5-FU) increased progression-free survival (6. The 309 eligible patients were randomly assigned to 5-FU 400 milligrams/square meter/day (mg/m(2)) for 5 days repeated every 28 days or the same dose of 5-FU plus LV 20 mg/m(2)/day. respectively (p=NS). Complete and partial responses were observed in 21% and 14%.25/10/12 Drug details . 1998). the median times to recurrence were 16.4 Gy total exposure) with weekly leucovorin and reduced-dose 5-FU 350 mg/m(2). measurable tumor response rates and quality of life also were improved in the FLUOROURACIL/LEUCOVORIN group. The additional six cycles of 5-FU/leucovorin exposure was not associated with greater toxicity (Queiber et al. 2001). Patients with colorectal cancer were randomized to receive FLUOROURACIL 500 milligrams/square meter (mg/m(2)) for 5 consecutive days (repeated every 5 weeks) or FLUOROURACIL plus LEUCOVORIN in either a high-dose or low-dose regimen. offered no significant advantage over intravenous 5-FU in preoperative concurrent chemoradiotherapy (Kim et al. However.0 received daily pelvic radiotherapy (up to 50. p=0. 1989).4 versus 10 months. n=14)in combination with leucovorin 20 mg/m(2)/d continuously during radiotherapy. respectively (p=NS). p=0. respectively (p=0. The highest objective response rate was observed with low-dose LEUCOVORIN (43%) versus high-dose LEUCOVORIN regimen (26%) (O'Connell.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. In this small prospective study. Toxicities included diarrhea. p=0. LV was administered immediately before 5-FU. Combination therapy versus 5-FU alone resulted in a significant (p=0. Patients received either a intravenous bolus infusion of 5-FU 450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years.7%. stomatitis. 2 oral. a synthetic 5-deoxynucleoside derivative. A greater extension in survival occurred with FLUOROURACIL/LEUCOVORIN than with FLUOROURACIL alone.3 and 17. and objective responses (p=0. p=0. both were given as a rapid intravenous push injection. A similar study of 309 patients demonstrated that combining leucovorin 20 mg/m(2)/day with 5-fluorouracil thomsonhc. 50% and 43%. alopecia. and other primarily hematologic toxicity but no therapy related deaths were reported. FLUOROURACIL plus LEUCOVORIN was found to be superior to FLUOROURACIL alone. Fair and good quality of life scores showed no difference between the 2 groups.IntermediateToDocumentPrintLink 210/317 .0001) increase in World Health Organization grade 2 or greater nausea/vomiting. 2000).2 versus 3. n=14) in combination with leucovorin 20 mg/ m (2)/d for 5 consecutive days on the first and fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age 52 years.307). Mean follow-up period was 15 months with local (oral groups) and 3 systemic failures (1 IV.MICROMEDEX® 2. stomatitis and leukopenia (not different between the 2 groups). DOXIFLURIDINE. only 51% of patients randomized to 12 cycles actually completed them. Based on data from 223 evaluable subjects with a median 34 months of follow-up. b) No differences were noted in efficacy. and quality of life when intravenous (IV) fluorouracil (5-FU) and leucovorin were compared to oral DOXIFLURIDINE and leucovorin in 28 patients with advanced rectal cancer.168.8 months in the 12-month and 6-month groups. diarrhea.02).003).235).

1. This regimen was repeated every 2 weeks. followed by a 5FU bolus. 1997). and 3. the median progression-free survival was greater (p=0. nor did time to death (median survival. with median progression-free survival of 9 months and median survival of 25 months.5 to 2 grams/m(2)/24 hours was given after day 1 LV treatment.lleucovorin 200 mg/m(2). oral d. 1997). followed by bolus 5-fluorouracil (5FU) and then continuous infusion of 5FU.MICROMEDEX® 2. on a 4-week cycle. this was repeated on day 2. and median survival was 18 months (Beerblock et al. The overall response rate was 33. However. The reponse rate (complete and partial) was 32. Only the l-isomer of leucovorin is active.067). a 48-hour infusion of 5-FU. on a 2-week cycle produced a significantly better response rate than did LOW-DOSE BOLUS LEUCOVORIN. c) There was no difference in response. 1.7% with 5% of patients having a complete response. Addition of interferon-alpha-2a (IFA) to this regimen in another study (n=50) gave an overall response of 44%. 11% experienced grade 3-4 toxicities.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. followed by an intravenous bolus of 5FU 425 mg/m(2). Time to progression (median. Drugs were administered for 5 consecutive days at weeks 0. Doses were: l-leucovorin 100 milligrams/square meter (mg/m(2)).0004). Toxic effects did not differ significantly among treatments (Goldberg et al.l-leucovorin 125 mg/m(2) on hours 0.lleucovorin (standard). Fifteen percent experienced Grade 3 to 4 toxicity.IntermediateToDocumentPrintLink 211/317 .5% for the low-dose regimen (p=0. the median survival time was 65. compared to 24% with the low-dose regimen (deGramont et al. and 8 and every 5 weeks thereafter. 1998).25/10/12 Drug details . 1997). e) Increasing the dose of leucovorin (LV) and administering higher doses of 5fluorouracil (5FU) in a continuous infusion (without bolus) produced about the same results as other regimens that used lower doses and a combination of bolus and infusion of 5FU. Median progression-free survival was 8 months. repeated on 5 consecutive days. oral leucovorin (of the racemic mixture. 42% experienced Grade 3 to 4 toxicity (Tournigand et al. For the high-dose regimen. 1997).4. a HIGH-DOSE LEUCOVORIN INFUSION. The high-dose leucovorin regimen was leucovorin 200 mg/m(2) infused over 2 hours. 1 year). With the high-dose leucovorin regimen. Ninety-nine patients with confirmed colorectal adenocarcinoma and who had received no previous chemotherapy received a 2-hour infusion of LV 500 milligrams/square meter (mg/m(2)) on days 1 and 2. d) In a randomized trial with 433 assessable colorectal cancer patients.6% for the high-dose regimen and 14. followed by 5FU bolus 400 mg/m(2) and then 600 mg/m(2) infused over 22 hours.8 for the lowdose regimen (p=0. Patients were given intravenous l-leucovorin. or intravenous d. intravenous d. 6 months) did not differ for the 3 treatments. l-leucovorin is preferentially absorbed from the intestine). The possibility that the d-isomer interferes with enhancement of 5-FU activity by competition with the l-isomer for the carrier was tested in a study of 926 patients with unresectable or metastatic colon cancer. Leucovorin doses were followed by 5-FU 370 mg/m(2) in all cases. The low-dose leucovorin regimen was an intravenous bolus of leucovorin 20 mg/m(2).001).0 weeks for the high-dose regimen and 56.0 (5-FU) 400 mg/m(2)/day for 5 days every month resulted in significantly higher response rates and longer survival than when 5-FU alone was administered (Borner et al. or toxicity in patients with 3 DIFFERENT LEUCOVORIN FORMULATIONS in combination with 5-FLUOROURACIL (5FU). 2. survival. f) Clinical response was similar when FLUOROURACIL (425 milligrams/square meter (mg/m(2) intravenously (IV)) plus low-dose LEUCOVORIN (20 mg/m(2) IV) for 5 days thomsonhc.

Median PFS was 7. on day 1 and 2. then fluorouracil 400 mg/m(2) IV bolus and fluorouracil 600 mg/m(2) IV infusion over 22 hours. randomized study. versus 9% in IV group). followed by 400 mg/m(2) fluorouracil IHA infusion in 100 milliliters (mL) saline over 15 minutes and fluorouracil 1600 mg/m(2) over 22 hours. 300 mg/m(2) IV on day 1. The authors do NOT recommend use of the IHA regimen for unresectable metastatic colorectal cancer outside of a clinical trial setting (Kerr et al. folinic acid (200 milligrams per square meter (mg/m(2)). of the patients who did not start treatment or received fewer than 6 cycles.8 months for the IHA and IV groups. Patients (n=290) were randomly assigned to receive fluorouracil by either the intravenous (IV) or intrahepatic arterial (IHA) route. The 5-day regimen resulted in more stomatitis and leukopenia.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink 212/317 . The delay in starting chemotherapy in the IHA group while patients waited for laparotomy for catheter insertion might account for this difference (median time from randomization to start of chemotherapy. 45 (51%) switched to the IV regimen. on day 1 and 2. h) In a randomized. age greater than or equal to 70 yr. 63 yr. respectively. Thirty of 145 (22%) patients in the IHA group could not start treatment due to catheter problems (abnormal vasculature or catheter malfunction). leucovorin. maximum 350 mg) IV over 2 hours. second-line treatment of metastatic colorectal cancer with irinotecan was noninferior in overall survival (OS) compared with infusional fluorouracil. In the IHA group (n=145). response rates were 22% and 19% in the IHA and IV groups. 1994). Analysis was based on the intention to treat population. but the weekly regimen resulted more often in diarrhea and other adverse effects requiring hospitalization (Buroker et al. 1996). noninferiority trial (n=491). No group differences were reported for serious adverse events (grades 3 or 4). fluorouracil 400 mg/m(2) plus leucovorin 200 mg/m(2) IV bolus followed by fluorouracil 600 mg/m(2) in 22-hr IV thomsonhc. given every 3 wk) or oxaliplatin 85 mg/m(2) IV on day 1. multicenter. phase 3. g) In a multicenter.7 months and 6. range. 36% of all IHA patients experienced catheter thrombosis and 14% were unable to complete at least 6 cycles of IHA treatment for this reason. A higher number of early deaths was observed in the IHA group (23% by 12 weeks after start of chemotherapy. Twelve weeks after the start of chemotherapy. The IV group (n=145) received folinic acid 200 mg/m(2) (maximum 350 mg) IV over 2 hours. 25 to 86 yr) refractory to a fluorouracil-based regimen (or within 6 months of adjuvant fluorouracil) were randomized to irinotecan 350 mg/m(2) IV on day 1. or a history of pelvic radiotherapy. given every 3 wk (for patients with an Eastern Cooperative Oncology group performance score of 2. Patients (median age. and oxaliplatin (FOLFOX4). INTRAHEPATIC arterial FLUOROURACIL plus LEUCOVORIN (FOLINIC ACID) offered no progression-free or overall survival advantage compared to intravenous FLUOROURACIL plus FOLINIC ACID in patients with colorectal cancer with unresectable metastases confined to the liver. Only 38% of IHA patients received 6 or more chemotherapy cycles.7 months. was administered every 14 days. and median OS was 14.0 was compared with weekly FLUOROURACIL (600 mg/m(2) IV) and high-dose LEUCOVORIN (500 mg/m(2) IV) in the management of metastatic colorectal cancer. every 14 days (de Gramont regimen). respectively.25/10/12 Drug details . 14 days in IV group versus 35 days in IHA group). No significant differences were seen in progression-free survival (PFS) or overall survival (OS) between the groups. 2003).7 months and 14. Similar results were reported when IV fluorouracil 500 mg/m(2) was administered weekly with high-dose leucovorin (500 mg/m(2) IV) or low-dose leucovorin (20 mg/m(2) IV) (n=291) (Jager et al.MICROMEDEX® 2.

25/10/12 Drug details . demonstrating noninferiority. A significantly better RR was observed in the FOLFOX4 crossover arm compared with irinotecan (13. 95% CI. respectively.9 months. p=0. The median survival in the FOLFOX and IROX groups was significantly better than the IFL group (p=0.3 to 17. or was initially irinotecan followed by FOLFOX4 (median 14. the primary endpoint.027). p=0. no significant difference was found between the IROX and IFL groups (p greater than 0.MICROMEDEX® 2.04 for IROX). the tumor response rate (RR) in the FOLFOX4 arm was significantly better compared with irinotecan (28% vs 15. consequently 227 patients (46%) also received third-line therapy. median 6.039). HR=0. The IROX regimen (n=264) was IV oxaliplatin 85 mg/m(2) and IV irinotecan 200 mg/m(2) every 3 weeks. Median OS. i) A randomized multicenter trial demonstrated that a regimen of infused FLUOROURACIL/LEUCOVORIN and OXALIPLATIN (FOLFOX) was more effective and better tolerated than either IRINOTECAN and OXALIPLATIN (IROX) or IRINOTECAN and bolus FLUOROURACIL/LEUCOVORIN (IFL) in patients with previously untreated metastatic colorectal cancer.9. and IFL groups was 19. Grade 3 or worse nausea. p less than or equal 0. 3. 5.3 to 5. p=0.38. p=0. Significantly more patients discontinued the FOLFOX4 regimen due to adverse reactions (17% vs 5% for irinotecan.0014). 95% CI. 95% CI. 13.0009).8 mo (95% CI.9 to 6.4 mo) compared with a median of 4.6 to 4. and febrile neutropenia were statistically significantly more common in the irinotecan arm. diarrhea.5 mo) in the irinotecan arm (HR=0.7 mo. p=0.5 mo) [462]. 8. 4. 14.5 months. hazard ratio (HR)=0. 17.0022). OS was not significantly different in those patients who continued on to third-line therapy whether the original treatment assignment was FOLFOX4 with subsequent irinotecan therapy (median 15.3 to 7. while grade 3 or worse neutropenia and paresthesias were statistically more common in the FOLFOX4 arm. was significantly better with FOLFOX4.5 mo). IROX. and 22 every 6 weeks.1 mo. Median survival for the FOLFOX. Median time to disease progression was superior in the FOLFOX group (8.65. p=0. FOLFOX4 crossover patients also had a significantly longer TTP (median 5. Crossover to the other treatment arm was required if disease progressed during second-line therapy. This IFL regimen (described by Saltz et al. 2.001) or the IFL group (6.0001) while irinotecan was discontinued more often due to disease progression (67% vs 57% for FOLFOX4.7 months) compared to either the IROX group (6. compared with the irinotecan arm (median 3.4 mo (95% CI. 12 to 15.9). p=0.0001 for FOLFOX. The IFL regimen (control regimen..3 months (mo) (95% confidence interval (CI).73. With respect to the secondary endpoints. in the intentto-treat population was 14.6% vs 5. The FOLFOX regimen (n=267) consisted of IV oxaliplatin 85 mg/m(2) on day 1 and fluorouracil 400 mg/m(2) plus leucovorin 200 mg/m(2) as an IV bolus followed by fluorouracil 600 mg/m(2) in 22 hour infusions on days 1 and 2 every 2 weeks. the patients described in this study received the full dose regimen.9 mo. but doses of irinotecan and fluorouracil were subsequently reduced in that study arm.3 mo.9 mo) for the irinotecan arm and 13. 95% CI.2 to 17.9 mo. p=0. n=264) was intravenous (IV) irinotecan 125 milligrams per square meter (mg/m(2)) and fluorouracil 500 mg/m(2) plus leucovorin 20 mg/m(2) as an IV bolus on days 1. 0.2 mo (95% CI. 0.5 to 0. and 15 months. respectively.4 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5 months.92.6 to 0.5% respectively. and time to progression (TTP).2%. For the entire study period. 15. 95% CI.1). 95% CI.0009).0 infusions on days 1 and 2 (FOLFOX4).8 to 1.5). 2000) led to a higher death rate within the first 60 days of treatment in this IFL group. 0. 95% CI.2 to 15 mo) for the FOLFOX4 arm (p=0. 12. survival in the FOLFOX and IROX groups thomsonhc.8 mo.IntermediateToDocumentPrintLink 213/317 .

Each FOLFIRI cycle consisted of a 2-hour infusion of l. FOLFIRI resulted in a 56% RR when compared to a 54% RR in the FOLFOX6 group (p= NS). In the IFL and IROX groups.6 months in patients treated with arm B (p=0. 5-FU alone was administered by continuous infusion at a dose of 850 mg/square meter for 5 days every five weeks in the combination therapy group and 1000 mg/square meter for 5 thomsonhc.03) or the IFL groups (31%. Response rate in the FOLFOX group (45%) was also significantly higher than either the IROX (35%. the postoperative combination of hepatic arterial infusion of floxuridine (FUDR) and systemic intravenous fluorouracil (5-FU).0 was not significantly different (p=0. 5-FU was administered as 370 mg/square meter intravenously for 5 days every four weeks. or arm B (n=111). If a patient in either study group had previously received 5-FU and leucovorin.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. nausea. a total of 74 patients were randomized to receive six cycles of the combination therapy. respectively. Each FOLFOX6 consisted of the same LV + FU regimen. preceded each day by a 30. and 2. In addition.000 units was administered for 14 days. respectively) and irinotecan 180 mg/m(2) given as a 90minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour infusion of fluorouracil 2.25 mg/kilogram (kg)/day. gastrointestinal (except for diarrhea).002). The authors conclude that the results of this study support FOLFOX as a first-line standard of care for patients with advanced colorectal cancer (Goldberg et al.26). when response rate (RR) was compared in the first-line therapies. FOLFIRI then FOLFOX6 (upon disease progression or unacceptable toxicity) and FOLFOX6 then FOLFIRI (upon disease progression or unacceptable toxicity). administered as a intravenous bolus of 5-FU 325 milligrams (mg)/square meter daily for 5 days.400 mg/m(2) for 2 cycles. with or without leucovorin.000 mg/m(2) from cycle 3 in cases where toxicities greater than grade 1 did not occur during the first two cycles. with the addition of a 2-hour infusion of oxaliplatin 100 mg/m(2) on day 1. FOLFOX6 then to FOLFIRI. 2004). respectively. followed by a 1-week rest period.003). increased to 3.0 months (p=0. Likewise.5 months versus 4. and heparin 50. no difference was found in survival and efficacy between the two arms. the adverse event profile was more favorable in the FOLFOX group than the other groups. Among the 82 patients randomized to receive six cycles of systemic monotherapy beginning 4 weeks after resection. Arm A offered a median survival of 21. FOLFIRI then to FOLFOX6. p=0.IntermediateToDocumentPrintLink 214/317 . hepatic arterial infusion of FUDR 0. vomiting. Two weeks later. Grade 3 oxaliplatin. dexamethasone 20 mg.2 months median PFS (p=0. patients had higher rates of diarrhea. following leucovorin 200 mg/square meter.5 months and 8. Beginning four weeks after resection.MICROMEDEX® 2. respectively. demonstrated an improved two-year overall survival and decreased rate of recurrence compared with systemic chemotherapy alone. p=0.09).05). median progression-free survival (PFS) was found to be 8. As first-line therapy.99). febrile neutropenia. In second-line therapy.25/10/12 Drug details . k) In 156 patients who underwent complete resection of hepatic metastases from colorectal cancer.minute infusion of leucovorin 200 mg/square meter. j) In a phase III study comparing two sequential therapies in metastatic colorectal cancer patients. FOLFIRI when compared to FOLFOX6 resulted in a 4% RR versus 15% RR (p= 0. and fatigue were more frequent with FOLFIRI and hematologic toxicities were more frequent with FOLFOX6. and dehydration while patients in the FOLFOX groups had higher rates of paresthesias and neutropenia. alopecia.or dl-leucovorin (LV) (200 or 400 milligrams per square meter (mg/m(2)).induced neurotoxicity was reported at a high rate (34%) [463].5 months compared to 20. Two hundred and twenty patients were randomized to either arm A (n=109).

mucositis. 37% of patients in the 5-mg/kg arm were alive at 18-months. All doses of bevacizumab thomsonhc.1.03). imbalances in randomization (i. respectively. sex. The median duration of progression. 2004). respectively.98. along with small sample size and chance for the more effective outcome seen with the lower dose bevacizumab (Kabbinavar et al. respectively (p=0. The rate of survival free of hepatic recurrence after two years was 90% in the combination therapy group and 60% in the monotherapy group (p less than 0. the risk ratio for death at two years in the systemic therapy alone group as compared with the combination therapy group was 2. The estimated median survival was 72. respectively.9. or 5-FU/LV/bevacizumab (n=110).8 to 9.e. and 5.005). The two-year overall actuarial survival rate was 86% in the combination therapy group compared with 72% in the monotherapy group (p=0.10 to 4. and 13. and duration of response as compared to bolus IFL alone. Patients (n=925) with untreated. Median survival was 21. objective responses were seen in 40% (95% CI 24% to 58%) and 24% (95% CI 12% to 43%) of those treated with intravenous bevacizumab 5 milligrams/kilogram (mg/kg) and 10 mg/kg. every 2 weeks in combination with the standard chemotherapy regimen of 5-fluorouracil plus leucovorin (Roswell Park regimen). response rate. The IFL regimen consisted of intravenous (IV) irinotecan 125 milligrams/square meter (mg/m(2)). leukopenia. the 5. 1999). Hospitalization for diarrhea.2 months (95% CI 3. and increased total bilirubin levels to more than 3. b) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5. p= 0.25/10/12 Drug details .FU/LV regimen consisted of bolus IV 5-FU 500 mg/m(2). progression-free survival. with a median follow-up of 62.free survival was 37.02) (Kemeny et al.MICROMEDEX® 2. LV 500 mg/m(2) repeated every 6 to 8 weeks. or small bowel obstruction was required in 29 and 18 patients in the combination therapy and monotherapy groups.8 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 7. bolus IV 5-FU 500 mg/m(2). Adverse effects of moderate severity were similar in both groups.2 months in the combination therapy group and 59.5. p=0. 16.2 months (95% CI 3. Times to disease progression in these three groups were 9 months (95% CI 5.2. p= 0.0 days every four weeks in the monotherapy group. with the exception of a higher frequency of diarrhea (29% versus 14%) and hepatic effects in the combination therapy group. tripling of the serum aspartate aminotransferase level occurred in 65%. Neoplasm of colon a) In a randomized phase II study involving previously untreated patients with metastatic colorectal cancer (n=104).07).IntermediateToDocumentPrintLink were 5 mg/kilogram IV every two weeks.34 (95% confidence interval.fluorouracil (5-FU)/leucovorin (LV) (IFL) therapy resulted in increased survival.5 to 5.8 to 10. respectively. ECOG performance status. and baseline serum albumin) in this study was a limitation and may be a possible explanation.027). In the combination therapy group.6). After adjustment for the location of primary tumor (rectum versus colon) and largest liver lesions (greater than or equal to 5 centimeters (cm) versus less than 5 cm). doubling of the serum alkaline phosphatase level occurred in 29%. and LV 20 mg/m(2) repeated every 4 to 6 weeks.7 months.2 months in the combination therapy and monotherapy groups. Results 215/317 reported for the primary comparison .4 and 17.3 months in the monotherapy group. bolus IFL/placebo (n=412).001). a response rate of 17% (95% CI 7% to 34%) was observed in patients treated with standard chemotherapy alone. The two-year actuarial rates of overall progression-free survival were 57% in the combination therapy group and 42% in the monotherapy group (p=0. metastatic colorectal cancer were randomized to bolus IFL/bevacizumab (n=403).0 mg per deciliter occurred in 18% of patients. 1.217).

diarrhea.80 (hazard radio.6 months).1%). p less than 0. 1.7% (n=70).3%.5 months. North American phase III trial of patients with metastatic or advanced colorectal cancer (n=964). 2003). p=0.9 and 28. bleeding events. Grade 3/4 toxicities included. The OR obtained in the full and reduced IFL dose groups was 33.2% in the oral eniluracil/fluorouracil group and 12.3 months versus 14. response rate (44. Proteinuria was infrequent (Giantonio et al. and gastrointestinal perforation (1.9% vs. and no adjuvant therapy in the 12 months prior to receiving a study regimen. 13. Patients with no chemotherapy for advanced or metastatic disease. The overall response rate was 12. Intravenous leucovorin 20 mg/m(2) followed by IV fluorouracil 425 mg/m(2) were administered once daily for the first 5 days of each 28-day cycle. median duration of response was 27. p=0. p=0.6 vs. pulmonary embolism. 95% CI 0. Thrombotic events such as deep vein thrombosis.4 vs. Median progression-free survival was 20 weeks in the EU/5-FU group compared with 22.0014). bolus IFL/placebo) were as follows: survival (20.0 were 5 mg/kilogram IV every two weeks.15 mg/m(2) were administered twice daily for 28 days followed by a 7-day rest period in 5-week cycles. bolus IV 5-FU 500 mg/m(2).com/micromedex2/librarian/PFDefaultActionId/evidencexpert.5%). There were significant differences between the 5FU/LV group and the EU/5-FU group in the following grade 3/4 nonhematologic thomsonhc.880.7% in the IV fluorouracil/leucovorin group. respectively. However.3% and 48. 4%.8 months). 34. hypertension (10.4% versus 0. and LV 20 mg/m(2).03).5% of patients respectively (Hurwitz et al.0106). irinotecan 125 mg/square meter (mg/m(2)) IV.2%.75 to 1. proteinuria (0.3 vs.2 months). c) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL (bolus irinotecan/5-fluorouracil (5-FU)/leucovorin (LV)) was safe and efficacious in patients with untreated metastatic colorectal cancer.9%).1 months. and myocardial infarction occurred in 9%. the EU/5-FU regimen did not meet the protocol-specified definition of equivalence.IntermediateToDocumentPrintLink 216/317 . reduced IFL group 10. respectively.7 weeks in the 5-FU/LV group (p=0. Patients (n=20) received intravenous (IV) bevacizumab 10 milligrams/kilogram every other week.5 milligrams/square meter (mg/m(2)) and oral fluorouracil 1.31). febrile neutropenia. Grade 3/4 adverse events potentially related to bevacizumab included bleeding (3. p less than 0. 15.001) and febrile neutropenia (9.7 weeks. Overall (OR) response rate (based on Response Evaluation Criteria In Solid Tumors (RECIST)) was 45. irinotecan 100 mg/m(2). there was no significant difference in median overall survival between the group that received oral eniluracil plus fluorouracil (EU/5-FU) compared with the group who received intravenous (IV) fluorouracil plus leucovorin (5-FU/LV.MICROMEDEX® 2. d) In a randomized. EU/5-FU did not demonstrate a median survival of at least 80% that of the 5-FU/LV regimen because the lower limit of the two-sided 95% confidence interval (CI) around the hazard radio did not exceed 0.0029). 0. Toxicity data (n=83) showed no statistical difference between grade 3 or 4 toxicities based on the starting dose of IFL (p value not reported). 6. neutropenia. Oral eniluracil 11.001). Time to progression was similar regardless of IFL regimen used (full IFL group 12. 7. open-label. The remaining patients enrolled into the study received REDUCED dose IFL. and LV 20 mg/m(2) weekly for 4 of 6 weeks. thromboembolism and hypertensions. Grade 3/4 hematologic toxicity in the 5-FU/LV group compared with the EU/5-FU group included granulocytopenia (47% versus 5%. were included.8%). and duration of response (10. progression-free survival (10. 5-FU 400 mg/m(2). Results reported for the primary comparison group (bolus IFL/bevacizumab vs.7%.25/10/12 Drug details .1 months. 2003).

vomiting (3.62.1 months). median overall survival was 47. neutropenia (2. 1. 2002). 0. g) In another randomized phase III trial (n=602) comparing capecitabine to fluorouracil (5-FU) plus leucovorin in patients with advanced or metastatic colorectal cancer.4%. Patients with advanced or metastatic colorectal cancer who had not received prior chemotherapy for metastatic disease were randomized to receive capecitabine orally (1250 milligrams/square meter (mg/m(2)) twice daily for 14 days followed by a 7-day rest period) or 5-FU/LV (rapid intravenous (IV) injection of 20 mg/m(2) LV followed by an IV bolus of 425 mg/m(2) 5-FU on days 1 to 5 every 4 weeks).2 months versus 4.4 weeks and 63. 16. f) An overall response rate of 24.7%).7 months).0 toxicities: nausea (7% versus 3%.4%).4 months).3 months.001). 0. p=0. respectively).0 months).831. No significant differences were seen between the capecitabine group and the 5-FU/leucovorin group in overall survival (13.9%).1%. median time to disease progression (5.2 months versus 4.2 months versus 12. nausea.012).3 months and 4. an overall response rate of 19% was achieved with capecitabine compared to 15% with fluorouracil/leucovorin. and median time to disease progression (4. respectively). 25. median duration of response (9. phase III trial conducted outside of North America compared oral eniluracil plus fluorouracil (EU/5-FU) with intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) in patients with advanced colorectal cancer (n=531).FU/LV group included diarrhea (15.6%. 95% CI: 0. A significantly lower incidence of any grade of diarrhea. a significantly greater incidence of hand-foot syndrome occurred in patients who received capecitabine.2 months versus 9.5 months and 13.5% of patients in the capecitabine group (usually hand-foot syndrome or diarrhea) and 49. A comparison of grade 3/4 toxicity in the capecitabine group and 5. and alopecia occurred in the capecitabine group (p less than 0.7%).7 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.00)(Van Cutsem et al. open-label.95) as was progression-free survival (hazard ratio 0. p less than 0. Dose reduction for adverse reactions was required in 40. favorable toxicity profile. and fever 7% versus 0%.9%) and hyperbilirubinemia (17.IntermediateToDocumentPrintLink 217/317 . p less than 0.25/10/12 Drug details . 95% confidence interval (CI): 0.7 weeks. However.001). Chemotherapy-naive patients received either capecitabine 1250 milligrams/square meter (mg/m(2)) orally twice daily for 14 days followed by a 7-day rest period or a rapid intravenous (IV) injection of 20 mg/m(2) of leucovorin followed by an IV bolus of 5-FU 425 mg/m(2) on days 1 thomsonhc. 2001).6% in the EU/5-FU arm compared with 14.0%).4% in the 5FU/LV arm. The overall response rate was 11.6% in patients who received fluorouracil and leucovorin (5-FU/LV) (p=0.3% of patients in the 5-FU/LV group (usually stomatitis or diarrhea. mucositis 12% versus 1%.1 months and 9.001). respectively.5 months. respectively).0001) in a randomized phase III trial (n=605).69.770. There were no significant differences between the capecitabine group and the 5-FU/LV group in overall survival (12.0%. The authors conclude that capecitabine is an acceptable alternative for the treatment of advanced colorectal cancer based on its response rate. The authors note that the overall survival in the 5-FU/LV group (median. 4.8% was achieved in patients with advanced or metastatic colorectal cancer who received capecitabine compared to a response rate of 11. The duration of overall survival was statistically inferior in the EU/5-FU group (hazard ratio 0. and time to treatment failure (4. hand-foot syndrome (18. 14. stomatitis. p less than 0. hyperbilirubinemia (9% versus 22%.MICROMEDEX® 2. 13.3%. e) A randomized.5 months) was superior to those reported in most other studies of 5-FU/LV in this patient population (Schilsky et al. median duration of response (7.6%.00002). 5. 2001). and the convenience of oral therapy (Hoff et al. stomatitis (3.

and telephone consultations with physicians (Twelves et al. However.6% versus 17. methotrexate 130 mg/m(2)/day 20 hours before leucovorin 300 mg/m(2)/day followed by FLUOROURACIL 500 mg/m(2)/day administered over 1 hour for 4 days. Capecitabine patients also required fewer hospital visits for drug administration. h) In a large multicenter prospective. and uncomplicated grade 3/4 hyperbilirubinemia (p less than 0. capecitabine therapy was shown to substantially reduce medical resource use and to improve response rate and tolerability compared to the Mayo Clinic Regimen of 5-fluorouracil (5-FU)/leucovorin (LV) in patients with advanced or metastatic colorectal cancer. Both regimens were repeated every 21 days for 6 cycles. intravenous leucovorin 300 milligrams/square meter (mg/m(2))/day followed by FLUOROURACIL 500 mg/m(2)/day administered over 1 hour for 4 days. 2003. and had reduced expenses for managing adverse events.foot syndrome. Treatment was continued for 30 weeks or until the development of progressive disease or unacceptable toxicity. Group B. patients receiving capecitabine needed more frequent unscheduled home. grade 3/4 neutropenia and alopecia (p less than 0. Three patients in group B versus one in 218/317 . Capecitabine treatment resulted in superior response rates (26. Oral capecitabine has at least equivalent efficacy compared with intravenous fluorouracil/leucovorin with clinically meaningful safety advantages (Cutsem et al. office.Drug details . Twenty-four hours after the methotrexate infusion. 2003). were randomly assigned to receive one of the following regimens: Group A. 2001). serious bleeding seen in 3% of the bevacizumab patients and none of the FOLFOX patients (Benson et al. j) Modulation of FLUOROURACIL with folinic acid (leucovorin) plus methotrexate in patients with advanced colorectal cancer resulted in a higher response rate but similar survival when compared with modulation using only leucovorin. Primary endpoints of the study (response rate. daycare. randomized phase III clinical trial. regimen repeated every 2 weeks) were increased bleeding and hypertension.MICROMEDEX® 2. leucovorin 15 mg every 6 hours for 6 doses was administered.008).0001) with capecitabine compared with 5-FU/leucovorin.0001) and significantly higher incidences of cutaneous hand. In abstract form.0 to 5 every 4 weeks. 2001). i) Preliminary results from a randomized phase III trial (E3200) indicate that the addition of bevacizumab to FOLFOX4 (5-fluorouracil (5-FU)/leucovorin (LV)) and oxaliplatin) is safe in patients with advanced/metastatic colorectal cancer. There were significantly lower incidences of stomatitis.9%) and improved safety compared to 5FU/LV. Patients (n=602) were randomized to receive either capecitabine (1250 mg/m2 orally twice daily for 2 weeks followed by 1 week rest) or 5 FU/LV (20 mg/m2 of LV as a rapid IV injection followed by 425 mg/m2 of 5-FU as an IV bolus given daily for 5 days. or for the management of treatment related adverse effects. grade 3 hand-foot syndrome (p less than 0. D'Orazio & Lee.00001). Eighty-three patients with recurrent or metastatic colon or rectal cancer. it appears that the toxicities associated with the addition of bevacizumab to FOLFOX (10 milligrams (mg)/kilogram intravenously (IV) every two weeks plus oxaliplatin 85 mg/square meter (m(2)) IV on day 1/leucovorin 200 mg/m(2) IV and 5-FU 400 mg/m(2) IV followed by 5-FU 600 mg/m(2) IV infused continuously over 22 hours on days 1 and 2. grade 3/4 stomatitis. every 4 weeks). time to progression. and overall survival) have not yet been determined but are anticipated since the results of a recent study (bevacizumab plus IFL) indicate a improvement in survival (20 months) equal to FOLFOX alone. Time to first onset of treatment-related grade 3/4 adverse reaction was significantly later in the capecitabine group (p=0.

however. nausea/vomiting. patients experienced grade 3 neutropenia and diarrhea mostly. 1. k) The addition of oxaliplatin to the North Central Cancer Treatment Group/Mayo Clinic regimen of 5-fluorouracil (FU)/leucovorin (LV) (LV5FU2) demonstrated a prolonged progression-free survival (PFS).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. p=0. The most common grade 3/4 adverse events reported in the oxaliplatin/5FU/LV group were neuropathies (7%).hour infusion of LV5FU2. and diarrhea occurred at a higher incidence and was more severe in group B (Polyzos et al. thrombocytopenia. Patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first line therapy were randomized to single-agent oxaliplatin (n=156.7 months for arm A versus 16. Intent-to-treat response rates were reported as 21. 2002). All regimens were repeated every 2-weeks.6 months).0002. randomized.0 group A had a complete response. diarrhea. oxaliplatin extends PFS significantly (8. or 5-FU/LV (n=151. Although there were significant increases in grade 3/4 toxicities in arm B. 15 patients in group B versus 7 in group A had a partial response. m) A combination of oxaliplatin with fluorouracil plus leucovorin resulted in better response rates than oxaliplatin alone in patients with progressive colorectal cancer in a non-randomized study. neutropenia (44%). oxaliplatin/5-FU/LV (n=152.25/10/12 Drug details . the overall QOL scores were comparable for the two arms [440]. patients treated with oxaliplatin/5-FU/LV had an increased response rate and median time to progression (9%. The results indicate that when added to the bimonthly two. FOLFOX4). Oxaliplatin 130 milligrams/square meter (mg/m(2)) was infused over 2 hours every 21 days. 2 treated more than 6 months before study). All patients had progressive disease despite prior treatment with fluorouracil-containing regimens (23 receiving treatment within 6 months of study. day 2: LV 200 mg/m(2) followed by 5-FU 400 mg/m(2) bolus. day 1: oxaliplatin 85 mg/m(2) + LV 200 mg/m(2) followed by 5-FU 400 mg/m(2) bolus. Fluorouracil was administered by continuous infusion via central venous catheter at a dose of 200 up to thomsonhc. mucositis. and nausea/vomiting/diarrhea (11%. 1996). l) The safety and efficacy of single-agent oxaliplatin in patients with metastatic colorectal cancer (n=459) was compared to oxaliplatin in combination with 5fluorouracil (5-FU)/leucovorin (LV) and to the same dose and schedule 5-FU/LV in a multicenter.9%) in arm A and 50. 600 mg/m(2) (22 hour infusion). Grade 3/4 toxicities (neutropenia. was not statistically different between the two treatment groups (log-rank test p=0. 17.9% to 25.7 months) or oxaliplatin alone (1%. mucositis. quality of life (QOL) measurements for that group were not significantly influenced.1% to 54. 46.2 months versus 6. p=0.6 months) versus patients given 5-FU/LV (0%. acceptable toxicities. 2. 4.05). Toxicity consisting of neutropenia. In arm A.0% (95% CI. same dose and schedule). Wilcoxon p=0. 600 mg/m(2) (22 hour infusion).9%.0001) in arm B. Four hundred and twenty chemotherapy-naïve patients with metastatic colorectal cancer were randomized in a multi-center study to treatment with LV5FU2 which consisted of a 2hour infusion of LV 200 milligrams per square meter/day (mg/m(2)) followed by a bolus of FU 400 mg/m(2)/day and then a 22-hour infusion of FU 600 mg/m(2)/day repeated for 2 consecutive days every 14 days (arm A) or oxaliplatin (85 mg/m(2)) on day 1 plus LV5FU2 group (arm B. p=0.9% (95% confidence interval (CI). and maintenance of quality of life as first-line therapy in advanced colorectal cancer. controlled trial.MICROMEDEX® 2. 11%) (Prod Info Eloxatin (TM).2 months for arm B). 9%. and neuropathy) were more common in arm B than arm A were.12. At an interim analysis. Median overall survival (14.0003). day 1: 85 milligrams/square meter (mg/m(2)).0 months.IntermediateToDocumentPrintLink 219/317 .

Among 30 assessable patients. patient selection may have influenced results in this nonrandomized study. FLUOROURACIL plus leucovorin resulted in a higher initial response rate. While the results suggest a better response with combination therapy.25/10/12 Drug details . respectively). p) A phase III randomized study demonstrated that combination interferon alfa-2a and FLUOROURACIL did not significantly improve response rates or offer a survival advantage in 245 advanced colorectal cancer patients in comparison with FLUOROURACIL alone. response rates were low with both treatments (20% and 13%. After 11 to 15 cycles. 2 received the 5day bolus infusion of fluorouracil with leucovorin and 2 received continuous infusion of only fluorouracil. with an oxaliplatin dose of 100 milligrams/square meter (mg/m(2)). 1995) revealed no significant differences in objective response rate.MICROMEDEX® 2. with a median survival of 57 weeks. time to progression. 1998). of the 4 partial responders.5 cycles. Responses with the leucovorin plus continuous infusion regimen (46% overall) had been recorded during a previous study. 4 achieved partial remission and 4 achieved stable disease. whereas oxaliplatin alone was given to those who were not receiving the drug at that time (deBraud et al. n) A bimonthly regimen of leucovorin plus 48-hour continuous fluorouracil and oxaliplatin achieved higher responses in patients with colorectal cancer but was not as well-tolerated as the same regimen with a lower dose of oxaliplatin. and the authors discourage further study of this combination in advanced colorectal cancer patients (Greco et al. The regimen in the second study included leucovorin 500 mg/m(2) plus oxaliplatin 85 mg/m(2) (through separate infusion lines) as a 2-hour infusion. This regimen was given for two consecutive days every two weeks for a median of 9.0 300 mg/m(2)/day. q) In a comparative trial. or as a bolus infusion of 375 mg/m(2) over 5 days with leucovorin 100 mg/m(2).5 to 2 grams/m(2) as a 22-hour infusion. and thrombocytopenia in 13%. 1997). Progression-free survival lasted a median of 26 weeks. or quality of life. 4 patients had severe sensory neuropathy that was of prolonged duration following discontinuation of chemotherapy. Grade 3 to 4 toxicities were observed in 27% of patients. Of 12 patients treated with combination therapy. 6 had a partial response (20%) lasting 37 weeks. The present study included patients refractory to the previous regimen. none achieved remission and 4 had stable disease. 1996). Whether the between-regimen difference in response and toxicity was a result of the lower oxaliplatin dose or patient selection was not established (Andre et al. and a longer duration of survival than FLUOROURACIL and leucovorin plus interferon alfa-2B in patients with advanced colorectal cancer.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. survival. and 15 had stabilization lasting 27 weeks.IntermediateToDocumentPrintLink 220/317 . A direct comparison of raltitrexed and the Mayo regimen of fluorouracil/leucovorin (Cunningham et al. One hundred patients were randomly assigned to receive racemic thomsonhc. although liver enzyme elevations occurred only in the raltitrexed arm. Of the 13 patients receiving oxaliplatin alone. The potential advantages of raltitrexed emerging from this trial were its greater convenience in administration (once every 3 weeks) and potentially lower propensity for toxicity (reduced mucositis and severe leukopenia). a longer disease-free interval. The combination was associated with greater toxicity resulting in treatment withdrawal. the most common adverse events were non-febrile neutropenia in 20% of patients. followed by fluorouracil 1. o) Combined fluorouracil/leucovorin is advocated as the regimen of choice for advanced colorectal carcinoma by many specialists (Anon. since combination therapy was given to those who were receiving fluorouracil at the time the study began. 1998).

subsequent studies using this regimen were associated with unexpectedly higher death rates (Sargent et al. accrual to the 5-FU/LV/IFN arm was stopped due to 3 toxic deaths (Kohne et al. and LEUCOVORIN increased progression-free survival and median survival compared to fluorouracil. open-label. 2000). The objective response rate (defined as a 50% reduction in measurable lesions) increased from 28% to 50% in patients receiving triple therapy (p less than 0. multicenter trial (Saltz et al.Intravenous (IV) infusion of irinotecan 125 milligrams/square meter (mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500 mg/m(2) as an IV bolus All given weekly for 4 weeks every 6 weeks or Double therapy . In this phase III. At an interim analysis. gastrointestinal) was more prevalent in the group receiving interferon (Recchia et al.25/10/12 Drug details . 2000).Irinotecan 125 mg/m(2) IV over 90 minutes Given weekly for 4 weeks every 6 weeks u) Progression-free survival (primary endpoint) was 7 and 4. 2001). Patients (n=236) were randomly assigned to 3 treatment regimens of which all included a weekly 24-hour continuous intravenous infusion (CI) of 5-FU 2600 milligrams/square meter (mg/m(2)) for 6 weeks with a 2-week rest modulated by: (1) LV 500 mg/m(2) as a 2-hour infusion before 5-FU.Intravenous (IV) infusion of irinotecan 125 milligrams/square 221/317 . or the same regimen plus subcutaneous interferon alfa-2b 3 x 10(6) international units subcutaneously 3 times weekly from days 6 through 27. and leucovorin in patients with metastatic colorectal cancer (Saltz et al. and leucovorin in patients with metastatic colorectal cancer (Saltz et al.7%) occurred at a higher incidence with triple therapy.2%). 1998). However. Due to toxicity (primarily diarrhea. Irinotecan alone was generally comparable to double therapy. FLUOROURACIL. However. Severe toxicity (hematologic.004).MICROMEDEX® 2. Grade III or IV diarrhea (22. r) Leucovorin (LV) plus 5-fluorouracil (5-FU) increased the objective response rate and increased time to progression compared to interferon alfa-2b (IFN) plus 5-FU or LV plus IFN plus 5-FU in patients with metastatic colorectal cancer.Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500 mg/m(2) as an IV bolus Both given daily on days 1 to 5 every 4 weeks or . v) Treatment with irinotecan. or (3) LV and IFN at the same doses.7 months for the 5-FU/IFN arm. whereas. 2000). the 5-FU dose was reduced by 20% in all treatment arms within the first or second cycle. multicenter trial (Saltz et al. 2001). 2000). 683 treatment-naive (for metastatic disease) patients were assigned via random allocation to one of the following regimens: t) Triple therapy . respectively (p=0. Results of this study suggest that triple therapy may become a new standard of care (Mayer. neutropenia (66.6 to 14.2 months (p=0. median survival was also extended from 12. and leucovorin increased progression-free survival and median survival compared to fluorouracil.6%) were more common after double therapy. fluorouracil. 2000). s) Treatment with IRINOTECAN.9%). (2) IFN 3 million units 3 times per week before 5-FU.8 months with triple therapy (p=0. Median survival was 16.3 months after triple and double therapy.0 leucovorin 200 milligrams/square meter (mg/m(2)) and FLUOROURACIL 370 mg/m(2) for 5 consecutive days. 683 treatment-naive (for metastatic disease) patients were assigned via random allocation to one of the following regimens: w) Triple therapy .02) for the 5-FU/LV arm versus 12. In the phase III. open-label. and neutropenic fever (14. mucositis). subsequent studies using this regimen were associated with unexpectedly higher death rates (Sargent et al.7%) and vomiting (9. mucositis (16. 1996).04).001).

LV was administered immediately before 5-FU.6%) were more common after double therapy. Irinotecan alone was generally comparable to double therapy.6 to 14. 12. The overall incidence of grade 3 or 4 toxicities was significantly lower with the biweekly versus monthly regimen (10% versus 26%.7%) and vomiting (9. and a 48-hour infusion of FLUOROURACIL 1.IntermediateToDocumentPrintLink 222/317 .l-leucovorin 200 milligrams/square meter (mg/m(2)) or l-leucovorin 100 mg/m(2) as a 2-hour infusion. diarrhea and mucositis. Efficacy data are forthcoming (Andre et al.004).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. metastatic colorectal cancer. respectively (p=0.Irinotecan 125 mg/m(2) IV over 90 minutes Given weekly for 4 weeks every 6 weeks x) Progression-free survival (primary endpoint) was 7 and 4. Subcutaneous interferon-alfa was given 3 times weekly: 3 million units for a body surface area (BSA) less than 1.4 versus 10 months).02. both were given as a rapid intravenous push injection. neutropenia (66. mucositis (16. Grade III or IV diarrhea (22.9%).2%). then 5-FU 400 mg/m(2) as a 15minute bolus for 5 consecutive days every 28 days. with statistical significance noted for grade 3 or 4 neutropenia.001).9 months). The cycles continued for 24 or 36 weeks.75 m(2) or more. while the comparative regimen included d. z) Preliminary toxicity results favor a biweekly over a monthly regimen of fluorouracil (5-FU) plus leucovorin in the treatment of recently resected stage B2 or C colorectal adenocarcinoma in an open-label. p less than 0. Overall response rate was 44% with 21 patients experiencing Grade 3 to 4 toxicity. median survival was also extended from 12. whereas.5 to 2 grams/m(2) per 24 hours starting the day after leucovorin. diarrhea. and neutropenic fever (14. The median progression-free survival was 9 months and the median survival was 25 months (Tournigand et al.001). and objective responses (p=0.04). 2001).25/10/12 Drug details .2 versus 3.0 meter (mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500 mg/m(2) as an IV bolus All given weekly for 4 weeks every 6 weeks or Double therapy . y) The addition of interferon-alfa to FLUOROURACIL and leucovorin was associated with higher toxicity.Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500 mg/m(2) as an IV bolus Both given daily on days 1 to 5 every 4 weeks or .5 million units for a BSA of 1. Intravenous (IV) d. aa) Monthly low-dose leucovorin (LV) plus 5-fluorouracil (5-FU) increased progression-free survival (p=0. The objective response rate (defined as a 50% reduction in measurable lesions) increased from 28% to 50% in patients receiving triple therapy (p less than 0.3 months after triple and double therapy. overall survival (p=0.75 m(2).0001) increase in World Health Organization grade 2 or greater nausea/vomiting.MICROMEDEX® 2. Combination therapy versus 5-FU alone resulted in a significant (p=0. alopecia. every two weeks until disease progression. then bolus 5-FU 400 mg/m(2) then 600 mg/m(2) as a 22-hour continuous infusion on 2 consecutive days every 14 days characterized the biweekly regimen. 1997). This phase II regimen consisted of a 2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) on 2 consecutive days. especially hematologic. 6. This study enrolled 310 patients of whom 309 were eligible and were randomly assigned to 5-FU 400 milligrams/square meter/day (mg/m(2)) for 5 days repeated every 28 days or the same dose of 5-FU plus LV 20 mg/m(2)/day.0002) compared to 5-FU alone for measurable. randomized phase III trial (n=905).003. stomatitis.8 months with triple therapy (p=0.l-leucovorin 200 mg/m(2) or l-leucovorin 100 mg/m(2) as a 15-minute infusion. and other primarily thomsonhc. and the combination offered no clinical advantage in the treatment of metastatic colorectal carcinoma in 50 patients.7%) occurred at a higher incidence with triple therapy. or 4.

l-isomer of LV.004).1% of patients in the bimonthly group (p=0. Results of this study confirm that 5-FU plus LV provides a survival advantage for patients with advanced colorectal cancer with acceptable toxicity (Borner et al. 1997). or (3) IV bolus of d. patients (n=422) were randomized to receive 1-LV 100 milligrams/square meter (mg/m(2)) or 10 mg/m(2) as an intravenous bolus followed by FLUOROURACIL 370 mg/m(2) administered as a 15minute infusion. survival. however. there was no difference in response or survival between low-dose and high-dose leucovorin (LV) (Labianca et al. repeated every 4 weeks (Labianca et al. The remaining 143 patients received the same regimen but at a leucovorin-dose of 20 mg/m(2) (Jager et al. schedule. ac) Bimonthly leucovorin and FLUOROURACIL bolus plus continuous infusion produced more objective responses (p=0. One treatment-related death occurred in the monthly group. and longer median survival than monthly leucovorin and FLUOROURACIL in patients with advanced colorectal cancer. the optimal dose. and vomiting.MICROMEDEX® 2.25/10/12 Drug details . the oral d. overall survival was not significantly different (de Gramont et al. 1997. 5-fluorouracil (5-FU) plus leucovorin (LV) is more effective than 5-FU alone. and a 22-hour infusion of FLUOROURACIL 600 mg/m(2)/day repeated for 2 consecutive days at 2-week intervals. The objective response rate was higher in patients receiving the bimonthly versus monthly regimen.9% of patients in the monthly group and 11. 1996). 2. and toxicity (Goldberg et al. 1998). and the IV d. or (bi-monthly) 2-hour infusion of leucovorin 200 mg/m(2)/day followed by bolus FLUOROURACIL 400 mg/m(2)/day. 1996). Dose-limiting toxicity comprised diarrhea. 1996). 1. In 1 study. In this phase III study. controlled clinical trials which included patients with advanced colorectal cancer (total patients=713).0004). longer median progression-free survival (p=0. however. In the second study. however. Each cycle was administered for 5 consecutive days. 926 patients with metastatic colon cancer received 5-FU 370 milligrams/square meter (mg/m(2)) with 1 of the following LV regimens: (1) IV bolus of l-LV 100 mg/m(2) immediately before 5-FU.l-LV 125 mg/m(2) (total dose 500 mg/m(2)) at hours 0. and method of administration have NOT been determined (Machover. repeated for 5 consecutive days every 4 weeks.l-isomer of LV resulted in a comparable response rate. toxic diarrhea occurred at a higher incidence in the high-dose group (27% versus 16%) (Jager et al. (2) oral d.001). Patients were randomly assigned to receive either: (Monthly) bolus leucovorin 20 milligrams/square meter/day (mg/m(2)/day) followed by bolus FLUOROURACIL 425 mg/m(2)/day. ad) For metastatic colorectal cancer. and 3 followed by 5-FU.l-LV 200 mg/m(2) followed by 5-FU. 1997). Another phase III trial which compared intravenous racemic LV with 5-FU to l-LV with 5-FU also showed comparable efficacy between the 2 forms of LV (Scheithauer et al. stomatitis.0 hematologic toxicity but no therapy-related deaths were reported. 1996).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. 1997. 1997). Although this regimen is useful for palliation. ab) Biochemical modulation of fluorouracil (5-FU) with the intravenous (IV) l-isomer of leucovorin (LV). Jager et al. a survival advantage has NOT been demonstrated. 148 patients were randomized to a 2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) plus bolus FLUOROURACIL 500 mg/m(2) after 1 hour of the leucovorin infusion. Grade 3 to 4 toxicity was reported in 23. Numerous studies have evaluated the combination of 5-FU and LV. 1997).IntermediateToDocumentPrintLink 223/317 . Schmoll. ae) In 2 randomized. Both drugs were given for 5 consecutive days with repeat courses at 4 and 8 weeks and then every 5 weeks. Neoplasm of gastrointestinal tract thomsonhc.

there was no significant difference in survival (15. Treatment was well tolerated with no treatment-related deaths. In both groups.9% of patients treated with 5FU/6S-LV and EEP-L. chemoradiotherapy (n=70). DOXIFLURIDINE. etoposide 100 mg/m(2) on days 1. chemotherapy (n=74).MICROMEDEX® 2. Of 541 patients. 2001). cisplatin.4 months for patients who received chemotherapy (n=146) versus 15.168. a synthetic 5-deoxynucleoside derivative. lonidamine. respectively. both administered by intravenous bolus injection. p=0.and 5.25/10/12 Drug details .IntermediateToDocumentPrintLink dose in 10 daily fractions over 2 224/317 .235). partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1.307).0 months in patients who received chemoradiotherapy or no treatment (n=235. Neoplasm of rectum a) No differences were noted in efficacy. p=0. however. this survival benefit was not significant in patients randomized in the original 2-by-2 factorial trial design with a median survival of 17. n=14) in combination with leucovorin 20 mg/m(2)/d for 5 consecutive days on the first and fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age 52 years.1 months.0005). Toxicities included diarrhea. Both regimens were repeated every 4 weeks (Barone et al. The 5-FU/6S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU 370 mg/m(2) daily on days 1 to 5. a median survival of 19. Mean follow-up period was 15 months with 1 local (oral group) and 3 systemic failures (1 IV. offered no significant advantage over intravenous 5.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.3. and lonidamine 50 mg orally 3 times daily.2% and 21. 2 oral.FU in preoperative concurrent chemoradiotherapy (Kim et al. 8 months) and EEP-L (epirubicin.24). Neither regimen produced a complete response. In this small prospective study. Fair and good quality of life scores showed no difference among the 2 groups.0 a) In a phase II study (n=65). toxicity. 285 were randomized in a 2-by-2 factorial design to receive no treatment (n=69). stomatitis and leukopenia (no difference between the 2 groups). 1998).7 months was achieved in patients who received ADJUVANT CHEMOTHERAPY with FLUOROURACIL and LEUCOVORIN (n=238) compared with 14. or chemoradiotherapy and chemotherapy (n=72). 9 months). p=0. continuously. partial responses were achieved in 28. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. p=0.9 months for patients who did not (n=139). cisplatin 30 mg/m(2) on days 2 and 4. The trial was expanded to allow clinicians to enroll patients in the original trial design as above or to select randomization to either chemoradiotherapy/no chemoradiotherapy (n=68) or chemotherapy/no chemotherapy (n=188) and to provide any additional treatment of their choosing prior to enrollment. etoposide. median survival was similar for 5-FU/6S-LV5 (fluorouracil and leucovorin. and quality of life when intravenous (IV) fluorouracil (5-FU) and leucovorin were compared to oral DOXIFLURIDINE and leucovorin in 28 patients with advanced rectal cancer. In a comparison of patients who received CHEMORADIOTHERAPY (n=175) and those who received chemotherapy or no treatment (n=178). respectively (p=0.5 versus 16. Complete and partial responses were observed in 21% and 14%. n=14)in combination with leucovorin 20 mg/m(2)/d continuously during radiotherapy. However. Patients received either a intravenous bolus infusion of 5-FU 450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years. Pancreatic cancer a) In interim results of a randomized controlled trial of patients with resectable pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1). Chemoradiotherapy consisted of 20 Gray (Gy) tumor thomsonhc. 50% and 43%.

Leucovorin Calcium Metastatic colorectal cancer a) Bimonthly high-dose leucovorin and bolus fluorouracil plus continuous infusion fluorouracil was more effective and less toxic than a monthly low-dose leucovorin and bolus fluorouracil regimen in patients (n=448) with previously untreated metastatic colorectal cancer [425]. repeated after a 2-week break. there was no significant difference in survival (15.5 versus 16. chemotherapy (n=74). The same regimens of chemoradiotherapy followed by chemotherapy were used for the combination therapy. 28 in the chemotherapy group. In a comparison of patients who received CHEMORADIOTHERAPY (n=175) and those who received chemotherapy or no treatment (n=178). Grade 3/4 toxicity was reported by 1 patient in the chemoradiotherapy group. 118 chemotherapy.0005). chemoradiotherapy (n=70). Chemotherapy consisted of leucovorin 20 mg/m(2) IV bolus followed by fluorouracil 425 mg/m(2) IV bolus on days 1 through 5 every 28 days for 6 cycles. p=0.7 months was achieved in patients who received ADJUVANT CHEMOTHERAPY with FLUOROURACIL and LEUCOVORIN (n=238) compared with 14. neutropenia (25%) and diarrhea (23%). or chemoradiotherapy and chemotherapy (n=72). 285 were randomized in a 2-by-2 factorial design to receive no treatment (n=69).1 months.0 Chemoradiotherapy consisted of 20 Gray (Gy) tumor dose in 10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 through 3. and 15 in the combination group and included stomatitis (32%). p=0. 2001). Grade 3/4 toxicity was reported by 1 patient in the chemoradiotherapy group. and 54 combination. 28 in the chemotherapy group. Of 541 patients. Chemoradiotherapy consisted of 20 Gray (Gy) tumor dose in 10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 through 3. and 15 in the combination group and included stomatitis (32%).24). Chemotherapy consisted of leucovorin 20 mg/m(2) IV bolus followed by fluorouracil 425 mg/m(2) IV bolus on days 1 through 5 every 28 days for 6 cycles. Toxicity data was collected on a subset of 246 patients (74 chemoradiotherapy. The trial was expanded to allow clinicians to enroll patients in the original trial design as above or to select randomization to either chemoradiotherapy/no chemoradiotherapy (n=68) or chemotherapy/no chemotherapy (n=188) and to provide any additional treatment of their choosing prior to enrollment. a median survival of 19. Further trials are needed to confirm the survival benefit of chemotherapy (Neoptolemos et al.MICROMEDEX® 2. Toxicity data was collected on a subset of 254 patients (74 chemoradiotherapy. Further trials are needed to confirm the survival benefit of chemotherapy (Neoptolemos et al. b) In a randomized trial of patients (n=429) with metastatic colorectal cancer.4 months for patients who received chemotherapy (n=146) versus 15. b) In interim results of a randomized controlled trial of patients with resectable pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1). repeated after a 2-week break. this survival benefit was not significant in patients randomized in the original 2-by-2 factorial trial design with a median survival of 17. The same regimens of chemoradiotherapy followed by chemotherapy were used for the combination therapy.0 months in patients who received chemoradiotherapy or no treatment (n=235. However. 2001).9 months for patients who did not (n=139). 118 chemotherapy. the 225/317 . and 54 combination. neutropenia (25%) and diarrhea (23%).25/10/12 Drug details .

IntermediateToDocumentPrintLink were observed with lonidamine/FAC 226/317 . doxorubicin. The following 6 regimens were compared [426]: Fluorouracil 500 mg/m(2)/day IV bolus Days 1 through 5. 8 weeks. IV = intravenous. Repeat course at 4.MICROMEDEX® 2. Repeat course at 3. Lonidamine Breast cancer a) Preliminary results from a large randomized trial (n=199) have indicated the superiority of oral lonidamine 600 milligrams daily plus FAC (5-fluorouracil. hrs = hours. All repeated days 1 through 5. suggesting that the latter represents an inferior pharmacoeconomic choice [467]. 6 weeks and then every 4 weeks OR Methotrexate 40 mg/m(2) IV on days 1 and 8.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and symptomatic relief. then every 5 weeks OR Leucovorin 20 mg/m(2)/day IV bolus immediately followed by Fluorouracil 370 mg/m(2)/day IV bolus. Cisplatin 20 mg/m(2)/day over 2 hours. 8 weeks. Only low-dose leucovorin plus fluorouracil was associated with a significant (p less than 0. Repeat course at 4. Leucovorin 14 mg/m(2) orally every 6 hrs for 8 doses (begin 24 hrs after the start of the methotrexate infusion).210 for intraportal chemotherapy and $2. cyclophosphamide) over FAC alone in patients with metastatic breast cancer [468]. performance status. weight gain. An indirect comparison derived a cost-effectiveness ratio per discounted life-year gained of $1. Repeat course every 5 weeks OR Methotrexate 200 mg/m(2) IV over 4 hours.05) superiority in quality of life. Response rates of 63% and 44% thomsonhc.094 for systemic chemotherapy. All repeated days 1 through 5. Fluorouracil 900 mg/m(2) bolus IV (7 hrs after the beginning of methotrexate). then every 5 weeks mg/m(2) = milligrams/square meter. Repeat course every 5 weeks OR Fluorouracil 325 mg/m(2)/day IV bolus. Levamisole Colon cancer a) The combination of oral levamisole and intravenous fluorouracil is more effective than levamisole alone as adjunctive therapy in patients with resected Dukes stage C colon cancer [466]. All repeated days 1 through 5. Repeat cycle every 28 days OR Leucovorin 200 mg/m(2)/day IV bolus followed by Fluorouracil 370 mg/m(2)/day IV bolus. CIV = continuous intravenous infusions.25/10/12 Drug details . A pharmacoeconomic evaluation of patients with colorectal cancer led to a better cost-effectiveness ratio with intraportal chemotherapy (with mitomycin and fluorouracil) as compared to systemic chemotherapy (with fluorouracil and levamisole).0 combination of fluorouracil and leucovorin demonstrated a therapeutic advantage (improved tumor response rates and survival) over fluorouracil alone. Fluorouracil 700 mg/m(2) IV bolus 24 hrs after each dose of methotrexate.

7 months. and fluorouracil (CMF) when used in premenopausal. the following hazard ratios (HR). node-positive early localized breast cancer. confidence intervals (CI) and statistical significance were thomsonhc. estrogen-receptor (ER) positive. Both regimens were repeated every 4 weeks (Barone et al. respectively). Neither regimen produced a complete response.0 cancer [468]. Response rates of 63% and 44% were observed with lonidamine/FAC and FAC alone. Neoplasm of gastrointestinal tract a) In a phase II study (n=65). median time to treatment failure was 7. lonidamine. continuously. FLUOROURACIL) in the treatment of metastatic breast cancer. Twelve of the 18 patients receiving CAF had objective responses. and number of positive lymph nodes.9% of patients treated with 5FU/6S-LV and EEP-L. 9 months).IntermediateToDocumentPrintLink 227/317 . median survival was 22. Nine of 18 patients receiving mitomycin plus medroxyprogesterone had objective responses. 797 patients randomized to goserelin (3. however. F 600 mg/m(2) IV days 1 and 8) for 6 28-day cycles became the primary efficacy population cohorts. 1998). The 5-FU/6S-LV regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU 370 mg/m(2) daily on days 1 to 5. respectively.25/10/12 Drug details . as well as those with unknown status. etoposide 100 mg/m(2) on days 1. cisplatin 30 mg/m(2) on days 2 and 4. CMF was preferred in ER-negative patients.MICROMEDEX® 2. After adjusting for age. Toxicity was similar with either regimen. n=18. Trial design anticipated 688 outcome events. partial responses were achieved in 28. median survival was 16. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomized 1.6 milligrams (mg) depot subcutaneously every 28 days for 2 years) and 817 randomized to CMF (per cycle: C=500 mg per meter square IV on day 1 and 8 or 100 mg/m(2) orally days 1 through 14. respectively. 34 patients were randomized to either treatment (n=18. Following first relapse. 8 months) and EEP-L (epirubicin. 1992).2% and 21. DOXORUBICIN.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Medroxyprogesterone Breast cancer a) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF (CYCLOPHOSPHAMIDE. Methotrexate Breast cancer a) Goserelin was as effective and well-tolerated as the three-drug cytotoxic combination of cyclophosphamide.7 months. cisplatin. tumor size. and lonidamine 50 mg orally 3 times daily. Disease-free (DFS) and overall survival (OS) were the primary outcomes. EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5. In both groups. methotrexate. After local therapy (surgical with or without radiotherapy). Treatment was well tolerated with no treatment-related deaths.6 months. median time to treatment failure was 5. Objective responses were not significantly different between the 2 regimens (Falkson et al.and 5.614 premenopausal or perimenopausal women 50 years old or younger with node-positive stage II operable breast cancer without metastasis. a significantly longer progression-free survival was also reported in the lonidamine/FAC group.5 months. etoposide. partial responses were more frequent in patients with resection of the primary tumor and a performance status of 0 or 1. M=40 mg/m(2) IV days 1 and 8. data analysis was performed after 684 events. both administered by intravenous bolus injection.3. median survival was similar for 5-FU/6S-LV5 (fluorouracil and leucovorin.

com/micromedex2/librarian/PFDefaultActionId/evidencexpert. but leading to treatment withdrawal in fewer than 2% (Jonat et al.(n=304) 1. overall approximately 15% of either treatment group reported a serious adverse event. Standard.8-1.2-2.8 0.and high-dose chemotherapy were administered according to the following schema: INDUCTION AND MAINTENANCE HIGH-D0SE (CONTINUOUS INFUSION) Doxorubicin 30 mg/m(2) days 1 and 8 IV Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg.3 ER. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized.14 b) From overall survival statistics. 183 of 194 deaths due to breast cancer were recorded among goserelin patients.25/10/12 Drug details . c) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high.67 0.0-1.0 0.2 1.0 1.8 OVERALL SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1.IntermediateToDocumentPrintLink received a median of 8 228/317 .8-1.1-3.0 0.0-1.dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone.5 ER+ (n=1189) 1.029 0. Side effect profiles (cytotoxic dominant or endocrinerelated) were reflective of the type of treatment received.1 p 0. mg/m(2)=milligrams/square meter IV=intravenous PO=oral d) Four to six cycles of induction therapy were given every 28 days.2 1.026 p 0.(n=304) 1.8 1.6 ER unknown (n=121) 1.94 0.4 ER+ (n=1189) 1. compared to 151 of 165 for CMS patients (overall death rates of 25% verus 20%).3-2.0006 0. Of 553 patients enrolled.92 0.8 1. 2002).MICROMEDEX® 2.4 ER unknown (n=121) 2.0043 0.8-4. Patients randomized to standard-dose (maintenance) chemotherapy thomsonhc.0 calculated (HR ratios less than 1 favor goserelin) for the median follow up time of 6 years: DISEASE-FREE SURVIVAL SUBGROUP ANALYSIS HR CI All (n=1614) 1.2 ER.

A greater incidence of severe leukopenia. respectively. and fluorouracil (CMF) as adjuvant therapy for stage II lymph-node positive breast cancer. respectively. Both chemotherapy regimens were administered every 21 days for 6 courses. 1. methotrexate 40 mg/m(2).dose/transplant groups (9 and 9. mitoxantrone 12 mg/m(2).31). respectively. respectively.0 randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles. and anemia was observed in the high-dose/transplant group.3 years) received CMF and 68 (average age 45.001). Disease-free survival was significantly lower for the CMF regimen compared with the CNF regimen (2. The CNF regimen included cyclophosphamide 500 mg/m(2). The CMF regimen included cyclophosphamide 600 milligrams/square meter (mg/m(2)). Of the 145 evaluable patients. 77 (average age 46. p less than 0. overall survival in this intentionto-treat analysis was not significantly different between standard. no patient required treatment discontinuation or dose reduction due to toxicity (Ron et al.or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. This improvement should be weighed against the difficulty (ie.5 years (mean survival time of 4.6 months. Median follow-up was 37 months. p = 0. Median follow-up duration in this study was 8.25/10/12 Drug details . prolonged therapy. PREDNISONE) produced statistically similar survival or disease-free survival rates. mucositis occurred at a similar rate for both groups [414]. p=0. respectively). respectively. predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%).6 and 4.001) were reported in significantly more patients treated with the CNF regimen compared with the CMF regimen. However. Relapse occurred in 14 and 30 patients treated with the CNF and CMF regimens. Thrombocytopenia (p less than 0.3 years) and 445 ER-negative. f) In a multicenter phase III randomized study. The overall survival demonstrated no significant difference between the 2 regimens at a median follow up of 4.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and FLUOROURACIL (CNF) demonstrated an improved disease-free survival compared with cyclophosphamide.MICROMEDEX® 2. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al. node. 5-FLUOROURACIL) over a shorter period. even with doses within the conventional range. METHOTREXATE. not statistically different. leukopenia (p less than or equal to 0. node-positive breast cancer patients were enrolled.and high. METHOTREXATE.4 years for CMF and CNF regimens.05). Subgroup analyses (estrogenreceptor status.4 years. MITOXANTRONE. All patients had undergone either modified radical mastectomy or lumpectomy with axillary lymph node dissection. respectively. CYCLOPHOSPHAMIDE.IntermediateToDocumentPrintLink cancer patients receiving either 6 229/317 . Although. Five-year survival was 57% and 62% in the 1and 2-year therapy groups. p=0. Likewise. methotrexate. FLUOROURACIL. Alopecia occurred in significantly more patients receiving the CNF regimen compared with the CMF regimen (29% versus 17%.7 years versus 4. g) Escalating doses of ACMF (DOXORUBICIN. thrombocytopenia. and fluorouracil 500 mg/m(2). were superior to low-dose. At 3 years.positive breast thomsonhc.23). VINCRISTINE. median time to progression was not different between the standard. and fluorouracil 600 mg/m(2). CYCLOPHOSPHAMIDE. A study was conducted in premenopausal. 2001).04).and highdose/transplant therapy (38% and 32%. and decreased hemoglobin (p less than or equal to 0. e) In one study. 1993). High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414].5 years) received CNF.01).6 years (maximum of 11.

METHOTREXATE. thrombocytopenia (9.4%) (Levine et al. 3. methotrexate 40 mg/m(2) IV days 1 and 8.2%. six-cycle ACMF group (Fukutomi et al. PREDNISONE) produced statistically similar survival or disease-free survival rates (Rivkin et al. there were nonsignificant trends toward better disease-free and overall survival rates in the highdose. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.4%.7%).6 years (maximum of 11. fluorouracil 600 mg/m(2) IV days 1 and 8). fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. n=97. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%). epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. respectively).positive breast cancer patients receiving either 6 cycles of conventional-dose ACMF or 12 cycles of low-dose ACMF (n=93. 60. 3. the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. node. leukopenia (94. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. EPIRUBICIN.9%).25/10/12 Drug details .7%.9%. toxicity) of administering 2 years of CMFVP therapy. Both regimens were administered for 6 cycles.positive breast cancer patients were enrolled. stomatitis (12. This was possibly due to a difference in acute toxicity between the 2 regimens. FLUOROURACIL. EPIRUBICIN. 1998).7%).4%. granulocytopenia (97. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.IntermediateToDocumentPrintLink was 63% and 53%. h) The combination regimen CEF (CYCLPHOSPHAMIDE. Both regimens were administered for 6 cycles. Also. respectively.4%. 78. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer.1%). epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. vomiting (11. Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13. more patients receiving the low-dose 12-cycle refused therapy.1%). This improvement should be weighed against the difficulty (ie. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively.03). METHOTREXATE. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14.3%.1%. i) In one study.MICROMEDEX® 2. Greater toxicity was noted in patients receiving the CEF regimen. Relapsefree survival at 5 years in the CEF and CMF groups thomsonhc.3%). FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. Although both treatment regimens were well tolerated overall.009). however. 1993). Median follow-up duration in this study was 8. Although. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0. 6. 2. node. 4. VINCRISTINE.and 2-year therapy groups.3 years) and 445 ERnegative. For patients in the CMF group it was 78% and 58% respectively. alopecia (42. j) The combination regimen CEF (CYCLOPHOSPHAMIDE. respectively 230/317 .0 conducted in premenopausal. Five-year survival was 57% and 62% in the 1. 1. not statistically different.2%). methotrexate 40 mg/m(2) IV days 1 and 8. 1995). diarrhea (0. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. METHOTREXATE. fluorouracil 600 mg/m(2) IV days 1 and 8).

but did not alter overall survival (Muss et al. For patients in the CMF group. respectively (Bonadonna et al. 78.03). respectively.1%.25/10/12 Drug details . FLUOROURACIL. it was 78% and 58%. respectively. maintenance therapy with cyclophosphamide. respectively. 1998). 1995).MICROMEDEX® 2. granulocytopenia (97. CYCLOPHOSPHAMIDE. patients were randomized to CMF for 6 or 12 cycles. vomiting (11.2%. the mean score in the CEF group decreased to a nadir more quickly then in the CMF group. respectively. l) Escalating doses of DOXORUBICIN.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. respectively) in a 20-year follow-up study. thrombocytopenia (9. but more patients receiving the low-dose 12-cycle regimen refused therapy. methotrexate. METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone in node-positive breast cancer patients (n=179. was nausea (13. respectively (p=0.9%). 4. in the CMF-treated group. node-positive breast cancer patients (n=190).4%. alopecia (42. Relapse-free and overall survivals in premenopausal patients after 20 years were 37% and 47%. respectively.3%. 1993). leukopenia (94. Also. 1992). 6. Following mastectomy. 26% and 22%. Overall survival was 77% and 70% in the CEF and CMF groups. 1991). In another study.4%. Greater toxicity was noted in patients receiving the CEF regimen.7%). stomatitis (12. No difference in survival or disease-free survival was found among the 3 groups at 10 years median follow-up. and PREDNISONE (CMFVP) produced similar survival/disease-free survival rates. 6-cycle ACMF group (Fukutomi et al. were superior to low-dose. n=207. but the difficulty (ie. toxicity) of 2-year administration may outweigh the benefit (Rivkin et al.6 years. METHOTREXATE.4%. and for the postmenopausal patients. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy. METHOTREXATE. 60.7%. and FLUOROURACIL (ACMF) over a short period. respectively. Relapse-free and overall survivals in premenopausal patients after 20 years were 26% and 24%.2%). Comparison of grade 3/4 toxicities in the CEF and CMF groups.4%) (Levine et al. Median follow-up duration was 8. and for postmenopausal patients.009). The strongest predictors of survival were positive nodes (negative correlation) and ideal or full dose of CMF (positive correlation) (Velez-Garcia et al.IntermediateToDocumentPrintLink marginally better outcomes231/317 than . Patients received either 6 cycles of ACMF or 12 cycles of low-dose ACMF. there were non-significant trends toward better disease-free and overall survival rates in the high-dose. VINCRISTINE. receptor-negative breast cancer. The 2-year therapy produced a moderate improvement in survival over the 1-year therapy (57% vs 62%). in the surgery-alone group. 1. o) A sixteen-week multidrug regimen achieved only thomsonhc.0 free survival at 5 years in the CEF and CMF groups was 63% and 53%.7%). n) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE. even with conventional doses.3%). 3. 1and 2-year therapy with CYCLOPHOSPHAMIDE. k) No advantage was achieved with 12 versus 6 cycles of CMF (CYCLOPHOSPHAMIDE.9%. 3. those with greater than or equal to 4 positive nodes were randomized to 1 of the CMF groups or regional radiotherapy followed by 6 cycles of CMF. however. m) In a study of 445 patients with node-positive. and fluorouracil prolonged time to progression.1%). 1995). Both regimens were well tolerated. respectively (p=0. METHOTREXATE.1%) diarrhea (0. 24% and 22%. prolonged therapy in premenopausal. 2. This was possibly due to a difference in acute toxicity between the 2 regimens. FLUOROURACIL) in the treatment of breast cancer in 622 women with positive axillary nodes. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group.

0001. beginning 24 hours after methotrexate. and was correlated highly with prior hormonal response. patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2. with a median follow-up of 3. The patients were randomly assigned to receive either the 16-week regimen or six cycles of CAF. had disease stabalization for at least 2 months. AND FLUOROURACIL (CAF) with similar toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive. Dose modification occurred based upon toxicity evaluated and classified by the Common Toxicity Criteria.04). During EVEN-NUMBERED WEEKS. respectively. doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500 mg/m(2) intravenously (IV) days 1 and 8. Survival rates favored tamoxifen as initial therapy (23 months versus 21 months for CMF). 1998). and 0.0001 to 0. Of the 163 patients participating in the quality-of-life study. p) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of cyclophosphamide.19. vincristine 1 mg IV day 1. Other significantly worse adverse events in the 16-week regimen were stomatitis (P=0.free survival rate for the 16-week regimen was 67. DOXORUBICIN.60). 0. methotrexate 100 mg/m(2) IV day 1.095. one-sided). methotrexate and 5-fluorouracil (CMF) in the initial treatment of stage IV breast cancer in elderly woman (over the age of 65 years).003.08) in the proportional hazards model. an additional 33% and 45% of patients treated with tamoxifen and CMF.04).0001). The estimated 4-year survival rate was 78. and thrombocytopenia were significantly worse with CAF than with the 16-week regimen (P=0.5% versus 62. the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0.o) A sixteen-week multidrug regimen achieved only marginally better outcomes than CYCLOPHOSPHAMIDE. neurotoxicity (P=0. granulocytopenia. Upon crossover to the opposite treatment. Response rates were 45% and 38% in tamoxifen and CMF-treated patients. Anemia was significantly higher with the 16-week regimen (P=0. however. skin toxicity (P=0.4% for CAF (P=0. Due to the complicated schedule and only marginally improved outcomes as compared with CAF. Leucovorin 10 mg/m(2) was administered orally every 6 hours for six doses. as well as continuous 5-FU infusion. nausea (P=0.10. two-sided. 5-FU 600 mg/m(2) IV day 2 at 20 hours after methotrexate.9 years. receptor-negative breast cancer patients.05.0001). The 16-week regimen consisted of greater doxorubicin and 5-FU dose intensity than CAF and sequential administration of methotrexate and 5-FU. P=0.0001). Leukopenia. respectively. a previous response with tamoxifen did not predict CMF response. A previous response to CMF tended to be associated with a better chance for tamoxifen response. Initiation of hormone therapy as opposed to CMF chemotherapy is recommended in . which reached a border line level of significance (p=0. Additional disease control with hormone withdrawal was observed in 23% of patients.0003). doxorubicin 40 mg/m(2) IV day 1. The 16-week regimen involved weekly treatments. Each 28-day cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2)) orally days 1 through 14. The 4-year recurrence. Febrile neutropenia hospital admission was not significantly different between the two regimens. P=0.0001 respectively). but was insignificant by 4 months posttreatment (P=0. one-sided). two-sided. the 16-week regimen should not be substituted for CAF without careful consideration (Fetting et al. response to either tamoxifen or the CMF regimen was less than that observed when given as initial therapy (29% and 31%.05) and weight loss (P=0.1% for the 16-week regimen and 71.7% for CAF (P=0. ODD-NUMBERED WEEKS as cyclophosphamide 100 mg/m(2) orally days 1 through 7. respectively).

Comparison of grade 3/4 toxicities in the CEF and thomsonhc. This was possibly due to a difference in acute toxicity between the 2 regimens. 3 patients with congestive heart failure (CHF). Greater toxicity was noted in patients receiving the CEF regimen.7 months for CEF versus 6. A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. methotrexate (40 mg/m(2) IV). In an analysis of assessable patients.01).25/10/12 Drug details . nausea/vomiting (21%. leukopenia (66%.IntermediateToDocumentPrintLink CMF groups respectively was 233/317 .com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Qualityof-life summary scores were identical in both groups by 6 months after chemotherapy. Median time to progression was 8. and alopecia (66%. diarrhea (1%.005). and fluorouracil (500 mg/m(2) IV on days 1 and 8 of each cycle). r) The combination regimen CEF (CYCLPHOSPHAMIDE. n=237. and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). q) In an intent-to-treat analysis. febrile neutropenia (11%. however. 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. respectively. the mean score in the CEF group decreased to a nadir more quickly than in the CMF group. 14%). toxicity. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. 1986). Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group respectively. 15%).3 months for CMF (p=0.MICROMEDEX® 2. or patient refusal occurred) or for a total of 9 cycles if complete or partial response occurred. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.1 months and 18. EPIRUBICIN.2 months.0 most elderly patients (Taylor et al. METHOTREXATE. EPIRUBICIN. In the CMF group. For patients in the CMF group it was 78% and 58% respectively. Both regimens were administered for 6 cycles. 14%). 58%). 2%). 68%). and FLUOROURACIL (CEF. 1%). METHOTREXATE. 2001). overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE. and mucositis (12%. n=223) compared to those who received CYCLOPHOSPHAMIDE. and fluorouracil 600 mg/m(2) IV days 1 and 8). The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al. p=0. Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 6 patients with declines in LVEF. FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer. response rates were 66% for CEF (n=189) and 52% for CMF (n=200. Overall survival was 77% and 70% in the CEF and CMF groups respectively (p=0. Cycles were repeated every 3 or 4 weeks (depending on toxicity recovery) for a total of 6 cycles (or until disease progression. methotrexate 40 mg/m(2) IV days 1 and 8.03). epirubicin (50 mg/m(2) IV).5%. 8%). In the CEF group. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. p=0. or cyclophosphamide (500 mg/m(2) IV). and 3 patients with changes on electrocardiogram (ECG).23). Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)).009). and FLUOROURACIL (CMF. Other toxicities in the CEF versus CMF group included grade 4 infections (0. P=0. 2 patients had significant falls in LVEF as previously described. Relapse-free survival at 5 years in the CEF and CMF groups was 63% and 53% respectively (p=0.01) but overall survival was not significantly different for CEF and CMF (20.

and FLUOROURACIL (CMF. EPIRUBICIN.7%).01) but overall survival was not significantly different for CEF and CMF (20. the other two agents being given without epirubicin on day 8. Five-year survival rates among the CMF2 group (n=199) and the FEC2 group (n=200) were 73.03). granulocytopenia (97. 3. Overall survival was 77% and 70% in the CEF and CMF groups. For patients in the CMF group. 1. Quality-of-life summary scores were identical in both groups by 6 months after chemotherapy.3%. respectively (p=0. Median time to progression was 8. vomiting (11. and CYCLOPHOSPHAMIDE).9%.0 Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was nausea (13. methotrexate 40 mg/m(2) IV days 1 and 8. p=0. respectively (p=0.1 months and 18.8% and 86.25/10/12 Drug details . respectively. respectively. Nausea. FEC1 and FEC2) and observed a clinically significant benefit only when FEC2 was compared with CMF2.7 months for CEF versus 6. epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8. and CYCLOPHOSPHAMIDE) provided better overall and relapse-free survival than CMF (FLUOROURACIL. u) In an intent-to-treat analysis.23). thrombocytopenia (9.6%. Both regimens were administered for 6 cycles.9%.4%. 3. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%.7%.03). 2.2 months. p=0. thrombocytopenia (9. were nausea (13. and leukopenia (94. METHOTREXATE.2%).9%). vomiting (11. 78. granulocytopenia (97.1%). 60. Survival stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group. CMF2 was administered on days 1 and 8 and included methotrexate 40 milligrams/square meter. EPIRUBICIN. FEC (FLUOROURACIL. t) The combination regimen CEF (CYCLOPHOSPHAMIDE. (p=0. fluorouracil 600 mg/m(2) IV days 1 and 8). Greater toxicity was noted in patients receiving the CEF regimen.3%. 4. stomatitis (12. 1.7%).1%).01).7%. 3. 6.3 months for CMF (p=0. respectively. and FLUOROURACIL (CEF. EPIRUBICIN. p=0.2%. the mean score in the CEF group decreased to a nadir more quickly then in the CMF group. vomiting. stomatitis (12. and alopecia were more frequent with either of the two FEC combinations compared with the CMF combinations (Coombes et al. The authors compared two separate dosing schedules for each adjuvant combination (CMF1 and CMF2.4%. Patients234/317 were . 3. overall response rate was improved in metastatic breast cancer patients who received CYCLOPHOSPHAMIDE. thomsonhc. METHOTREXATE FLUOROURACIL) in a large study (n=710) evaluating premenopausal women with node-positive breast cancer.MICROMEDEX® 2. however. In an analysis of assessable patients. Women previously untreated for breast cancer were randomized to receive monthly treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14.4%.4%. fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14. response rates were 66% for CEF (n=189) and 52% for CMF (n=200. 2. The FEC2 combination included epirubicin 50 milligrams/square meter on day 1.IntermediateToDocumentPrintLink respectively. This was possibly due to a difference in acute toxicity between the 2 regimens.1%.7%). 6.4%) (Levine et al. 78.2%). 1998).7%). 1996). it was 78% and 58%. s) In premenopausal women with node-positive operable breast cancer. FLUOROURACIL) demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE. METHOTREXATE. alopecia (42.009). 1998). diarrhea (0.2%.1%. Both schedules included cyclophosphamide and fluorouracil in equivalent doses of 600 milligrams/square meter. n=237.9%). alopecia (42. leukopenia (94.005).3%).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. n=223) compared to those who received CYCLOPHOSPHAMIDE.4%. Comparison of grade 3 and 4 toxicities in the CEF and CMF groups.3%). 4.1%) diarrhea (0. respectively.4%.4%) (Levine et al. 60.1%).

febrile neutropenia (11%. 2%). respectively). 19 patients had a significant decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). and fluorouracil (500 mg/m(2) IV on days 1 and 8 of each cycle). METHOTREXATE. 2001). Although both treatment regimens were well tolerated overall. CYCLOPHOSPHAMIDE. 14%). patients were randomized to CMF for 6 or 12 cycles. epirubicin (50 mg/m(2) IV).25/10/12 Drug details .IntermediateToDocumentPrintLink years median follow-up. Eight percent of docetaxel patients and 3% of MF patients experienced complete response. randomized study received docetaxel 100 milligrams/square meter (mg/m(2)) over 1 hour every 3 weeks or sequential methotrexate 200 mg/m(2) and 5-fluorouracil 600 mg/m(2) on days 1 and 8 every 3 weeks. and 3 patients with changes on electrocardiogram (ECG).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Other toxicities in the CEF versus CMF group included grade 4 infections (0. 2 patients had significant falls in LVEF as previously described. 1%). 14%). Patients were randomized to receive either cyclophosphamide (400 milligrams/square meter (mg/m(2) intravenously (IV)).2 months. 3 patients with congestive heart failure (CHF). n=97.23). FLUOROURACIL) in the treatment of breast cancer in 622 women with positive axillary nodes.1 months and 18. Patients who relapsed on randomized study treatment were encouraged to crossover to the alternate treatment. node-positive breast cancer patients receiving either 6 cycles of ACMF or 12 cycles of low-dose ACMF (n=93. 68%). Also. Patients enrolled in this open-label. diarrhea (1%. p less than 0. there were non-significant trends toward better disease-free and overall survival rates in the high-dose. 5-FLUOROURACIL) over a shorter period. methotrexate (40 mg/m(2) IV).0 months. There was no difference in survival or disease-free survival among the 3 groups at approximately 10 thomsonhc. In the CMF group. and alopecia (66%. prolonged therapy. 8%). or cyclophosphamide (500 mg/m(2) IV). v) DOCETAXEL MONOTHERAPY was associated with a significantly longer time to progression (6.MICROMEDEX® 2. METHOTREXATE. respectively. Docetaxel was associated with more toxicity than MF with 3 treatment related deaths in the docetaxel arm and one in the MF arm (Sjostrom et al 1999). leukopenia (66%. In the CEF group. A comparison of grade 3/4 toxicity in the CEF versus the CMF group included granulocytopenia (78%. even with doses within the conventional range. those with greater than or equal to 4 positive nodes were randomized to 1 of the CMF groups or regional radiotherapy followed by 6 cycles of CMF. Fifteen patients in the CEF group discontinued treatment because of adverse cardiac events including 9 patients with declines in LVEF. A study was conducted in premenopausal. Cycles were repeated every 3 or 4 weeks for a total of 6 cycles or for a total of 9 cycles if complete or partial response occurred.001) in patients (n=282) with advanced breast cancer who had failed anthracycline treatment. were superior to low-dose. and mucositis (12%. Almost twice as many docetaxel patients experienced a partial response (34%) compared to MF (18%). 1995). 58%). Following mastectomy.0 for CEF and CMF (20. p=0. w) Escalating doses of ACMF (DOXORUBICIN. The authors conclude that this dose and schedule of CEF is a safe and effective option as first-line chemotherapy for metastatic breast cancer (Ackland et al. nausea/vomiting (21%.5%. The 235/317 . and fluorouracil (600 mg/m(2) on days 1 and 8 of each cycle). x) No advantage was observed with 12 versus 6 cycles of CMF (CYCLOPHOSPHAMIDE. six-cycle ACMF group (Fukutomi et al. more patients receiving the lowdose 12-cycle refused therapy. 15%).3 months) compared to METHOTREXATE and 5-FLUOROURACIL (MF) combination therapy (3.

025). but the differences between groups were not statistically significant.021). 5-fluorouracil. methotrexate 40 mg/m(2) IV.001) and required fewer hospital days for appropriate treatment (1. The NFL and CMF regimens produced a 45% vs 26% response rate. PREDNISONE) produced statistically similar survival or disease-free survival rates. and appetite were slightly better in paclitaxel-treated patients. 2 years of therapy produced a moderate improvement in survival (57% vs 62%) over 1 year of therapy. VINCRISTINE. However. METHOTREXATE.6 years (maximum of 11. Patients received intravenous mitoxantrone 12 milligrams/square meter (mg/m(2)) on day 1. 1997). 29% partial). the median duration of response was 9 months and 6 months in the NFL and CMF groups respectively. Although median survival was similar in both groups. reduced myleosuppression. methotrexate. and peripheral neuropathy than combination therapy. respectively. The strongest predictors of survival were positive nodes (negative correlation) and ideal or full dose of CMF (positive correlation) (Velez-Garcia et al. 2 and 3. 1992). mucositis. This improvement should be weighed against the difficulty (ie. and leucovorin 300 milligrams as a 1hour infusion followed by fluorouracil 350 milligrams/square meter IV push on days 1. and a slightly higher quality of life rating was observed following first-line treatment with paclitaxel as compared to the combination of cyclophosphamide. methotrexate (40 mg/m(2) intravenously (IV) on days 1 and 8). myalgia. and prednisone (40 mg/m(2) PO on days 1 to 14) every 28 days for 6 courses (n=102). 18 partial) was achieved with combination MITOXANTRONE. node. (p=0. 1991). The regimen was compared to combination (CMF) cyclophosphamide 600 mg/m(2) IV.5 days versus 4.2. Quality of life measures. Two hundred and nine women (median age 54 years) were randomized to receive paclitaxel (200 milligrams per square meter (mg/m(2)) every 21 days for 8 courses (n=107) or cyclosphosphamide (100 mg/m(2) orally (PO) on days 1 to 14). aa) An overall response rate of 65% (2 complete. The regimens were repeated at 21-day intervals and given to chemotherapynaive patients with metastatic breast cancer.survival among the 3 groups at approximately 10 years median follow-up. Five-year survival was 57% and 62% in the 1. (p=0. p=0.positive breast cancer patients were enrolled.06).3 years) and 445 estrogen receptor (ER)negative. including physical wellbeing. LEUCOVORIN.and 3 (Hainsworth et al. thrombocytopenia. 5-fluorouracil (600 mg/m(2) IV on days 1 and 8). respectively. p=0. and prednisone in patients with metastatic breast cancer. repeated every 21 days. which was significantly different. and fluorouracil 600 mg/m(2) given on day one. Febrile neutropenia with or without infection occurred significantly less frequently with paclitaxel as compared to combination therapy (10% versus 27%. Median follow-up duration in this study was 8. and FLUOROURACIL among 31 patients with metastatic breast cancer. Although. Response duration ranged from 3 to 16+ months (Hainsworth et al. 1993). Multivariate analysis revealed a signifcantly improved survival with paclitaxel therapy (17. 27% partial) and in those treated with combination therapy (35%: 6% complete. mood. and nausea/vomiting were less severe with paclitaxel treatment. Leukopenia.9 months. Objective response rates were similar in paclitaxel-treated patients (29%: 2% complete. not statistically different.0006). y) In one study. paclitaxel caused more alopecia. The above regimen was tested in another study with the addition of fluorouracil (NFL) 350 mg/m(2) IV bolus on days 1. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al.and 2-year therapy groups. z) Prolonged survival.3 months versus 13.236/317 . 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE.4 days. p=0. FLUOROURACIL.

Both regimens were repeated every 21 days for 6 cycles. and doxorubicin 30 milligrams/m(2) produced comparable results to the EAP regimen with much less toxicity in one study. stage I to IIIB breast cancer and a tumor diameter greater than 1 centimeter were randomized to thomsonhc. Chemotherapy was administered weekly for 4 courses and then biweekly for 4 courses. All 297 patients received FLUOROURACIL 60 milligrams (mg) per kilogram as a continuous infusion over 48 hours. nausea/vomiting. Stomatitis occurred in significantly more patients receiving combination therapy versus FLUOROURACIL alone (p less than 0.5 g/m(2). FAMTX. thrombocytopenia. methotrexate. nausea and vomiting also occurred in more patients receiving combination therapy (48% versus 35%) (Blijham et al. fluorouracil 1. 15 patients in group B versus 7 in group A had a partial response.IntermediateToDocumentPrintLink 237/317 .com/micromedex2/librarian/PFDefaultActionId/evidencexpert. p=0.025) and a 3-month increase in survival compared with FLUOROURACIL alone in patients with advanced unresectable or metastatic colorectal cancer. 1996). Three patients in the FAMTX experienced complete remissions. Eighty-three patients with recurrent or metastatic colon or rectal cancer. and diarrhea occurred at a higher incidence and was more severe in group B (Polyzos et al.MICROMEDEX® 2.5 grams/square meter (g/m(2)). 7.0 was 9 months and 6 months in the NFL and CMF groups respectively.25/10/12 Drug details . 146 patients also received methotrexate 40 mg/square meter (m(2)) as an intravenous injection immediately before the FLUOROURACIL infusion. Toxicity consisting of neutropenia.06). Objective responses were observed in 20% of the patients in the EAP group and 30% in the FAMTX group. mucositis. leucovorin 15 mg every 6 hours for 6 doses was administered. 6.001). but none occurred in the EAP group. Neoplasm of colon a) Methotrexate and leucovorin are equally effective modulators of FLUOROURACIL in patients with metastatic colorectal cancer. The median survival in the 2 groups were similar (EAP. (p=0. Neoplasm of gastrointestinal tract a) The FAMTX regimen (methotrexate 1. High-dose FLUOROURACIL with methotrexate resulted in a significantly higher response rate (23% versus 11%.1 months. were randomly assigned to receive one of the following regimens: Group A.3 months) [424]. Sixty patients with advanced gastric cancer were randomly assigned to the EAP or FAMTX regimen. intravenous leucovorin 300 milligrams/square meter (mg/m(2))/day followed by FLUOROURACIL 500 mg/m(2)/day administered over 1 hour for 4 days. and fluorouracil (CMF) as adjuvant therapy in elderly patients with early stage breast cancer. noninferiority for relapse-free survival (RFS) was not established between single-agent capecitabine and standard therapy with cyclophosphamide and doxorubicin (AC) or cyclophosphamide. Three patients in group B versus one in group A had a complete response. methotrexate 130 mg/m(2)/day 20 hours before leucovorin 300 mg/m(2)/day followed by FLUOROURACIL 500 mg/m(2)/day administered over 1 hour for 4 days. Women 65 years (yr) of age or older with operable. in women 65 years of age or older a) In a randomized trial (n=633). Methotrexate Sodium Breast cancer. Twenty-four hours after the methotrexate infusion. Adjuvant therapy. b) Modulation of FLUOROURACIL with folinic acid (leucovorin) plus methotrexate in patients with advanced colorectal cancer resulted in a higher response rate but similar survival when compared with modulation using only leucovorin. Group B. 1996).

24 patients in the capecitabine arm and 16 patients in the standard chemotherapy arm had experienced disease recurrence. resulting in a hazard ratio (HR) for disease recurrence (standard chemotherapy compared with capecitabine) of 0. 3. distant metastases. In multivariate analyses.76.8046 was 96% which was greater than the limit of 80% predicting futility).38 to 3.85.39. and symptomatic relief. The following 6 regimens were compared [426]: Fluorouracil 500 mg/m(2)/day IV bolus Days 1 through 5. Adjuvant therapy with capecitabine consisted of 6 cycles of 2000 milligrams/square meter (mg/m(2))/day in 2 divided doses for 14 days every 3 weeks. Unplanned post hoc analyses demonstrated that patients with hormone receptor-negative tumors who received capecitabine had significantly worse RFS (HR. At the time of this preplanned interim analysis. 33%). or death from any cause. 1.25/10/12 Drug details .4 yr. 24%. 95% CI. performance status. AC. and 40% of patients who received capecitabine. p=0. 95% CI.09. 54%. respectively. 60 patients (20%) in the capecitabine arm and 35 patients (11%) in the standard chemotherapy arm experienced a relapse.9 to 6.53 (probability of HR less than 0.MICROMEDEX® 2.05) superiority in quality of life.08. Standard adjuvant chemotherapy consisted of 4 cycles of AC with cyclophosphamide 600 mg/m(2) intravenously (IV) and doxorubicin 60 mg/m(2) IV given on day 1 every 21 days (n=184) or 6 cycles of CMF with cyclophosphamide 100 mg/m(2)/day orally days 1 to 14 and methotrexate 40 mg/m(2) IV and fluorouracil 600 mg/m(2) IV on days 1 and 8 every 28 days (n=133). At a median follow-up of 2. p less than 0.23 to 6. the futility of capecitabine therapy was determined using a Bayesian predictive probability method and the trial was closed. After chemotherapy.001) compared with patients with hormone receptor-negative tumors who received standard therapy. hormone receptor-negative tumors. Repeat course every 5 thomsonhc. One or more serious (grade 3 or higher) hematologic adverse events (AE) occurred less frequently with capecitabine (2%) compared with standard therapy (AC. patients with hormone receptorpositive tumors could receive tamoxifen or an aromatase inhibitor. Only low-dose leucovorin plus fluorouracil was associated with a significant (p less than 0. Metastatic colorectal cancer a) Bimonthly high-dose leucovorin and bolus fluorouracil plus continuous infusion fluorouracil was more effective and less toxic than a monthly low-dose leucovorin and bolus fluorouracil regimen in patients (n=448) with previously untreated metastatic colorectal cancer [425]. and CMF.IntermediateToDocumentPrintLink 238/317 . Treatment-related death occurred in 2 patients in the capecitabine arm and in no patients in the standard therapy arm [412]. and 62% of patients treated with capecitabine.02) with capecitabine compared with standard therapy were confirmed.0 treatment with oral capecitabine (n=307. and CMF. AC. 18 of 38 deaths (47%) in the capecitabine arm and 8 or 24 deaths (33%) in the standard chemotherapy arm were attributed to breast cancer. 1. 95% CI. the combination of fluorouracil and leucovorin demonstrated a therapeutic advantage (improved tumor response rates and survival) over fluorouracil alone. 52%) and one or more serious nonhematologic AE occurred in 33%. Additionally. 2. respectively.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.7.17. significantly worse RFS (HR. hormone receptor-negative tumors. b) In a randomized trial of patients (n=429) with metastatic colorectal cancer. 92%. CMF.34. p less than 0. 1. 2.11 to 3. 2. p less than 0. All scheduled cycles of chemotherapy were received by 80%. 95% confidence interval (CI).001) and OS (HR. weight gain.001) and overall survival (OS) (HR. 4. 32%) or standard chemotherapy (n=326. Following the enrollment of 600 patients.

All repeated days 1 through 5. Nineteen patients required fluorouracil dose reductions during the second course.MICROMEDEX® 2. Leucovorin 14 mg/m(2) orally every 6 hrs for 8 doses (begin 24 hrs after the start of the methotrexate infusion). then every 5 weeks mg/m(2) = milligrams/square meter. CIV = continuous intravenous infusions. a unit of absorbed radiation dose equal to 100 rads) administered over 5 weeks (1. hrs = hours. significantly lowering the locoregional recurrence rate (p=0. Dose/study details and statistical analysis were not provided [427][428]. 6 weeks and then every 4 weeks OR Methotrexate 40 mg/m(2) IV on days 1 and 8. 45%. then every 5 weeks OR Leucovorin 20 mg/m(2)/day IV bolus immediately followed by Fluorouracil 370 mg/m(2)/day IV bolus. IV = intravenous.25/10/12 Drug details .0 weeks OR Fluorouracil 325 mg/m(2)/day IV bolus. 110 patients received either radiotherapy alone or radiotherapy with chemotherapy. Repeat course at 3. Mitomycin Anal cancer a) Combined radiotherapy and chemotherapy resulted in significantly better locoregional control. Fluorouracil 900 mg/m(2) bolus IV (7 hrs after the beginning of methotrexate). All repeated days 1 through 5. Repeat course at 4.02). Cisplatin 20 mg/m(2)/day over 2 hours. 8 weeks. The complete remission rate increased from 54% to 80% with the addition of chemotherapy to radiotherapy. and improved event-free survival in patients with advanced anal cancer. Repeat course every 5 weeks OR Methotrexate 200 mg/m(2) IV over 4 hours. fewer colostomies. Respective rates of excellent cosmetic outcome were 59%. and this difference persisted throughout the follow-up period. Repeat course at 4. and 30%. Although thomsonhc. this was followed by a 6-week rest and an additional boost of 15 to 20 Gy depending on initial response. and a bolus dose of mitomycin 15 mg/m(2) on day 1. a complete lesion response rate of 93% was reported with methyl aminolevulinate photodynamic therapy (PDT). Methyl Aminolevulinate Squamous cell carcinoma a) In an unpublished phase III study involving patients with early squamous cell skin carcinoma (n=229). In this phase III study. All repeated days 1 through 5.IntermediateToDocumentPrintLink 239/317 . Repeat cycle every 28 days OR Leucovorin 200 mg/m(2)/day IV bolus followed by Fluorouracil 370 mg/m(2)/day IV bolus.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.8 Gy daily). Fluorouracil 700 mg/m(2) IV bolus 24 hrs after each dose of methotrexate. Radiotherapy consisted of 45 Gray (Gy. 8 weeks. Patients assigned to combination therapy also received continuous infusion fluorouracil 750 milligrams/square meter(mg/m(2)) per 24 hours on days 1 to 5 and 29 to 33. compared to 83% with topical 5-fluorouracil and 86% with cryotherapy.

event-free survival was significantly improved (p=0. repeated at 4 and 8 weeks. median survival was 22.5 months. epirubicin 45 mg/m(2) (days 1 and 29). median time to treatment failure was 7.7 months. 1985). Combination therapy consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily on days 1 to 4. EPIRUBICIN. b) Concurrent radiation therapy and chemotherapy with fluorouracil and mitomycin resulted in significantly fewer local failures than radiation therapy alone in patients with epidermoid anal cancer.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.6 months. and alopecia. 15 patients (7 partial responders and 8 complete responders) underwent surgery. median time to treatment failure was 5. Due to the greater cost and toxicity of combination therapy. Following first relapse. 34 patients were randomized to either treatment (n=18. 1992). and FLUOROURACIL did NOT produce a statistically significant difference (p=0. 1997). diarrhea. 1996). respectively). b) MITOMYCIN. 36). fibrosis) did not differ between treatment groups. n=18.03) (Bartelink et al.02) in the radiotherapy group versus combination therapy group. FLUOROURACIL) in the treatment of metastatic breast cancer. although not statistically significant. 29. and mitomycin 10 mg/m(2) (day 1). Acute side effects (skin reactions and diarrhea) and late complications (fistula. the authors advocate FLUOROURACIL monotherapy in advanced pancreatic or gastric cancer (Cullinan et al. This 8-week chemotherapy cycle was repeated three times. While overall survival did not improve with combination therapy. Within two weeks of surgery.related thomsonhc. Twelve of the 18 patients receiving CAF had objective responses. median survival was 16. Objective responses were not significantly different between the 2 regimens (Falkson et al. Patients . An additional cycle of fluorouracil was given during the final week of radiotherapy.310) in disease-free survival compared to NO chemotherapy in patients with operable gastric cancer. however. and every 5 weeks thereafter. Partial or complete responders received a boost course of radiotherapy. There was no overall survival advantage for patients treated with combination therapy. Gastric cancer a) Survival rates with FLUOROURACIL ALONE were similar to those observed with FLUOROURACIL plus DOXORUBICIN with or without MITOMYCIN in patients with advanced pancreatic and gastric carcinoma (n=305). Single-agent fluorouracil was administered as 500 milligrams/square meter per day for 5 days. This study enrolled 92 patients with STAGE I to III disease who had complete resection of the tumor and lymph nodes or who had poorly differentiated tumors. Nine of 18 patients receiving mitomycin plus medroxyprogesterone had objective responses. 8. eight treatment. nausea/vomiting. stenosis. 3-year mortality was significantly higher (p=0. patients with lymph node metastases or low grade differentiation of the tumor showed a trend toward longer overall survival. and the combination group had a higher incidence of anal ulcers. patients were randomly assigned to treatment with 5-FU 600 milligrams/square meter (mg/m(2)) (days 1.25/10/12 Drug details . or radiotherapy plus fluorouracil 750 mg/m(2)/day on days 1 to 5 and mitomycin 12 mg/m(2) on day 1. DOXORUBICIN. skin ulceration. however.IntermediateToDocumentPrintLink 240/317 infectious episodes). Breast cancer a) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF (CYCLOPHOSPHAMIDE.MICROMEDEX® 2. mucositis.0 surgical resection was planned only for non-responders. 1 patient receiving combination therapy died during neutropenic sepsis. However.7 months. Toxicity was manageable and included neutropenia (eg. patients with a less than 50% response were recommended for radical surgery (Anon.

respectively. with regard to patient survival in the treatment of advanced pancreatic and gastric carcinoma in a study involving 305 patients with advanced disease. alopecia) were greater with the combination regimens. patients were randomized to picibanil alone or picibanil plus MFC.5 milligram/milliliter (mg/mL) for 3. respectively (p=NS). At a mean follow-up of 10 months. All patients received induction commensurability with intramuscular picibanil plus MFC for 6 weeks following surgery. other postoperative measures such as complications.MICROMEDEX® 2. mucositis. neither combination is indicated over fluorouracil alone in advanced pancreatic or gastric cancer (Cullinan et al. However. Glaucoma a) Intraoperative fluorouracil (5-FU) 50 milligrams/milliliter (mg/mL) for 5 minutes and mitomycin-C 0. and cytarabine) in patients with advanced untreated gastric cancer following palliative gastrectomy. argon laser suture lysis or IOP-lowering medication also did not differ statistically between groups [433]. b) Mitomycin C versus fluorouracil (5-FU) used intraoperatively during trabeculectomy resulted in a significantly (p=0. analysis based on carcinoma histology revealed a significant difference in survival rates only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma. It is speculated that the MFC regimen may have concealed the immunopotentiating effect of picibanil. randomized trial of 113 eyes (n=113 patients) with various forms of glaucoma. 1981). fluorouracil. blood dyscrasias and nonhematologic toxicity (GI disturbances. 1996). 8 weeks after surgery. particularly in patients with undifferentiated gastric cancer (Yasue et al. repeated at 4 and 8 weeks and every 5 weeks thereafter) was as effective as a combination of fluorouracil plus doxorubicin.25/10/12 Drug details . Eighty-one patients were randomly assigned to receive either mitomycin C 0. Although thomsonhc. nausea/vomiting. However. 1985). and alopecia. Patients were followed for a median of 5 years (Tsavaris et al. picibanil maintenance therapy alone appears preferable to picibanil plus MFC. c) Fluorouracil alone (500 milligrams/square meter (mg/m(2)) daily for 5 days per course. changes in visual acuity and necessity for 5-FU injections.05) lower postoperative intraocular pressure in a black West African population [433]. none of the patients had developed a persistent wound leak or endophthalmitis.5 minutes or 5-FU 50 mg/mL for 5 minutes on the trabeculectomy flap. diarrhea. The average reductions in intraocular pressure (IOP) were 50% and 46% for 5-FU and mitomycin-C recipients. d) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL alone has been significantly more effective than commensurability with intramuscular picibanil plus MFC (mitomycin.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and maintenance therapy was continued until death. The authors indicate that. accounting for greater benefits with picibanil alone. both stomatitis and diarrhea occurred more frequently in patients receiving fluorouracil alone. Except for diarrhea and stomatitis. With over 300 days of average follow-up. Based on these results.0 infectious episodes). Survival rates following 8 months of therapy were 81% and 57% in patients receiving maintenance picibanil alone and picibanil plus MFC. or a combination of fluorouracil plus doxorubicin plus mitomycin C. with over 90% of both groups attaining an IOP target of less than 21 millimeters of mercury. further studies are required to confirm these findings.IntermediateToDocumentPrintLink 241/317 . due to failure to induce improved survival or palliation combined with excessive cost of combination therapy and greater toxicity. signet-ring cell carcinoma) as compared to those with differentiated histology.4 mg/mL for 2 minutes exhibited equivalent efficacy as an adjunct to primary trabeculectomy in a multicenter.

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mitomycin C produced a lower mean postoperative intraocular pressure than 5-FU, 5FU is still preferred in this population because it is less expensive, easier to store, and
possibly less intimidating to the novice surgeon. This study differed from those in
developed countries in the following respects: (1) Many patients had decreased vision
at the time of surgery; (2) Medical therapy is often prohibitively expensive and
inaccessible; and (3) Postoperative follow-up care is often suboptimal. Due to these
limitations, an antimetabolite trabeculectomy is the preferred treatment in this
population.
c) Greater reduction of intraocular pressure after trabeculectomy was achieved with
single intraoperative application of MITOMYCIN compared with postoperative
subconjunctival injection of 5-FLUOROURACIL multiple-dose therapy in patients with
refractory open angle glaucoma. The most significant differences were observed at 2week and 3-month follow-up. Twelve months postoperatively, mitomycin-treated
patients retained lower intraocular pressures than 5-fluorouracil-treated patients
without medication. Mild choroidal detachment occurred in 3 patients receiving
mitomycin, and drug-induced corneal epithelial defects occurred in 3 patients receiving
5-fluorouracil [434].
Pancreatic cancer
a) Survival rates with FLUOROURACIL ALONE were similar to those observed with
FLUOROURACIL plus DOXORUBICIN with or without MITOMYCIN in patients with
advanced pancreatic and gastric carcinoma (n=305). Single-agent fluorouracil was
administered as 500 milligrams/square meter per day for 5 days, repeated at 4 and 8
weeks, and every 5 weeks thereafter. Due to the greater cost and toxicity of
combination therapy, the authors advocate FLUOROURACIL monotherapy in advanced
pancreatic or gastric cancer (Cullinan et al, 1985).
Mitoxantrone
Breast cancer
a) In a multicenter phase III randomized study, CYCLOPHOSPHAMIDE,
MITOXANTRONE, and FLUOROURACIL (CNF) demonstrated an improved disease-free
survival compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) as
adjuvant therapy for stage II lymph-node positive breast cancer. All patients had
undergone either modified radical mastectomy or lumpectomy with axillary lymph
node dissection. Of the 145 evaluable patients, 77 (average age 46.3 years) received
CMF and 68 (average age 45.5 years) received CNF. The CMF regimen included
cyclophosphamide 600 milligrams/square meter (mg/m(2)), methotrexate 40
mg/m(2), and fluorouracil 600 mg/m(2). The CNF regimen included cyclophosphamide
500 mg/m(2), mitoxantrone 12 mg/m(2), and fluorouracil 500 mg/m(2). Both
chemotherapy regimens were administered every 21 days for 6 courses. The overall
survival demonstrated no significant difference between the 2 regimens at a median
follow up of 4.5 years (mean survival time of 4.6 and 4.4 years for CMF and CNF
regimens, respectively). Disease-free survival was significantly lower for the CMF
regimen compared with the CNF regimen (2.7 years versus 4.4 years, respectively; p
= 0.04). Relapse occurred in 14 and 30 patients treated with the CNF and CMF
regimens, respectively. Alopecia occurred in significantly more patients receiving the
CNF regimen compared with the CMF regimen (29% versus 17%, respectively; p less
than 0.05). Thrombocytopenia (p less than 0.01), leukopenia (p less than or equal to
0.001), and decreased hemoglobin (p less than or equal to 0.001) were reported in
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significantly more patients treated with the CNF regimen compared with the CMF
regimen. However, no patient required treatment discontinuation or dose reduction
due to toxicity (Ron et al, 2001).
b) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL,
CYCLOPHOSPHAMIDE, and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed
that there was no significant difference in overall response (OR) rate (34.5% versus
33.3%), median overall survival (20 versus 17 months), or progression- free survival
(PFS; 7 months for both). Patients who had received prior neoadjuvant/adjuvant
therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a
higher OR rate (33% versus 13%, p=0.025), a longer PFS (8 versus 5 months;
p=0.0007), and a longer OS (20 versus 16 months; p=0.25). Patients who had not
received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC
rather than MV had a higher OR rate (43% versus 35%, p=0.26), a longer PFS (9
versus 6 months, p=0.014), and a longer OS (22 versus 16 months, p=0.027). Febrile
neutropenia and delayed hematological recovery was more frequent in the MV arm
(p=0.001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0.031)
as was alopecia (p=0.0001). The MV regimen consisted of mitoxantrone 12
milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and
vinorelbine 25 mg/m(2) IV on days 1 and 8. The choice of FAC or FEC was decided by
participating institution preference with all patients at one institution receiving the
same regimen. The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day
1, doxorubicin or epirubicin 50 mg/m(2) on day 1, and cyclophosphamide 500
mg/m(2) IV on day 1. Cycles of both MV and FAC/FEC were repeated every 21 days.
Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC
with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the
FAC/FEC arm (p=0.001). A comparison of grade 3/4 nonhematologic toxicity in the
FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%,
p=0.031) and alopecia (30% versus 7%, p=0.001)(Namer et al, 2001).
c) An overall response rate of 65% (2 complete, 18 partial) was achieved with
combination MITOXANTRONE, LEUCOVORIN, and FLUOROURACIL among 31 patients
with metastatic breast cancer. Patients received intravenous mitoxantrone 12
milligrams/square meter (mg/m(2)) on day 1, and leucovorin 300 milligrams as a 1hour infusion followed by fluorouracil 350 milligrams/square meter IV push on days 1,
2 and 3, repeated every 21 days. Response duration ranged from 3 to 16+ months
(Hainsworth et al, 1991). The above regimen was tested in another study with the
addition of fluorouracil (NFL) 350 mg/m(2) IV bolus on days 1,2,and 3 (Hainsworth et
al, 1997). The regimen was compared to combination (CMF) cyclophosphamide 600
mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) given on day
one. The regimens were repeated at 21-day intervals and given to chemotherapynaive patients with metastatic breast cancer. The NFL and CMF regimens produced a
45% vs 26% response rate, respectively, which was significantly different, (p=0.021).
Although median survival was similar in both groups, the median duration of response
was 9 months and 6 months in the NFL and CMF groups respectively, (p=0.06).
Oxaliplatin
Carcinoma of pancreas, First-line therapy
a) The overall survival was increased by 4.3 months with the combination regimen
(oxaliplatin, leucovorin, irinotecan, fluorouracil (FOLFIRINOX)) treatment compared
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with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma who
had not received prior chemotherapy for advanced disease in a multicenter,
randomized, phase 2/3 trial (n=342). Patients (median age, 61 years) were
randomized to the FOLFIRINOX group (oxaliplatin 85 mg/m(2) IV over 2 hours,
immediately followed by leucovorin 400 mg/m(2) IV over 2 hours, with the addition,
after 30 minutes, of irinotecan 180 mg/m(2) IV over 90 minutes through a Yconnector, immediately followed by fluorouracil 400 mg/m(2) IV bolus followed by
fluorouracil 2.4 g/m(2) IV over 46 hours continuous infusion repeated every 2 weeks
(n=171) or gemcitabine 1000 mg/m(2) IV over 30 minutes once weekly for 7
consecutive weeks, followed by one week off treatment; subsequent cycles were
administered once weekly for 3 weeks, followed by one week off treatment (n=171).
The recommended duration of chemotherapy was 6 months. At a median duration of
follow-up of 26.6 months (95% confidence interval (CI), 20.5 to 44.9 months), the
median overall survival (primary endpoint for phase 3) was 11.1 months (95%
confidence interval (CI), 9 to 13.1 months) and 6.8 months (95% CI, 5.5 to 7.6
months) for the FOLFIRINOX and gemcitabine groups (hazard ratio (HR) was 0.57
(95% CI, 0.45 to 9.73; p less than 0.001), respectively. The overall survival rates for
the FOLFIRINOX group and gemcitabine group, respectively, were 75.9% vs 57.6% at
6 months, 48.4% vs 20.6% at 12 months, and 18.6% vs 6% at 18 months. The
adjusted HR for death in the FOLFIRINOX was 0.57 (95% CI, 0.45 to 0.73; p less than
0.001. The objective response (complete + partial response) rate, the primary
endpoint for phase 2, was 31.6% (95% CI, 24.7% to 39.1%) in the FOLFIRINOX
group and 9.4% (95% CI, 5.4% to 14.7%; p less than 0.001) in the gemcitabine
group. The median progression-free survival was 6.4 months (95% CI, 5.5 to 7.2
months) in the FOLFIRINOX group and 3.3 months (95% CI, 2.2 to 3.6 months) in the
gemcitabine group (HR, 0.47 (95% CI, 0.37 to 0.59; p less than 0.001). Grade 3 or 4
adverse events and corresponding rates for the FOLFIRINOX and gemcitabine groups,
respectively, were neutropenia (45.7% vs 21%; p less than 0.001), febrile
neutropenia (5.4% vs 1.2%; p=0.03), thrombocytopenia (9.1% vs 3.6%; p=0.04),
diarrhea (12.7% vs 1.8%; p less than 0.001). sensory neuropathy (9% vs 0%; p less
than 0.001), and elevated level of alanine aminotransferase (7.3% vs 20.8%; p less
than 0.001) [442].
Metastasis from malignant tumor of colon
a) In a randomized, multicenter, phase 3, noninferiority trial (n=491), second-line
treatment of metastatic colorectal cancer with irinotecan was noninferior in overall
survival (OS) compared with infusional fluorouracil, leucovorin, and oxaliplatin
(FOLFOX4). Patients (median age, 63 yr; range, 25 to 86 yr) refractory to a
fluorouracil-based regimen (or within 6 months of adjuvant fluorouracil) were
randomized to irinotecan 350 mg/m(2) IV on day 1, given every 3 wk (for patients
with an Eastern Cooperative Oncology group performance score of 2, age greater than
or equal to 70 yr, or a history of pelvic radiotherapy, 300 mg/m(2) IV on day 1, given
every 3 wk) or oxaliplatin 85 mg/m(2) IV on day 1, fluorouracil 400 mg/m(2) plus
leucovorin 200 mg/m(2) IV bolus followed by fluorouracil 600 mg/m(2) in 22-hr IV
infusions on days 1 and 2 (FOLFOX4). Median OS, the primary endpoint, in the intentto-treat population was 14.3 months (mo) (95% confidence interval (CI), 12 to 15.9
mo) for the irinotecan arm and 13.8 mo (95% CI, 12.2 to 15 mo) for the FOLFOX4
arm (p=0.38; hazard ratio (HR)=0.92; 95% CI, 0.8 to 1.1), demonstrating
noninferiority. With respect to the secondary endpoints, the tumor response rate (RR)
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in the FOLFOX4 arm was significantly better compared with irinotecan (28% vs 15.5%
respectively; p=0.0009), and time to progression (TTP), was significantly better with
FOLFOX4, median 6.2 mo (95% CI, 5.3 to 7.4 mo) compared with a median of 4.4 mo
(95% CI, 3.3 to 5.5 mo) in the irinotecan arm (HR=0.73; 95% CI, 0.6 to 0.9;
p=0.0009). Significantly more patients discontinued the FOLFOX4 regimen due to
adverse reactions (17% vs 5% for irinotecan; p less than or equal 0.0001) while
irinotecan was discontinued more often due to disease progression (67% vs 57% for
FOLFOX4; p=0.027). Grade 3 or worse nausea, diarrhea, and febrile neutropenia were
statistically significantly more common in the irinotecan arm, while grade 3 or worse
neutropenia and paresthesias were statistically more common in the FOLFOX4 arm.
Crossover to the other treatment arm was required if disease progressed during
second-line therapy; consequently 227 patients (46%) also received third-line
therapy. A significantly better RR was observed in the FOLFOX4 crossover arm
compared with irinotecan (13.6% vs 5.2%, respectively; p=0.039). FOLFOX4
crossover patients also had a significantly longer TTP (median 5.8 mo, 95% CI; 4.9 to
6.7 mo; p=0.0022), compared with the irinotecan arm (median 3.3 mo, 95% CI; 2.6
to 4.1 mo; HR=0.65; 95% CI; 0.5 to 0.9). For the entire study period, OS was not
significantly different in those patients who continued on to third-line therapy whether
the original treatment assignment was FOLFOX4 with subsequent irinotecan therapy
(median 15.9 mo; 95% CI; 14.3 to 17.5 mo), or was initially irinotecan followed by
FOLFOX4 (median 14.9 mo; 95% CI; 13.2 to 17.5 mo) [462].
b) A randomized multicenter trial demonstrated that a regimen of infused
FLUOROURACIL/LEUCOVORIN and OXALIPLATIN (FOLFOX) was more effective and
better tolerated than either IRINOTECAN and OXALIPLATIN (IROX) or IRINOTECAN
and bolus FLUOROURACIL/LEUCOVORIN (IFL) in patients with previously untreated
metastatic colorectal cancer. The IFL regimen (control regimen; n=264) was
intravenous (IV) irinotecan 125 milligrams per square meter (mg/m(2)) and
fluorouracil 500 mg/m(2) plus leucovorin 20 mg/m(2) as an IV bolus on days 1, 8, 15,
and 22 every 6 weeks. This IFL regimen (described by Saltz et al., 2000) led to a
higher death rate within the first 60 days of treatment in this IFL group; the patients
described in this study received the full dose regimen, but doses of irinotecan and
fluorouracil were subsequently reduced in that study arm. The FOLFOX regimen
(n=267) consisted of IV oxaliplatin 85 mg/m(2) on day 1 and fluorouracil 400
mg/m(2) plus leucovorin 200 mg/m(2) as an IV bolus followed by fluorouracil 600
mg/m(2) in 22 hour infusions on days 1 and 2 every 2 weeks. The IROX regimen
(n=264) was IV oxaliplatin 85 mg/m(2) and IV irinotecan 200 mg/m(2) every 3
weeks. Median time to disease progression was superior in the FOLFOX group (8.7
months) compared to either the IROX group (6.5 months, p=0.001) or the IFL group
(6.9 months, p=0.0014); no significant difference was found between the IROX and
IFL groups (p greater than 0.5). Median survival for the FOLFOX, IROX, and IFL
groups was 19.5 months, 17.4 months, and 15 months, respectively. The median
survival in the FOLFOX and IROX groups was significantly better than the IFL group
(p=0.0001 for FOLFOX, p=0.04 for IROX); survival in the FOLFOX and IROX groups
was not significantly different (p=0.09). Response rate in the FOLFOX group (45%)
was also significantly higher than either the IROX (35%, p=0.03) or the IFL groups
(31%, p=0.002). In addition, the adverse event profile was more favorable in the
FOLFOX group than the other groups. In the IFL and IROX groups, patients had higher
rates of diarrhea, nausea, vomiting, febrile neutropenia, and dehydration while
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patients in the FOLFOX groups had higher rates of paresthesias and neutropenia. The
authors conclude that the results of this study support FOLFOX as a first-line standard
of care for patients with advanced colorectal cancer (Goldberg et al, 2004).
c) In a phase III study comparing two sequential therapies in metastatic colorectal
cancer patients, FOLFIRI then FOLFOX6 (upon disease progression or unacceptable
toxicity) and FOLFOX6 then FOLFIRI (upon disease progression or unacceptable
toxicity), no difference was found in survival and efficacy between the two arms. Two
hundred and twenty patients were randomized to either arm A (n=109), FOLFIRI then
to FOLFOX6, or arm B (n=111), FOLFOX6 then to FOLFIRI. Each FOLFIRI cycle
consisted of a 2-hour infusion of l- or dl-leucovorin (LV) (200 or 400 milligrams per
square meter (mg/m(2)), respectively) and irinotecan 180 mg/m(2) given as a 90minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour
infusion of fluorouracil 2,400 mg/m(2) for 2 cycles, increased to 3,000 mg/m(2) from
cycle 3 in cases where toxicities greater than grade 1 did not occur during the first
two cycles. Each FOLFOX6 consisted of the same LV + FU regimen, with the addition
of a 2-hour infusion of oxaliplatin 100 mg/m(2) on day 1. Arm A offered a median
survival of 21.5 months compared to 20.6 months in patients treated with arm B
(p=0.99). Likewise, when response rate (RR) was compared in the first-line
therapies, FOLFIRI resulted in a 56% RR when compared to a 54% RR in the
FOLFOX6 group (p= NS); median progression-free survival (PFS) was found to be 8.5
months and 8.0 months (p=0.26), respectively. In second-line therapy, FOLFIRI when
compared to FOLFOX6 resulted in a 4% RR versus 15% RR (p= 0.05), respectively,
and 2.5 months versus 4.2 months median PFS (p=0.003), respectively. As first-line
therapy, gastrointestinal (except for diarrhea), alopecia, and fatigue were more
frequent with FOLFIRI and hematologic toxicities were more frequent with FOLFOX6.
Grade 3 oxaliplatin- induced neurotoxicity was reported at a high rate (34%) [463].
Neoplasm of colon
a) Preliminary results from a randomized phase III trial (E3200) indicate that the
addition of bevacizumab to FOLFOX4 (5-fluorouracil (5-FU)/leucovorin (LV)) and
oxaliplatin) is safe in patients with advanced/metastatic colorectal cancer. Primary
endpoints of the study (response rate, time to progression, and overall survival) have
not yet been determined but are anticipated since the results of a recent study
(bevacizumab plus IFL) indicate a improvement in survival (20 months) equal to
FOLFOX alone. In abstract form, it appears that the toxicities associated with the
addition of bevacizumab to FOLFOX (10 milligrams (mg)/kilogram intravenously (IV)
every two weeks plus oxaliplatin 85 mg/square meter (m(2)) IV on day 1/leucovorin
200 mg/m(2) IV and 5-FU 400 mg/m(2) IV followed by 5-FU 600 mg/m(2) IV infused
continuously over 22 hours on days 1 and 2; regimen repeated every 2 weeks) were
increased bleeding and hypertension; serious bleeding seen in 3% of the bevacizumab
patients and none of the FOLFOX patients (Benson et al, 2003; D'Orazio & Lee, 2003).
b) The addition of oxaliplatin to the North Central Cancer Treatment Group/Mayo
Clinic regimen of 5-fluorouracil (FU)/leucovorin (LV) (LV5FU2) demonstrated a
prolonged progression-free survival (PFS), acceptable toxicities, and maintenance of
quality of life as first-line therapy in advanced colorectal cancer. Four hundred and
twenty chemotherapy-naïve patients with metastatic colorectal cancer were
randomized in a multi-center study to treatment with LV5FU2 which consisted of a 2hour infusion of LV 200 milligrams per square meter/day (mg/m(2)) followed by a
bolus of FU 400 mg/m(2)/day and then a 22-hour infusion of FU 600 mg/m(2)/day
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repeated for 2 consecutive days every 14 days (arm A) or oxaliplatin (85 mg/m(2)) on
day 1 plus LV5FU2 group (arm B; FOLFOX4). The results indicate that when added to
the bimonthly two- hour infusion of LV5FU2, oxaliplatin extends PFS significantly (8.2
months versus 6.0 months; p=0.0003). Intent-to-treat response rates were reported
as 21.9% (95% confidence interval (CI), 17.9% to 25.9%) in arm A and 50.0% (95%
CI, 46.1% to 54.9%; p=0.0001) in arm B. Median overall survival (14.7 months for
arm A versus 16.2 months for arm B), however, was not statistically different
between the two treatment groups (log-rank test p=0.12; Wilcoxon p=0.05). In arm
A, patients experienced grade 3 neutropenia and diarrhea mostly. Grade 3/4 toxicities
(neutropenia, diarrhea, mucositis, and neuropathy) were more common in arm B than
arm A were. Although there were significant increases in grade 3/4 toxicities in arm B,
quality of life (QOL) measurements for that group were not significantly influenced;
the overall QOL scores were comparable for the two arms [440].
c) The safety and efficacy of single-agent oxaliplatin in patients with metastatic
colorectal cancer (n=459) was compared to oxaliplatin in combination with 5fluorouracil (5-FU)/leucovorin (LV) and to the same dose and schedule 5-FU/LV in a
multicenter, randomized, controlled trial. Patients with advanced colorectal cancer
who had relapsed/progressed during or within 6 months of first line therapy were
randomized to single-agent oxaliplatin (n=156; day 1: 85 milligrams/square meter
(mg/m(2)), oxaliplatin/5-FU/LV (n=152; day 1: oxaliplatin 85 mg/m(2) + LV 200
mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour infusion), day
2: LV 200 mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour
infusion), or 5-FU/LV (n=151; same dose and schedule). All regimens were repeated
every 2-weeks. At an interim analysis, patients treated with oxaliplatin/5-FU/LV had
an increased response rate and median time to progression (9%, 4.6 months) versus
patients given 5-FU/LV (0%; p=0.0002, 2.7 months) or oxaliplatin alone (1%, 1.6
months). The most common grade 3/4 adverse events reported in the oxaliplatin/5FU/LV group were neuropathies (7%), neutropenia (44%), and
nausea/vomiting/diarrhea (11%, 9%, 11%) (Prod Info Eloxatin (TM), 2002).
d) A combination of oxaliplatin with fluorouracil plus leucovorin resulted in better
response rates than oxaliplatin alone in patients with progressive colorectal cancer in
a non-randomized study. All patients had progressive disease despite prior treatment
with fluorouracil-containing regimens (23 receiving treatment within 6 months of
study; 2 treated more than 6 months before study). Oxaliplatin 130 milligrams/square
meter (mg/m(2)) was infused over 2 hours every 21 days. Fluorouracil was
administered by continuous infusion via central venous catheter at a dose of 200 up to
300 mg/m(2)/day, or as a bolus infusion of 375 mg/m(2) over 5 days with leucovorin
100 mg/m(2). Of 12 patients treated with combination therapy, 4 achieved partial
remission and 4 achieved stable disease; of the 4 partial responders, 2 received the 5day bolus infusion of fluorouracil with leucovorin and 2 received continuous infusion of
only fluorouracil. Of the 13 patients receiving oxaliplatin alone, none achieved
remission and 4 had stable disease. While the results suggest a better response with
combination therapy, patient selection may have influenced results in this nonrandomized study, since combination therapy was given to those who were receiving
fluorouracil at the time the study began, whereas oxaliplatin alone was given to those
who were not receiving the drug at that time (deBraud et al, 1998).
e) A bimonthly regimen of leucovorin plus 48-hour continuous fluorouracil and
oxaliplatin achieved higher responses in patients with colorectal cancer but was not as
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p less than 0.3 months with AT compared with 6. and thrombocytopenia in 13%. The regimen in the second study included leucovorin 500 mg/m(2) plus oxaliplatin 85 mg/m(2) (through separate infusion lines) as a 2-hour infusion. fever (8% versus 4%). 5-fluorouracil. with an oxaliplatin dose of 100 milligrams/square meter (mg/m(2)). Overall response rate was 68% in the AT arm and 55% in the FAC arm (p=0. infection (2% versus 0%). Grade 3 to 4 toxicities were observed in 27% of patients. nausea/vomiting (8% versus 19%. Whether the between-regimen difference in response and toxicity was a result of the lower oxaliplatin dose or patient selection was not established (Andre et al. doxorubicin 50 mg/m(2) IV. and prednisone (40 mg/m(2) PO on days 1 to 14) every 28 days for 6 courses (n=102). followed by fluorouracil 1.25/10/12 Drug details . arthralgia/myalgia (10% versus 0%. and 15 had stabilization lasting 27 weeks. and a slightly higher quality of life rating was observed following first-line treatment with paclitaxel as compared to the combination of cyclophosphamide.3 months and 18. diarrhea (2% versus 0%). Grade 3/4 toxicity with the AT regimen compared with the FAC regimen included neutropenia (89% versus 65%. 4 patients had severe sensory neuropathy that was of prolonged duration following discontinuation of chemotherapy. 2001). b) Prolonged survival.001). 1998). Two hundred and nine women (median age 54 years) were randomized to receive paclitaxel (200 milligrams per square meter (mg/m(2)) every 21 days for 8 courses (n=107) or cyclosphosphamide (100 mg/m(2) orally (PO) on days 1 to 14).001). p=0. Objective response rates were similar in paclitaxel-treated patients (29%: 2% complete. median time to disease progression. 27% partial) and in those treated with combination therapy (35%: 6% complete. p less than 0. Progression-free survival lasted a median of 26 weeks. respectively (p=0. Paclitaxel Breast cancer a) In a phase III trial of women with metastatic breast cancer (n=267). methotrexate. reduced myleosuppression. Responses with the leucovorin plus continuous infusion regimen (46% overall) had been recorded during a previous study.3 months. thomsonhc. thrombocytopenia (2% versus 3%).028).034) and overall survival was 23. anemia (9% versus 7%). The present study included patients refractory to the previous regimen.001). This regimen was given for two consecutive days every two weeks for a median of 9. The AT regimen consisted of doxorubicin 50 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 followed 24 hours later with paclitaxel 220 mg/m(2) administered IV over 3 hours. The FAC regimen consisted of 5.MICROMEDEX® 2. methotrexate (40 mg/m(2) intravenously (IV) on days 1 and 8). Both regimens were administered every 3 weeks for 8 cycles.0 well-tolerated as the same regimen with a lower dose of oxaliplatin. peipheral neuropathy (12% versus 0%. and cyclophosphamide 500 mg/m(2) IV.013). Median time to disease progression was 8.2 months with FAC (p=0. and CYCLOPHOSPHAMIDE (FAC) as first-line therapy for metastatic disease.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. and stomatitis (1% for both)(Jassem et al. After 11 to 15 cycles. overall survival.5 to 2 grams/m(2) as a 22-hour infusion. and prednisone in patients with metastatic breast cancer.5 cycles. the most common adverse events were non-febrile neutropenia in 20% of patients. 29% partial).fluorouracil 500 mg/m(2) IV. 6 had a partial response (20%) lasting 37 weeks. p less than 0.IntermediateToDocumentPrintLink 248/317 . Among 30 assessable patients. 5-fluorouracil (600 mg/m(2) IV on days 1 and 8). and response rate were significantly increased with DOXORUBICIN and PACLITAXEL (AT) versus FLUOROURACIL. DOXORUBICIN. with a median survival of 57 weeks.032).

56 to 0. fluorouracil and cyclophosphamide as neoadjuvant therapy of operable (stage IIA to IIIA) breast cancer in a randomized trial (n=174). paclitaxel caused more alopecia. fluorouracil 500 mg/m(2). Paclitaxel Protein-Bound Metastatic breast cancer. including physical wellbeing. Leukopenia.025). range 23 to 88 years. and cyclophosphamide 500 mg/m(2) IV every 3 weeks.25/10/12 Drug details . consisting of fluorouracil 500 mg/m(2) IV on days 1 and 4. paclitaxel 250 milligrams/square meter (mg/m(2)) as a 24-hour intravenous (IV) infusion resulted in an 80% response rate (27% complete plus 53% partial). randomized. Toxicities such as neutropenic fever. elicited a statistically similar 79% response rate (24% complete plus 55% partial). but were not analyzed statistically (Buzdar et al. epirubicin 90 to 100 mg/m(2). range. in the international. . mucositis. 0. However. Quality of life measures.2 months. type of surgery and use of irradiation also did not differ significantly between groups. After a median follow-up of 15.6 months. HER2-negative.69.0 Multivariate analysis revealed a signifcantly improved survival with paclitaxel therapy (17. median PFS (primary outcome) was 8.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. p=0. myalgia. c) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of doxorubicin. multicenter.9 months. median age. phase 3 Regimens in Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). p less than 0. median age.MICROMEDEX® 2. doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3 weeks. epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus placebo. and nausea/vomiting were less severe with paclitaxel treatment. Other parameters including nodal disease at surgery. With a median follow-up of 19.6 months with capecitabine plus bevacizumab (n=409. p=0. 28 to 91 years) compared with 5. or an anthracycline-based regimen (fluorouracil 500 mg/m(2). and appetite were slightly better in paclitaxel-treated patients. pathologic stage after neoadjuvant therapy. locally recurrent or metastatic breast cancer previously untreated with chemotherapy. When administered preoperatively as four 21-day cycles. The combination regimen.001).7 months with capecitabine plus placebo (n=206. mood.0006). hazard ratio (HR). 57 years. and peripheral neuropathy than combination therapy. as first-line therapy in combination with capecitabine or taxane.or anthracycline-based chemotherapy a) The addition of bevacizumab to capecitabine or to a taxane.001) and required fewer hospital days for appropriate treatment (1. cyclophosphamide 500 mg/m(2) IV on day 1 and doxorubicin 50 mg/m(2) as a 72-hour IV infusion.5 days versus 4.4 days. 56 years. The incidences of in situ or no residual disease in the breast at surgery were 14% and 23% in the paclitaxel and combination arms. and cyclophosphamide 500 mg/m(2) IV every 3 weeks. respectively (p not significant). a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel protein-bound particles 260 mg/m(2) IV every 3 weeks). p=0. The choice of capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle).3 months versus 13.IntermediateToDocumentPrintLink 249/317 interval. 1999). 95% confidence thomsonhc.84.or anthracycline-based chemotherapy regimen significantly improved progression-free survival (PFS) in women with human epidermal growth factor receptor 2-negative. myalgias and paresthesias were numerically more frequent in the paclitaxel group. thrombocytopenia. doxorubicin 50 mg/m(2). 0. Febrile neutropenia with or without infection occurred significantly less frequently with paclitaxel as compared to combination therapy (10% versus 27%. placebo-controlled. but the differences between groups were not statistically significant.

5 to 10.3 months)) and with a taxane. 51.2 months.2%. 0%). median age. and maintenance therapy was continued until death.or anthracycline-based regimen plus placebo (n=177.0 interval.9%.7%) vs 37.4% vs 21.or anthracycline-based regimen plus bevacizumab (n=345) compared with a taxane. 0%. 0. the taxane arm (8. Survival rates following 8 months of therapy were 81% and 57% in patients receiving maintenance picibanil alone and picibanil plus MFC. Grade 3 to 5 adverse effects were higher with bevacizumab than with placebo in the capecitabine arm (35. 55 years.4 months) vs 7. median PFS was 9.8% and 2. 17. proteinuria and febrile neutropenia. p less than 0.1%. Based on these results. 30. p=0. and the anthracycline arm (34.6% to 30.2% to 40. 0%.or anthracycline-based regimen plus placebo (8. The median duration of response was longer with capecitabine plus bevacizumab compared with capecitabine plus placebo (9. picibanil maintenance therapy alone appears preferable to picibanil plus MFC.1 months (95% CI. 2%).3% vs 15%).9%.5%. However. median age.6% (95% CI.84. Hypertension.2 months (95% CI. 2%. particularly in patients with undifferentiated gastric cancer (Yasue et al. However. 28 to 88 years) compared with 8 months with a taxane.0097) and with a taxane.7%. signet-ring cell carcinoma) as compared to those with differentiated histology. 0%. 7.2 (95% CI.64. patients were randomized to picibanil alone or picibanil plus MFC. fluorouracil. the objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better with capecitabine plus bevacizumab (n=325) compared with capecitabine plus placebo (n=161. accounting for greater benefits with picibanil alone. p less than 0. range. Among patients with measurable disease at baseline. 1%.001). range 29 to 85 years.56 to 0. 55 years. p=0.2% vs 38. Pirarubicin 250/317 . 0% and 2.MICROMEDEX® 2. Picibanil Gastric cancer a) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL alone has been significantly more effective than commensurability with intramuscular picibanil plus MFC (mitomycin. 6. 30. and cytarabine) in patients with advanced untreated gastric cancer following palliative gastrectomy. 5. 95% CI.001).7 months) vs 7. 0.25/10/12 Drug details . and the anthracycline arm (10. 8.9%).2 to 10.3% (95% CI. With a median follow-up of 19.2 months with a taxane.0054). respectively. the taxane arm (57. 0%. analysis based on carcinoma histology revealed a significant difference in survival rates only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma.9% to 56. but the majority of patients received additional systemic treatment that might have affected OS.or anthracycline-based regimen plus bevacizumab compared with a taxane.7% vs 45.4% and 3. 3. It is speculated that the MFC regimen may have concealed the immunopotentiating effect of picibanil.3%).8. 45.3 (95% CI.4% (95% CI. 0. All patients received induction commensurability with intramuscular picibanil plus MFC for 6 weeks following surgery. HR. were also higher consistently with bevacizumab than with placebo in the capecitabine arm (10.or anthracycline-based regimen plus bevacizumab (n=415.6%) vs 23.2 to 8. further studies are required to confirm these findings.52 to 0. 35.1 to 9. respectively. 5%) [413]. 8.or anthracycline-based regimen plus placebo (n=207. Overall survival (OS) and 1-year survival were not significantly different with bevacizumab than with placebo.9% (95% CI.8 months)). 1981). 8 weeks after surgery.9%.2%).

Median follow-up duration in this study was 8. but did not alter overall survival (Muss et al. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%). not statistically different. d) In one study. FLUOROURACIL. intravenous fluorouracil) were comparable in efficacy in predominantly pretreated patients with advanced breast cancer. Alopecia was significantly less frequent with the FPC regimen. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%). but the difficulty (ie. VINCRISTINE. oral cyclophosphamide. Prednisone Breast cancer a) In one study. FLUOROURACIL.0 Breast cancer a) In a randomized comparison (n=78). node.25/10/12 Drug details . Five-year survival was 57% and 62% in the 1and 2-year therapy groups.6 years (maximum of 11. toxicity) of 2-year administration may outweigh the benefit (Rivkin et al. Objective responses (complete or partial) were observed in 30% and 35% of patients. oral cyclophosphamide.3 years) and 445 ER-negative. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. respectively. Median follow-up duration in this study was 8. 1and 2-year therapy with CYCLOPHOSPHAMIDE. VINCRISTINE. Five-year survival was 57% and 62% in the 1. PREDNISONE) produced statistically similar survival or disease-free survival rates (Rivkin et al. METHOTREXATE. In another study. The 2-year therapy produced a moderate improvement in survival over the 1-year therapy (57% vs 62%). intravenous fluorouracil) and an FPC regimen (intravenous pirarubicin. Median follow-up duration was 8. node. Although. METHOTREXATE. methotrexate. maintenance therapy with cyclophosphamide.and 2-year therapy groups. and PREDNISONE (CMFVP) produced similar survival/disease-free survival rates. respectively. 1993). receptor-negative breast cancer. toxicity) of administering 2 years of CMFVP therapy. respectively. PREDNISONE) produced statistically similar survival or disease-free survival rates. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE.6 years (maximum of 11.positive breast cancer patients were enrolled. 1993). This improvement should be weighed against the difficulty (ie.positive breast cancer patients were enrolled. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al. an FAC regimen (intravenous doxorubicin. FLUOROURACIL. b) In one study. Five-year survival was 57% and 62% in the 1. respectively. METHOTREXATE. 2 years of therapy produced a moderate improvement in survival 251/317 .MICROMEDEX® 2. 1. PREDNISONE) produced statistically similar survival or disease-free survival rates.and 2-year therapy groups. 1993).or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. 1991). electrocardiogram abnormalities occurred in 3 of 16 evaluable patients in the FAC group (18%) but in none of 23 evaluated in the FPC group (Tominaga et al. 1989). VINCRISTINE. Although.6 years. Median follow-up duration in this study was 8.3 years) and 445 ERnegative. c) In a study of 445 patients with node-positive. METHOTREXATE. Although. node-positive breast cancer patients were enrolled. FLUOROURACIL. not statistically different.3 years) and 445 estrogen receptor (ER)negative.6 years (maximum of 11. This improvement should be weighed against the difficulty (ie. VINCRISTINE. and fluorouracil prolonged time to progression. A complete response was reported in 1 patient in each group. Durations of partial response were 19 weeks with FPC and 14 weeks in the FAC group. not statistically different.

03) (Bartelink et al. b) Concurrent radiation therapy and chemotherapy with fluorouracil and mitomycin . 27% partial) and in those treated with combination therapy (35%: 6% complete.8 Gy daily). Multivariate analysis revealed a signifcantly improved survival with paclitaxel therapy (17. and improved event-free survival in patients with advanced anal cancer. 15 patients (7 partial responders and 8 complete responders) underwent surgery. Radiation therapy Anal cancer a) Combined radiotherapy and chemotherapy resulted in significantly better locoregional control. significantly lowering the locoregional recurrence rate (p=0. paclitaxel caused more alopecia. including physical wellbeing.001) and required fewer hospital days for appropriate treatment (1. reduced myleosuppression. myalgia. p=0.3 months versus 13.(57% vs 62%) over 1 year of therapy. Although surgical resection was planned only for non-responders. methotrexate.025). but the differences between groups were not statistically significant. Radiotherapy consisted of 45 Gray (Gy. e) Prolonged survival. event-free survival was significantly improved (p=0. and prednisone in patients with metastatic breast cancer. and peripheral neuropathy than combination therapy. Two hundred and nine women (median age 54 years) were randomized to receive paclitaxel (200 milligrams per square meter (mg/m(2)) every 21 days for 8 courses (n=107) or cyclosphosphamide (100 mg/m(2) orally (PO) on days 1 to 14). The complete remission rate increased from 54% to 80% with the addition of chemotherapy to radiotherapy. 1997). this was followed by a 6-week rest and an additional boost of 15 to 20 Gy depending on initial response. and the combination group had a higher incidence of anal ulcers. skin ulceration. 29% partial). Objective response rates were similar in paclitaxel-treated patients (29%: 2% complete. Febrile neutropenia with or without infection occurred significantly less frequently with paclitaxel as compared to combination therapy (10% versus 27%. stenosis. While overall survival did not improve with combination therapy. and this difference persisted throughout the follow-up period. and a bolus dose of mitomycin 15 mg/m(2) on day 1. thrombocytopenia. p=0. mood. This improvement should be weighed against the difficulty (ie. and prednisone (40 mg/m(2) PO on days 1 to 14) every 28 days for 6 courses (n=102).4 days. Acute side effects (skin reactions and diarrhea) and late complications (fistula.9 months. In this phase III study. Patients assigned to combination therapy also received continuous infusion fluorouracil 750 milligrams/square meter(mg/m(2)) per 24 hours on days 1 to 5 and 29 to 33. mucositis. and appetite were slightly better in paclitaxel-treated patients.02). p=0. However. 110 patients received either radiotherapy alone or radiotherapy with chemotherapy. and nausea/vomiting were less severe with paclitaxel treatment. 1993). toxicity) of administering 2 years of CMFVP therapy (Rivkin et al. and a slightly higher quality of life rating was observed following first-line treatment with paclitaxel as compared to the combination of cyclophosphamide. Quality of life measures. Nineteen patients required fluorouracil dose reductions during the second course. however. fewer colostomies. Leukopenia. 1 patient receiving combination therapy died during neutropenic sepsis. 5-fluorouracil. methotrexate (40 mg/m(2) intravenously (IV) on days 1 and 8). 5-fluorouracil (600 mg/m(2) IV on days 1 and 8).0006). a unit of absorbed radiation dose equal to 100 rads) administered over 5 weeks (1. fibrosis) did not differ between treatment groups.5 days versus 4.

05) for patients who received chemoradiotherapy. Chemotherapy consisted of leucovorin 20 mg/m(2) as an IV bolus followed by an IV bolus of fluorouracil 425 mg/m(2) on days 1 through 5 every 28 days for 6 cycles. however. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. Partial or complete responders received a boost course of radiotherapy. Intent-to-treat analysis was used to conduct 2 comparisons: patients who received chemotherapy with patients who did not receive chemotherapy and patients who received chemoradiotherapy with patients who did not receive chemoradiotherapy. patients with a less than 50% response were recommended for radical surgery (Anon. alopecia. Chemoradiotherapy was administered as a 20 Gray dose to the previous tumor bed in 10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 through 3.MICROMEDEX® 2. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. diarrhea. All randomized patients received a fourth course of the up-front chemotherapy regimen. chemoradiotherapy (n=73). Breast cancer a) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. Combination therapy consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily on days 1 to 4. An additional cycle of fluorouracil was given during the final week of radiotherapy. In addition to that.Drug details . fatigue. or combination chemoradiotherapy and chemotherapy (n=72). However limitations in the trial design. repeated after a 2-week break. The calculated hazard ratio for death was 1. Median survival did not significantly differ between those who received chemotherapy and those who did not. There was no overall survival advantage for patients treated with combination therapy. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter.0 resulted in significantly fewer local failures than radiation therapy alone in patients with epidermoid anal cancer. p=0. large drop out rates and potential bias hamper the interpretation of these results.99 to 1. A total of 289 patients were randomized in a 2-by-2 factorial design to receive no treatment (n=69). Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al.28 (95% confidence interval (CI) 0.66. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.02) in the radiotherapy group versus combination therapy group. EPIRUBICIN (120 mg/m(2). or radiotherapy plus fluorouracil 750 mg/m(2)/day on days 1 to 5 and mitomycin 12 mg/m(2) on day 1. 1996). All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). The same regimens of chemoradiotherapy followed by chemotherapy were used for the combination therapy. THIOTEPA 480 mg/m(2). phlebitis. and neutropenia. radiation therapy and 2 years of TAMOXIFEN therapy. 1998). vomiting. Toxicities were greater in the high-dose group but both groups experienced nausea. 3-year mortality was significantly higher (p=0. mucositis. Carcinoma of pancreas a) Results from a randomized controlled trial of patients with resectable pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1) suggest that postoperative chemotherapy with fluorouracil and leucovorin improves survival whereas postoperative chemoradiotherapy negatively affects survival. Chemotherapy was associated with a 253/317 . chemotherapy (n=75).

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0.71 hazard ratio for death (95% CI 0.55 to 0.92; p=0.009). Median survival times
also did not significantly differ between patients who received chemotherapy and
those who did not. However only 70% of patients assigned to receive
chemoradiotherapy received a total of 40 Gray according to the protocol and only 50%
of patients assigned to receive chemotherapy received all 6 cycles of therapy. Analysis
of patient drop out was not presented. Although these results are suggestive, the
ESPAC-3 trial and the Radiation Therapy Oncology Group trial 97-04 will shed further
light on the role of chemoradiotherapy and chemotherapy in this patient population
[439].
Cervical cancer
a) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA
cervical carcinoma, the combination of 5-fluorouracil (5-FU) and cisplatin was superior
to hydroxyurea alone as an adjunct to radiation therapy. Cisplatin 50
milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation
on days 1 and 29, while 5-FU was dosed at 1 gram/m(2)/day on days 2, 3, 4, 5, 30,
31, 32, and 33. Patients randomized to oral hydroxyurea received 80
milligrams/kilogram/day twice weekly. The median duration of therapy in both groups
was 9 weeks. After a median follow-up of 8.7 years, the rates of disease progression
were 43% and 53% in the 5-FU/cisplatin and hydroxyurea groups, respectively.
Corresponding overall mortality rates were 45% and 57% (p=0.018). Relative risks
for progression/death and mortality were 0.79 (90% confidence interval, 0.62 to 0.99)
and 0.74 (90% CI, 0.58 to 0.95), respectively, both favoring the 5- FU/cisplatin
regimen. The only statistically significant difference in toxicity was more
frequent/severe neutropenia with hydroxyurea (p less than 0.00001) (Whitney et al,
1999).
b) The combination of CISPLATIN and RADIATION therapy or CISPLATIN,
FLUOROURACIL, HYDROXYUREA, and RADIATION therapy produced significantly
better survival than a control group receiving hydroxyurea and radiation for the
treatment of STAGE IIB, III or IVB cancer of the cervix. There were 3 arms in this
large (n=526), randomized, multicenter, controlled trial. The first study group received
cisplatin 40 milligrams/square meter (mg/m(2)) over 4 hours before radiotherapy at
weeks 1 through 6. The second study group received cisplatin 50 mg/m(2) on days 1
and 29, fluorouracil 4 grams/square meter as a 96 hour infusion on days 1 and 29, and
hydroxyurea 2 grams/square meter orally twice a week before radiation therapy at
weeks 1 through 6. The control group was administered only hydroxyurea 3
grams/square meter orally twice weekly before radiation therapy on weeks 1 through
6. All groups received radiation at varying doses depending on stage of disease. The
median follow-up was 35 months. Actual survival rates among the first study group,
the second study group, and the control group were 66%, 67%, and 49.7%
respectively. Progression-free survival relative risk was 0.57 and 0.55 for the first and
second study groups respectively when compared to the control group. The rates of
progression-free survival at 24 months for the first and second study group and the
control group were 67%, 64%, and 47% respectively. The occurrence of grade 3/4
toxicities was greatest in the 3-drug regimen, but was similar in the other 2 groups.
Grade 3/4 leukopenia was double the rate in the 3-drug group compared to the other
2 groups. This was also true for the other hematologic effects. There were no
treatment-related deaths (Rose et al, 1999).
c) In a large, randomized, open-label, multicenter, controlled, PHASE III trial, patients
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receiving CISPLATIN and FLUOROURACIL with RADIATION therapy had significantly
better survival (73%) versus patients receiving radiation alone (58%) in the
treatment of cervical cancer (p=0.004). A total of 388 women were evaluated having
STAGE IIB through IVA cancer of the cervix and followed for a median of 43 months.
The study group was administered cisplatin 75 milligrams/square meter (mg/m(2))
infused over 4 hours followed by fluorouracil 4000 mg/m(2) infused over 96 hours plus
a total of 85 Gy radiation. Chemotherapy was given every 3 weeks for a total of 3
cycles. The control group received only radiation (85 Gy). Disease-free survival at 5
years was also better in the study group (67%) compared to radiation alone (40%).
When stratified according to stage IB, IIA, or IIB, again the study group showed
better survival (77%) compared to radiation only (58%). There was no difference in
survival between the 2 groups with stage III or IVA disease. Rates of distant relapse
and (14%, relative risk=0.39) locoregional recurrence (19%, relative risk=0.47) were
significantly lower in the study group compared to the radiation-only group (33% and
35% respectively). Grade 3 and 4 toxicities occurred more frequently with combined
therapy but were usually self-limited. Hematologic effects were generally moderate
(Morris et al, 1999).
Esophageal cancer
a) The addition of a preoperative chemoradiation regimen offered no statistical
survival advantage over surgery alone in a randomized trial of 100 patients with
previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma
(n=25) of the esophagus. Chemoradiation consisted of CISPLATIN 20
milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5
and days 17 through 21; FLUOROURACIL 300 mg/m(2)/day as a continuous infusion
on days 1 through 21; VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17
through 20; and twice-daily radiation on days 1 through 5, 8 through 12 and 15
through 19 for a total dose of 45 Gy. On day 42, subjects underwent transhiatal
esophagectomy. Forty-five patients in each arm obtained complete surgical resection
of the carcinoma. The median survival in the preoperative chemoradiation and
surgery-only groups were 16.9 and 17.6 months, respectively (p=NS). Corresponding
1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ
statistically. This trial was powered to detect only large overall survival differences.
Significant negative independent prognostic factors included tumor size greater than 5
centimeters, squamous cell histology and age over 70 years. Of the subset (n=14)
who attained complete histologic response to the preoperative regimen, 86% and
64% were alive at 1 year and 3 years, respectively (median survival: 49.7 months)
(Urba et al, 2001).
Malignant tumor of rectum
a) A 12-month course of fluorouracil (5-FU) plus leucovorin offered no significant
advantage over a 6-month course in the postoperative treatment of patients with
stage II or III RECTAL cancer (n=263). Dosing consisted of leucovorin 100
milligrams/square meter (mg/m(2)) over 15-30 minutes then 5-FU 450 mg/m(2) over
60 minutes on days 1 to 5 of a 4-week cycle. During the second cycle only, all subjects
received daily pelvic radiotherapy (up to 50.4 Gy total exposure) with weekly
leucovorin and reduced-dose 5-FU 350 mg/m(2). Based on data from 223 evaluable
subjects with a median 34 months of follow-up, the median times to recurrence were
16.3 and 17.8 months in the 12-month and 6-month groups, respectively (p=NS).
Corresponding 3-year mortality rates were 20.5% and 23.7%, respectively (p=NS).
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However, only 51% of patients randomized to 12 cycles actually completed them. The
additional six cycles of 5-FU/leucovorin exposure was not associated with greater
toxicity (Queiber et al, 2000).
Pancreatic cancer
a) In interim results of a randomized controlled trial of patients with resectable
pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1), a
median survival of 19.7 months was achieved in patients who received ADJUVANT
CHEMOTHERAPY with FLUOROURACIL and LEUCOVORIN (n=238) compared with
14.0 months in patients who received chemoradiotherapy or no treatment (n=235;
p=0.0005). However, this survival benefit was not significant in patients randomized
in the original 2-by-2 factorial trial design with a median survival of 17.4 months for
patients who received chemotherapy (n=146) versus 15.9 months for patients who
did not (n=139). In a comparison of patients who received CHEMORADIOTHERAPY
(n=175) and those who received chemotherapy or no treatment (n=178), there was
no significant difference in survival (15.5 versus 16.1 months; p=0.24). Of 541
patients, 285 were randomized in a 2-by-2 factorial design to receive no treatment
(n=69), chemoradiotherapy (n=70), chemotherapy (n=74), or chemoradiotherapy and
chemotherapy (n=72). The trial was expanded to allow clinicians to enroll patients in
the original trial design as above or to select randomization to either
chemoradiotherapy/no chemoradiotherapy (n=68) or chemotherapy/no chemotherapy
(n=188) and to provide any additional treatment of their choosing prior to enrollment.
Chemoradiotherapy consisted of 20 Gray (Gy) tumor dose in 10 daily fractions over 2
weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV)
bolus on days 1 through 3, repeated after a 2-week break. Chemotherapy consisted of
leucovorin 20 mg/m(2) IV bolus followed by fluorouracil 425 mg/m(2) IV bolus on days
1 through 5 every 28 days for 6 cycles. The same regimens of chemoradiotherapy
followed by chemotherapy were used for the combination therapy. Toxicity data was
collected on a subset of 254 patients (74 chemoradiotherapy, 118 chemotherapy, and
54 combination. Grade 3/4 toxicity was reported by 1 patient in the
chemoradiotherapy group, 28 in the chemotherapy group, and 15 in the combination
group and included stomatitis (32%), neutropenia (25%) and diarrhea (23%). Further
trials are needed to confirm the survival benefit of chemotherapy (Neoptolemos et al,
2001).
Raltitrexed
Colorectal cancer
a) SUMMARY: A single dose of raltitrexed every three weeks has been comparable in
efficacy to the Mayo regimen of 5-fluorouracil/leucovorin in the treatment of patients
with advanced colorectal carcinoma. Survival, quality of life, and time to disease
progression were similar with each regimen, although toxicity tended to be less with
raltitrexed. However, the low response rates observed with each regimen suggest the
need for additional comparisons.
b) Raltitrexed 3 mg/m(2) every 3 weeks offered no significant therapeutic advantage
over the Mayo regimen of combined 5-fluorouracil/leucovorin (425/20 mg/m(2) daily
for 5 consecutive days every 4 to 5 weeks) in one phase III comparison involving
untreated patients with advanced metastatic or recurrent colorectal carcinoma
(n=434) [435]. At a mean duration of follow-up of 5.3 months, objective (complete or
partial) response rates were slightly higher in the raltitrexed group (20% versus
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13%), although this was not significant. Median time to disease progression in
raltitrexed and 5-fluorouracil/leucovorin groups (two-sided alpha (5%) significance
level) also did not differ significantly (20 and 15 weeks, respectively), and there was
no difference in survival. Modest and similar improvements in quality of life,
performance status, and body weight were observed. Grade 3 or 4 leukopenia and
mucositis were more common with the 5-fluorouracil/leucovorin regimen, whereas
liver enzyme abnormalities occurred only with raltitrexed (10% of patients); there
was no difference in the incidence of infection or occurrence of fever between
regimens. A shorter time for drug administration in the hospital was evident in the
raltitrexed group.
c) Objective response rates with 5-fluorouracil/leucovorin in this study were low,
suggesting flaws in trial design. Other trials evaluating 5-fluorouracil plus leucovorin in
advanced colorectal carcinoma revealed response rates of up to 45% [436][437];
with the addition of interferon-alpha(2a), a response rate of 54% has been
demonstrated in preliminary studies [436]. In the Cunningham study, one potential
reason to explain low response rates was the unusually long interval between
response evaluations (12 weeks); 6-week evaluation periods would have been more
appropriate. Other flaws (eg, differences in patient characteristics) may have been
operative and suggest the need for a confirmatory comparative trial.
d) Considering available data, raltitrexed does not offer an advantage with respect to
survival or quality of life; its principal advantages are the potential for less toxicity and
greater convenience. However, even these attributes have been questioned by at
least one oncologist, who offers the practical reminder that 5-fluorouracil/leucovorin
chemotherapy does not require hospitalization [437]. At present, data are insufficient
to recommend raltitrexed over conventional 5-fluorouracil/leucovorin.
Neoplasm of colon
a) Combined fluorouracil/leucovorin is advocated as the regimen of choice for
advanced colorectal carcinoma by many specialists (Anon, 1997). A direct comparison
of raltitrexed and the Mayo regimen of fluorouracil/leucovorin (Cunningham et al,
1995) revealed no significant differences in objective response rate, time to
progression, survival, or quality of life; response rates were low with both treatments
(20% and 13%, respectively). The potential advantages of raltitrexed emerging from
this trial were its greater convenience in administration (once every 3 weeks) and
potentially lower propensity for toxicity (reduced mucositis and severe leukopenia),
although liver enzyme elevations occurred only in the raltitrexed arm.
Streptozocin
Malignant tumor of Islets of Langerhans
a) The combination of STREPTOZOCIN plus DOXORUBICIN was superior to
STREPTOZOCIN plus 5-FLUOROURACIL or CHLOROZOTOCIN alone in the treatment
of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients. The
dose of streptozocin was 500 milligrams/square meter (mg/m(2))/day given every 6
weeks. Doxorubicin was administered at 50 mg/m(2) on day 1 of streptozocin and for
day 22 of each 6-week cycle. Tumor regression occurred in 69% and 45% of patients
receiving streptozocin plus doxorubicin and streptozocin plus 5-fluorouracil,
respectively; time to tumor progression was 20 versus 6.9 months, respectively.
Survival was also extended in the streptozocin plus doxorubicin group, 2.2 versus 1.4
years, respectively. Chlorozotocin alone produced a 30% regression rate with length
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of time to tumor progression and survival time equivalent to the streptozocin plus 5fluorouracil group (Moertel et al, 1992).
b) A later retrospective analysis of 16 patients receiving the previously described
regimen of streptozocin and doxorubicin revealed only a 6% (ie, 1 of 16) response
rate to therapy. Nine patients (56%) had stable disease, and 6 patients (38%)
showed disease progression. Proposed reasons for this discrepancy are that previous
trials have accepted a so-called "biologic response" and the clinical measurement of
hepatomegaly on physical examination or measurement on radionuclide liver-spleen
scan as indicators of a major objective response. The authors conclude that an
expectation of frequent major tumor regressions after treatment with this regimen
may be overly optimistic (Cheng & Saltz, 1999).
Sulodexide
Trabeculectomy ab externo
a) In a randomized prospective trial, postoperative SULODEXIDE (SDX) adjunctive
treatment provided comparable success rates and similar levels of intra-ocular
pressure (IOP) to 5-FLUOROURACIL (5-FU), without the adverse side effects
associated with 5-FU, in glaucoma patients undergoing trabeculectomy. Forty-one
consecutive patients had standard- technique trabeculectomy operations. Afterwards,
in randomized fashion, 22 eyes received SDX treatment and 19 eyes received 5-FU
therapy. Five subconjunctival injections of SDX or 5-FU were given postoperatively on
days 10, 17, 24, 31, and 38. Each SDX injection was comprised of 0.1 milliliter (mL) of
drug at a concentration of 300 USL/mL. 5-FU injections were given as 0.1 mL at a
concentration of 50 milligrams (mg)/mL (total 25 mg). No significant differences in
IOP were found between the 2 groups at any time point (2, 6, 12, 18, 24 months
postop). No ocular complication occurred in 73% of the SDX group compared with
63% of the 5-FU group. No cases of superficial punctate keratopathy occurred in SDXtreated cases, compared with 6 in the 5-FU group. Six cases of modest
subconjunctival hemorrhage suffusion were associated with SDX and 1 case with 5FU. A common side effect/complication associated with 5-FU use is perforation of the
filtering bleb; 2 cases in the 5-FU group occurred, requiring surgical repair; no case of
this complication occurred with SDX. All study subjects received a subconjunctival
injection of betamethazone acetate 1.5 mg at the inferior conjunctival fornix at the
end of the operation. Six-week topical therapy given to all patients included
dexamethazone 0.2% eyedrops and tobramycin 0.3% eyedrops 6 times a day, along
with tropicamide 0.1% eyedrops twice daily [465].
Surgical procedure
Breast cancer
a) Postoperative sequential therapy with intravenous methotrexate and fluorouracil,
followed by leucovorin, was not associated with a survival advantage as compared to
no postoperative therapy in a randomized study involving 679 patients with primary
breast cancer, histologically negative axillary nodes, and estrogen-receptor negative
tumors [418]. In this study, intravenous methotrexate 100 mg/m(2) and intravenous
fluorouracil 600 mg/m(2) were given as bolus doses on days 1 and 8 every 4 weeks,
with fluorouracil being given 1 hour after the methotrexate; intravenous leucovorin 10
mg/m(2) was given every 6 hours for 6 consecutive doses beginning 24 hours after
the methotrexate. The methotrexate with fluorouracil therapy was initiated no sooner
than 2 weeks and no later than 35 days after mastectomy, and an average of 10.2
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courses per patient were administered. At 4 years, the survival of patients who
received adjunctive chemotherapy was almost identical to survival in patients treated
with surgery alone (87% versus 86%). However, a significant prolongation of diseasefree survival was observed in women who had received sequential therapy as opposed
to those who had not (80% versus 71%). An advantage was seen both in women
over 50 years and women less than 50 years. At 4 years, treatment failure was
reduced by 24% in the younger group and 50% in the older group.
b) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE, METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone
in node-positive breast cancer patients (n=179, n=207, respectively) in a 20-year
follow-up study. Relapse-free and overall survivals in premenopausal patients after 20
years were 37% and 47%, respectively, in the CMF-treated group; and for
postmenopausal patients, 26% and 22%, respectively. Relapse-free and overall
survivals in premenopausal patients after 20 years were 26% and 24%, respectively,
in the surgery-alone group; and for the postmenopausal patients, 24% and 22%,
respectively (Bonadonna et al, 1995).
Esophageal cancer
a) The addition of a preoperative chemoradiation regimen offered no statistical
survival advantage over surgery alone in a randomized trial of 100 patients with
previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma
(n=25) of the esophagus. Chemoradiation consisted of CISPLATIN 20
milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5
and days 17 through 21; FLUOROURACIL 300 mg/m(2)/day as a continuous infusion
on days 1 through 21; VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17
through 20; and twice-daily radiation on days 1 through 5, 8 through 12 and 15
through 19 for a total dose of 45 Gy. On day 42, subjects underwent transhiatal
esophagectomy. Forty-five patients in each arm obtained complete surgical resection
of the carcinoma. The median survival in the preoperative chemoradiation and
surgery-only groups were 16.9 and 17.6 months, respectively (p=NS). Corresponding
1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ
statistically. This trial was powered to detect only large overall survival differences.
Significant negative independent prognostic factors included tumor size greater than 5
centimeters, squamous cell histology and age over 70 years. Of the subset (n=14)
who attained complete histologic response to the preoperative regimen, 86% and
64% were alive at 1 year and 3 years, respectively (median survival: 49.7 months)
(Urba et al, 2001).
Tamoxifen
Breast cancer
a) Tamoxifen 10 mg PO BID was reported as effective as a combination of
cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in the initial treatment of
stage IV breast cancer in elderly women (over the age of 65 years). Response rates
were 45% to 38% in tamoxifen and CMF-treated patients, respectively; an additional
33% and 45% of patients treated with tamoxifen and CMF, respectively, had disease
stabalization for at least 2 months. Survival rates favored tamoxifen as initial therapy
(23 months versus 21 months for CMF), which reached a borderline level of
significance (P=0.08) in the proportional hazards model. Additional disease control
with hormone withdrawal was observed in 23% of patients, and was correlated highly
259/317

Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. 5-year OS was 77. FEC 50. radiation therapy and 2 years of TAMOXIFEN therapy. Contralateral breast cancer developed in 21 patients (FEC 100. acute leukemia occurred in 2 patients (FEC 100.IntermediateToDocumentPrintLink 260/317 . Treatment was started within 42 days after initial surgery. During chemotherapy. Initiation of hormone therapy as opposed to CMF chemotherapy is recommended in most elderly patients [419]. EPIRUBICIN. and infection (3.007). Upon crossover to the opposite treatment. epirubicin 100 mg/m(2). 0%).8% with FEC 50 (p=0.1%). Toxicities were greater in the high-dose group but both groups experienced nausea. All randomized patients received a fourth course of the up-front chemotherapy regimen.4% for FEC 100 and 65. and CYCLOPHOSPHAMIDE (FEC) with an epirubicin dose of 100 milligrams/square meter (mg/m(2)) (FEC 100) compared to an epirubicin dose of 50 mg/m(2) (FEC 50). and cyclophosphamide 500 mg/m(2) every 21 days) or 6 cycles of FEC 50 (fluorouracil 500 mg/m(2). 1998). alopecia. 13 cardiac abnormalities were diagnosed (7 in the FEC 100 group. Patients were randomized to receive 6 cycles of FEC 100 (fluorouracil 500 mg/m(2). There were 10 cases of delayed cardiac toxicity (decrease in left ventricular ejection fraction or congestive heart failure and one myocardial infarction) in patients who had received regional radiation. A comparison of grade 3/4 toxicity in the FEC 100 group versus the FEC 50 group included neutropenia (25.3% with FEC 100 and 54. fatigue. n=7. A previous response to CMF tended to be associated with a better chance for tamoxifen response. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.3%). mucositis. 0%). anemia (0. and cyclophosphamide 500 mg/m(2) every 21 days).2%. FEC 50.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. however the thomsonhc. n=14). 0%). and neutropenia. 1 in the FEC 50 group). THIOTEPA 480 mg/m(2). This study was not powered for a subset analysis.25/10/12 Drug details . This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. n=7). In addition to that. nausea/vomiting (34. n=7. phlebitis. n=1).0 with prior hormonal response. epirubicin 50 mg/m(2). and 14 patients developed second malignancies (FEC 100.4%.03). Five-year DFS was 66. 6 in the FEC 50 group) which included 3 grade 2 conditions requiring treatment interruptions (2 in the FEC 100 group. respectively). vomiting.7%. EPIRUBICIN (120 mg/m(2). 20. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. FEC 50. response to either tamoxifen or the CMF regimen was less than that observed when given as initial therapy (29 and 31%.8%. however. 23. Tamoxifen (30 mg/day) was prescribed to postmenopausal patients for 3 years starting with the first chemotherapy cycle. diarrhea.MICROMEDEX® 2. Patients with operable breast cancer with either three positive nodes or between one and three positive nodes with Scarff Bloom Richardson (SBR) grade of 2 or greater and both estrogen and progesterone receptor negativity were enrolled. n=1. c) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were significantly increased in patients with breast cancer and axillary node involvement (n=565) who received ADJUVANT chemotherapy with FLUOROURACIL. b) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. stomatitis (3. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.3% for FEC 50 (p=0.8%. alopecia (78. 11.8%. a previous response with tamoxifen did not predict CMF response.1%).

had disease stabalization for at least 2 months. Initiation of hormone therapy as opposed to CMF chemotherapy is recommended in most elderly patients (Taylor et al. radiation therapy and 2 years of TAMOXIFEN therapy. Survival rates favored tamoxifen as initial therapy (23 months versus 21 months for CMF). mucositis.0 authors note that the difference in 5-year DFS and 5-year OS was significant only in patients with more than three positive nodes (Anon. vomiting. respectively. which reached a border line level of significance (p=0. response to either tamoxifen or the CMF regimen was less than that observed when given as initial therapy (29% and 31%. alopecia. Renal cell carcinoma. day 1 weeks 5-8). A previous response to CMF tended to be associated with a better chance for tamoxifen response. twice-daily days 3-5 weeks 1 and 4. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. 1986).com/micromedex2/librarian/PFDefaultActionId/evidencexpert. days 1. diarrhea. 10 x 10(6) IU/m(2) days 1. All randomized patients received a fourth course of the up-front chemotherapy regimen. a previous response with tamoxifen did not predict CMF response. d) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. methotrexate and 5-fluorouracil (CMF) in the initial treatment of stage IV breast cancer in elderly woman (over the age of 65 years). phlebitis. and was correlated highly with prior hormonal response. respectively. e) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of cyclophosphamide. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. 5 weeks 5-8) plus interleukin-2 (10x 10(6) IU/m(2). 3. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))).9% partial response) in the combination therapy group compared to an overall survival of 13 months and no objective remissions in the tamoxifen group (Atzpodien et al. patients were treated with interferon-alfa (5 x 10(6) international units/square meter (IU/m(2)). Response rates were 45% and 38% in tamoxifen and CMF-treated patients. Metastatic a) The combination of interleukin-2 with interferon-alfa and 5-fluorouracil (5-FU) has demonstrated significant therapeutic efficacy in patients with metastatic renal cell carcinoma compared to tamoxifen. The tamoxifen group received 80 mg twice daily for 8 weeks. however. 5 x 10(6) IU/m(2) days 1. 21. respectively). 2001).. day 1 weeks 1 and 4.3. THIOTEPA 480 mg/m(2). and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery.IntermediateToDocumentPrintLink 261/317 .25/10/12 Drug details . 5 weeks 2 and 3. Upon crossover to the opposite treatment.08) in the proportional hazards model. and neutropenia. Tegafur thomsonhc.5 weeks 2 and 3) plus 5-FU (1000 milligrams/square meter (mg/m(2)). In addition to that. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al.MICROMEDEX® 2. 1998).1% (17% complete response. Results of the study showed an overall survival of 24 months and an objective response rate of 39. an additional 33% and 45% of patients treated with tamoxifen and CMF. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. EPIRUBICIN (120 mg/m(2). Additional disease control with hormone withdrawal was observed in 23% of patients. fatigue. 3. Toxicities were greater in the high-dose group but both groups experienced nausea. In this study (n=78). 2001).

the difference was not statistically significant [444]. the combination of intravenous tegafur plus mitomycin C or methyl-CCNU did not appear to offer any advantage over the use of 5-fluorouracil in these regimens. which was not thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. the incidence of toxicity was comparable for both treatments. and I II were 72% and 53%. and anemia.25/10/12 Drug details . the 5-year survival rate was 66%. Frequently reported adverse effects included alopecia. ataxia) have been frequent and severe with intravenous tegafur. The overall survival duration was NOT reported. gastrointestinal toxicity (persistent nausea and vomiting) and central nervous system toxicity (dizziness.IntermediateToDocumentPrintLink 262/317 . and mitomycin C) in gastrointestinal malignancies [446][449][450][451]. tegafur offers the advantage of oral administration. headache. A response rate of only 20% has been reported with FAM II compared to 42% to 50% with FAM. 5year survival rates in combined subsets of stages 1. Patients (n=62) were randomly assigned to receive cyclophosphamide 500 milligrams/square meter (mg/m(2)) and doxorubicin 50 mg/m(2) on day 1 followed by fluorouracil 500 mg/m(2) on days 1 and 8 or UFT(R) 350 mg/m(2)/day orally in 2 divided doses from day 1 to 14. In addition.5% with a fluorouracil-containing regimen.5 grams/square meter/day for 5 days every 3 to 5 weeks) has produced objective responses (complete or partial) in 4% to 11% of patients (previously treated or untreated) with advanced colorectal carcinoma [445][446][447]. In the MF'C + F' group. mitomycin C. visual changes. vomiting. The efficacy of the MFC + F regimen (induction therapy with intravenous 5-fluorouracil. response rates with single-agent intravenous tegafur have generally been lower than those reported for 5-fluorouracil in colorectal carcinoma (17% in 1 series of 359 patients) [448]. In addition. long-term studies are needed to evaluate this regimen before using it as standard therapy. MFC + C was statistically superior to the control group with regard to postoperative survival. has offered no advantage over 5-fluorouracil (5-FU) in the treatment of gastrointestinal malignancies. toxicity has been greater with the FAM II regimen (nausea. Central nervous system toxicity with tegafur regimens was significant. and have occasionally been intolerable [445]. Although direct comparative studies are lacking.MICROMEDEX® 2. Additional large. respectively. either alone or in combination regimens. central nervous system symptoms). with the exception of grade I anemia and stomatitis. d) In other studies. or a control group (surgery only) on the 7th to 10th day following surgery. Malignant tumor of digestive organ a) SUMMARY: Intravenous tegafur. stomatitis. Patients were randomized to either MFC + F. and cytosine arabinoside. where intravenous/oral tegafur was substituted for 5-fluorouracil. MF'C + F'.0 Breast cancer a) Women with biopsy-proven metastatic breast cancer had an overall response of 48. toxicity has been greater with intravenous tegafur compared to 5-FU. II. Both regimens were repeated every 4 weeks for 6 cycles. followed by intermittent oral therapy with 5-fluorouracil for 2 years) was compared with that of MF'C + F'. b) Intravenous tegafur as single-agent therapy in relatively high doses (2. nausea/vomiting. as adjunctive therapy following curative gastrectomy in patients with gastric cancer. c) Combination therapy with intravenous tegafur and intravenous doxorubicin plus intravenous mitomycin C (FAM II) appears less effective than the conventional FAM regimen (intravenous 5-fluorouracil.4% with a UFT(R) (tegafur and uracil)-containing regimen versus 35. occurring in up to 36% of patients treated [446][451][452]. doxorubicin.

MICROMEDEX® 2. abdominal cramping. nausea.IntermediateToDocumentPrintLink 263/317 . skin rashes. neutropenia or mucositis were not reported. due to grade 3 diarrhea. The duration of survival has been similar with tegafur and 5fluorouracil. and sometimes diarrhea have been more frequent with oral tegafur. mostly grade 1 or 2 consisted of diarrhea. Time to progression and overall survival were similar with each regimen. 7 received UFT 350 milligrams/square meter/day (mg/m(2)/day) with LV 150 mg/day for 28 days. preliminary survival data suggest a survival rate similar to intravenous fluorouracil (5-FU) and LV. and have necessitated withdrawal of therapy in some patients [456][443][455][457]. and fatigue. 7. 14. vomiting. Efficacy appeared similar for the lower dose. f) In a phase II study. Of the 45 treated patients.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. diarrhea) occurred more frequently in the MF'C + F' group (53%) compared to patients treated with MFC + F (40%). Toxicity. then 250 mg/m(2) on days 6. however.25/10/12 Drug details . The authors concluded that the 5-fluorouracil regimen was preferable to the tegafur regimen [453]. and 21) plus intravenous doxorubicin in the same doses in previously untreated patients with advanced gastric carcinoma in 1 randomized trial. diarrhea was significantly more frequent in the tegafur/doxorubicin group [457]. h) The combination of oral tegafur (1 gram/square meter/day (g/m(2)) from day 1 to 21) plus intravenous doxorubicin (50 milligrams/square meter/day (mg/m(2)/day on days 1 and 21) offered no advantage over intravenous 5-fluorouracil (500 mg m(2)/day on days 1. 10. vomiting. 8. although the convenience of oral therapy with tegafur and its lesser myelosuppression are advantages over intravenous 5-fluorouracil. UFT(R) (tegafur and uracil) and leucovorin (LV) produced an overall response of 42% in patients with metastatic colorectal cancer. A trend toward a higher incidence of neurologic symptoms (particularly dizziness and malaise) has been observed in tegafur-treated patients [443][456]. vomiting. Metastatic colorectal cancer a) A randomized study in patients with metastatic colorectal cancer was conducted to compare the relative efficacy and toxicities of oral tegafur (1 g/m(2) days 1 to 21) with those of 5-FU (IV 500 mg/m(2) days 1 to 4. anorexia. g) Oral tegafur (1 gram/square meter/day (g/m(2)) or 30 milligrams/kilogram/day (mg/kg) for 14 to 21 days. and no toxicity advantage was realized in patients treated with tegafur. with each cycle being repeated every 4 to 6 weeks) has produced responses comparable to those achieved with intravenous 5-fluorouracil in direct comparative trials involving patients with gastric or colorectal carcinoma [455][456][443]. e) SUMMARY: Oral tegafur was as effective as intravenous 5-fluorouracil (5-FU) in treating patients with gastrointestinal malignancies. substitution of oral tegafur for 5-FU in combination regimens has not been associated with improved efficacy or reduced toxicity. Gastrointestinal toxicity (nausea. These are countered by the higher incidence of other toxic effects (particularly gastrointestinal/cutaneous toxicity) observed with this agent.0 significantly different than the control group. nausea. Doses of UFT and LV were divided and administered every 8 hours. thomsonhc. The place of UFT(R) in therapy awaits the results of phase III trials comparing UFT and LV to 5-FU and LV for adjuvant therapy in Dukes' B and C colon cancer and for metastatic colorectal cancer [454]. although a nonsignificant trend toward more prolonged survival has been observed in 5-fluorouracil-treated patients in some studies [443][456]. Hematologic toxicity and stomatitis have generally been less with oral tegafur as compared to intravenous 5-fluorouracil. the dose of UFT was reduced to 300 mg/m(2)/day in the subsequent 38 patients.

mucositis occurred at a similar rate for both groups [414]. median time to progression was not different between the standard.25/10/12 Drug details . thrombocytopenia. Subgroup analyses (estrogenreceptor status.31).23). p=0.and highdose/transplant therapy (38% and 32%.6 months. Likewise. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). EPIRUBICIN (120 mg/m(2). Of 553 patients enrolled. overall survival in this intentionto-treat analysis was not significantly different between standard.and high-dose chemotherapy were administered according to the following schema: Doxorubicin INDUCTION AND MAINTENANCE 30 mg/m(2) days 1 and 8 IV HIGH-D0SE (CONTINUOUS INFUSION) Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV 14 days PO Fluorouracil 500 mg/m(2) days 1 and 8 IV Methotrexate* 40 mg/m(2) days 1 and 8 IV Thiotepa 125 mg/m(2)/day for 4 days IV Carboplatin 200 mg/m(2)/day for 4 days IV *methotrexate substituted for doxorubicin when the total dose of doxorubicin previously received was 400 to 500 mg.dose chemotherapy and autologous stem-cell transplant when compared to standard-dose chemotherapy alone. Median follow-up was 37 months.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.dose/transplant groups (9 and 9. mg/m(2)=milligrams/square meter IV=intravenous PO=oral b) Four to six cycles of induction therapy were given every 28 days. A greater incidence of severe leukopenia.0 12). predominant site of metastatic disease) also revealed no differences in these endpoints between the 2 groups. thomsonhc. Oral tegafur and IV 5-FU were equally effective but tegafur was associated with minimal myelosuppression [443]. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. p=0. respectively.and high. 110 achieved either a complete or partial response to induction chemotherapy and were subsequently randomized. At 3 years. and anemia was observed in the high-dose/transplant group. Thiotepa Breast cancer a) Survival is NOT improved for women with metastatic breast cancer undergoing treatment with standard-dose chemotherapy followed by high. c) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. Standard. respectively. High-dose chemotherapy with stem-cell transplantation is ineffective for women with metastatic breast cancer and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414]. Patients randomized to standard-dose (maintenance) chemotherapy received a median of 8 cycles.MICROMEDEX® 2.IntermediateToDocumentPrintLink and CYCLOPHOSPHAMIDE (500264/317 .

epirubicin. 1998). CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. respectively. then high. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. The estimated 3-year relapse-free survival rate (72% versus 63%.0 meter (mg/m(2))). fatigue. e) No difference in survival or progression free survival was detected in patients with breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL (PBPC) support compared to those who did not. mucositis. mucositis. THIOTEPA 480 mg/m(2). Vinblastine Esophageal cancer a) The addition of a preoperative chemoradiation regimen offered no statistical survival advantage over surgery alone in a randomized trial of 100 patients with previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma thomsonhc. p=0. phlebitis. All subjects underwent post-chemotherapy radiation and tamoxifen therapy.IntermediateToDocumentPrintLink 265/317 .MICROMEDEX® 2. Toxicities were greater in the high-dose group but both groups experienced nausea. All randomized patients received a fourth course of the up-front chemotherapy regimen. CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion. a tailored FEC (fluorouracil (5-FU). alopecia. 1998). Group 2 patients were administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU. and neutropenia. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. EPIRUBICIN (120 mg/m(2). phlebitis.01) but not overall survival (83% versus 77%.25/10/12 Drug details . with doses adjusted according to hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU. and CYCLOPHOSPHAMIDE (500 mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. cyclophosphamide) dosage regimen was associated with improved relapse-free survival compared to standard FEC followed by high-dose chemotherapy and stem-cell support in a randomized trial of 525 women under age 60 with high-risk primary breast cancer. vomiting. diarrhea. In addition to that. radiation therapy and 2 years of TAMOXIFEN therapy. In addition to that. fatigue. This randomized study analyzed 81 patients with extensive axillary lymph-node involvement. a third FEC course with higher cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. EPIRUBICIN (120 mg/m(2). A drawback to the tailored FEC regimen was the development of acute myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al. THIOTEPA 480 mg/m(2). alopecia. radiation therapy and 2 years of TAMOXIFEN therapy. Three cases of reversible renal failure were reported in the high-dose group (Rodenhuis et al. vomiting. 600 mg/m(2) cyclophosphamide). diarrhea. All randomized patients received a fourth course of the up-front chemotherapy regimen.dose chemotherapy: 6000 mg/m(2) cyclophosphamide. Toxicities were greater in the high-dose group but both groups experienced nausea. and neutropenia. 75 mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide). p=NS) favored group 1 over group 2. those randomized to the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter. 500 mg/m(2) thiotepa and 800 mg/m(2) carboplatin prior to stem cell transfusion.0001). Grade 3 and 4 gastrointestinal toxicities and infection were significantly less frequent in group 1 than group 2 (p less than 0. d) Following breast cancer surgery. 2000). 60 mg/m(2) epirubicin. All patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square meter (mg/m(2))). Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support.

1. squamous cell histology and age over 70 years. 1993). 8 through 12 and 15 through 19 for a total dose of 45 Gy. b) In one study. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%).9 and 17. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. This trial was powered to detect only large overall survival differences. On day 42. FLUOROURACIL 300 mg/m(2)/day as a continuous infusion on days 1 through 21. Vincristine Breast cancer a) In one study. 8 through 12 and 15 through 19 for a total dose of 45 Gy. The median survival in the preoperative chemoradiation and surgery-only groups were 16. FLUOROURACIL. METHOTREXATE.0 previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma (n=25) of the esophagus. Corresponding 1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ statistically.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. The median survival in the preoperative chemoradiation and surgery-only groups were 16. FLUOROURACIL 300 mg/m(2)/day as a continuous infusion on days 1 through 21. VINCRISTINE. PREDNISONE) produced thomsonhc. VINCRISTINE. Of the subset (n=14) who attained complete histologic response to the preoperative regimen. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al.6 months. This trial was powered to detect only large overall survival differences. 86% and 64% were alive at 1 year and 3 years. 86% and 64% were alive at 1 year and 3 years.IntermediateToDocumentPrintLink 266/317 . subjects underwent transhiatal esophagectomy. Forty-five patients in each arm obtained complete surgical resection of the carcinoma.6 years (maximum of 11. Median follow-up duration in this study was 8. respectively (p=NS). respectively (median survival: 49. VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17 through 20.6 months. 2001). Chemoradiation consisted of CISPLATIN 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5 and days 17 through 21. METHOTREXATE. Although.3 years) and 445 ER-negative. squamous cell histology and age over 70 years.or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE.25/10/12 Drug details . VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17 through 20. Corresponding 1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ statistically.MICROMEDEX® 2. PREDNISONE) produced statistically similar survival or disease-free survival rates. respectively (p=NS). node-positive breast cancer patients were enrolled. FLUOROURACIL. subjects underwent transhiatal esophagectomy.7 months) (Urba et al. Significant negative independent prognostic factors included tumor size greater than 5 centimeters. Forty-five patients in each arm obtained complete surgical resection of the carcinoma. This improvement should be weighed against the difficulty (ie. not statistically different. b) The addition of a preoperative chemoradiation regimen offered no statistical survival advantage over surgery alone in a randomized trial of 100 patients with previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma (n=25) of the esophagus. Of the subset (n=14) who attained complete histologic response to the preoperative regimen. and twice-daily radiation on days 1 through 5. Significant negative independent prognostic factors included tumor size greater than 5 centimeters. 2001). respectively (median survival: 49. and twice-daily radiation on days 1 through 5.9 and 17. Chemoradiation consisted of CISPLATIN 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5 and days 17 through 21.7 months) (Urba et al. On day 42. respectively. Five-year survival was 57% and 62% in the 1and 2-year therapy groups.

and 2-year therapy groups. Due to the complicated schedule and only marginally improved 267/317 . PREDNISONE) produced statistically similar survival or disease-free survival rates (Rivkin et al. neurotoxicity (P=0. two-sided. and fluorouracil prolonged time to progression.3 years) and 445 ERnegative.Drug details .60). P=0.6 years (maximum of 11. Median follow-up duration in this study was 8. but the difficulty (ie. Other significantly worse adverse events in the 16-week regimen were stomatitis (P=0. one-sided).0001 to 0.10.0001). 0. During EVEN-NUMBERED WEEKS.003.0001. 2 years of therapy produced a moderate improvement in survival over 1 year of therapy (57% vs 62%).0001 respectively). and thrombocytopenia were significantly worse with CAF than with the 16-week regimen (P=0. with a median follow-up of 3. doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500 mg/m(2) intravenously (IV) days 1 and 8. In another study.positive breast cancer patients were enrolled. as well as continuous 5-FU infusion. The patients were randomly assigned to receive either the 16-week regimen or six cycles of CAF. receptor-negative breast cancer.0 METHOTREXATE. P=0. toxicity) of administering 2 years of CMFVP therapy. 1991). d) A sixteen-week multidrug regimen achieved only marginally better outcomes than CYCLOPHOSPHAMIDE. nausea (P=0.4% for CAF (P=0.1% for the 16-week regimen and 71. Leukopenia. toxicity) of 2-year administration may outweigh the benefit (Rivkin et al. Five-year survival was 57% and 62% in the 1.0001).04). 5-FU 600 mg/m(2) IV day 2 at 20 hours after methotrexate. Leucovorin 10 mg/m(2) was administered orally every 6 hours for six doses.04). Although. methotrexate 100 mg/m(2) IV day 1. AND FLUOROURACIL (CAF) with similar toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive. node. The 16-week regimen consisted of greater doxorubicin and 5-FU dose intensity than CAF and sequential administration of methotrexate and 5-FU. Dose modification occurred based upon toxicity evaluated and classified by the Common Toxicity Criteria. The 4-year recurrence. Anemia was significantly higher with the 16-week regimen (P=0. the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0.9 years. 1993). skin toxicity (P=0. FLUOROURACIL. but was insignificant by 4 months posttreatment (P=0. 1and 2-year therapy with CYCLOPHOSPHAMIDE. Median follow-up duration was 8.05. VINCRISTINE. receptor-negative breast cancer patients. and 0. The estimated 4-year survival rate was 78. Each 28-day cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2)) orally days 1 through 14.095.MICROMEDEX® 2. METHOTREXATE. methotrexate. one-sided). and PREDNISONE (CMFVP) produced similar survival/disease-free survival rates. granulocytopenia. The 16-week regimen involved weekly treatments. VINCRISTINE. maintenance therapy with cyclophosphamide.6 years.7% for CAF (P=0. two-sided. not statistically different.free survival rate for the 16-week regimen was 67. ODD-NUMBERED WEEKS as cyclophosphamide 100 mg/m(2) orally days 1 through 7. beginning 24 hours after methotrexate. Of the 163 patients participating in the quality-of-life study.5% versus 62. vincristine 1 mg IV day 1. doxorubicin 40 mg/m(2) IV day 1. c) In a study of 445 patients with node-positive. DOXORUBICIN. Febrile neutropenia hospital admission was not significantly different between the two regimens. The 2-year therapy produced a moderate improvement in survival over the 1-year therapy (57% vs 62%). patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2.05) and weight loss (P=0. FLUOROURACIL. 1993). This improvement should be weighed against the difficulty (ie. but did not alter overall survival (Muss et al.0001). respectively.0003).19.

3 and 17.and 2-year therapy groups.04). p=0.014).MICROMEDEX® 2. CYCLOPHOSPHAMIDE.0007).3 years) and 445 estrogen receptor (ER)negative. 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE. each given intravenously on day 1 of a 21-day cycle for a median duration of 5 cycles. VINCRISTINE. p=0. toxicity) of administering 2 years of CMFVP therapy (Rivkin et al.positive breast cancer patients were enrolled. p=0. p=0.25/10/12 Drug details .0 outcomes as compared with CAF. p=0. The only significant differences in toxicity profiles were higher incidences of constipation.8 months. the 16-week regimen should not be substituted for CAF without careful consideration (Fetting et al. not statistically different. e) In one study. median overall survival (20 versus 17 months). The MV regimen consisted of mitoxantrone 12 milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and vinorelbine 25 mg/m(2) IV on days 1 and 8. The overall response rates for FAC and NA were 74% and 75%. The NA regimen included doxorubicin (same dose and frequency) plus vinorelbine 25 mg/m(2) on days 1 and 8 of a 21-day cycle for a median of 4 cycles. Febrile neutropenia and delayed hematological recovery was more frequent in the MV arm (p=0. phlebitis and cutaneous toxicity with NA. and cyclophosphamide 500 thomsonhc. p=0. Median follow-up duration in this study was 8. respectively. Patients who had received prior neoadjuvant/adjuvant therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a higher OR rate (33% versus 13%.025). 1999).26). respectively (p = NS).031) as was alopecia (p=0. 7 months for both). doxorubicin or epirubicin 50 mg/m(2) on day 1. This improvement should be weighed against the difficulty (ie. a comparison of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL.free survival (PFS. The choice of FAC or FEC was decided by participating institution preference with all patients at one institution receiving the same regimen. Although. The average dose intensity of doxorubicin was 90% with FAC and 83% with NA. The subset of patients with liver metastases had significantly improved survival with NA as compared to FAC (p = 0. Patients who had not received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC rather than MV had a higher OR rate (43% versus 35%. a longer PFS (9 versus 6 months. doxorubicin 50 mg/m(2) and cyclophosphamide 500 mg/m(2). and a longer OS (20 versus 16 months. 1993). Five-year survival was 57% and 62% in the 1.5% versus 33. METHOTREXATE. node.3%). a longer PFS (8 versus 5 months. The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day 1. and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed that there was no significant difference in overall response (OR) rate (34.6 years (maximum of 11. Vinorelbine Breast cancer a) Two doxorubicin-containing regimens were equally effective in the treatment of advanced breast cancer in a Phase III trial (n=177). and a longer OS (22 versus 16 months. 1998). The FAC regimen consisted of 5fluorouracil (5-FU) 500 milligrams/square meter (mg/m(2)). neuropathy. 2 years of therapy produced a moderate improvement in survival (57% vs 62%) over 1 year of therapy. FLUOROURACIL. b) In a phase III trial of women with metastatic breast cancer (n=281).0001). and a higher incidence of cardiotoxicity with FAC (Blajman et al. Corresponding median overall survival rates were 17. respectively (p = NS). or progression.027). PREDNISONE) produced statistically similar survival or disease-free survival rates.IntermediateToDocumentPrintLink 268/317 .25).001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.

et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. 2. 7. p=0. Although not statistically significant. 3rd. In this study involving 211 patients with stage IV NSCLC.and anthracycline. Skeel RT: Handbook of Cancer Chemotherapy. asthenia. O'Neill A. REFERENCES 1. USA. et al: Phase II study of oxaliplatin and fluorouracil in taxane.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.MICROMEDEX® 2. Fink DJ. arthralgia. Vinorelbine caused a higher incidence of peripheral neuropathy compared with 5FU/LV (20% and 4%. 1st. 1991. Grade 1/2 anemia was seen in 70% of patients given vinorelbine compared with 42% given 5-FU/LV. Grade 3 or 4 granulocytopenia was reported in 54% of patients receiving vinorelbine compared with 24% receiving 5-FU/LV. thomsonhc.001). Cycles of both MV and FAC/FEC were repeated every 21 days. treatment with vinorelbine was associated with a higher response rate (12% vs 3%) and time to treatment failure (10 weeks vs 8 weeks) compared with 5-FU/LV. 20:2551-2558. Product Information: fluorouracil IV injection solution. fluorouracil injection. respectively) [422]. Stadtmauer EA. McGraw-Hill Book Company. and pain). New York. randomized study indicate that monotherapy with vinorelbine is more effective than the combination regimen of 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced non-small cell lung cancer (NSCLC). NY. cough. & Murphy GP: Clinical Oncology.0 mg/m(2) IV on day 1. Sicor Pharmaceuticals. respectively) for 5 consecutive days every 4 weeks. 2001). 11th. Brown. p=0. Zelek L. MA. The American Cancer Society. Sandoz Inc (per DailyMed).25/10/12 Drug details . 4. Princeton. dyspnea. A comparison of grade 3/4 nonhematologic toxicity in the FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%. 2003.pretreated breast cancer patients. CA. patients received either vinorelbine (30 milligrams/square meter (m(2)) weekly intravenously) or the combination of 5-FU/LV (425 milligrams/m(2) and 20 milligrams/m(2). Isselbacher KJ. Irvine. fluorouracil IV injection solution. Little. Goldstein LJ. 1987. et al (Eds): Harrison's Principles of Internal Medicine. 1991. Atlanta. 5. Holleb AI. in an intent-to-treat analysis. J Clin Oncol 2002. Inc. There were no differences between the two treatments with respect to relief of cancer symptoms (eg. hemoptysis. NJ. Braunwald E. 3. Median survival time for patients receiving vinorelbine was 30 weeks with 25% alive at 1 year compared with a median survival time of 22 weeks with 16% alive at 1 year for patients receiving 5-FU/LV. 6.IntermediateToDocumentPrintLink 269/317 . Boston. Cottu P. GA.. and Co. 2011.031) and alopecia (30% versus 7%. Non-small cell lung cancer a) The results of a prospective. Inc. Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the FAC/FEC arm (p=0. N Engl J Med 2000. 42:1069-1076. Petersdorf RG.001)(Namer et al. Product Information: Adrucil(R). Tubiana-Hulin M.

2001.. 14:79-85. 20. Kakolyris S. PubMed Abstract: http://www. Rodenhuis S. and leucovorin for colorectal cancer (letter). 39(996):21-28.gov/.. McArdle CS. Cancer Invest 1996. Douillard J-Y. Jouve M. Valagussa P. 342:1119-1120. 11. 332:901-906. Figer A. 19. N Engl J Med 1995. Ledermann J. Mavroudis D. 16.nih.IntermediateToDocumentPrintLink 270/317 .0 2003. 361:368-373. Souglakos J. vincristine. et al: Protracted continuous infusion of 5-fluorouracil in combination with doxorubicin. Med Lett Drugs Ther 1997. de Gramont A.asp (cited 5/17/01). Valladares M. et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. 18. 14:91-97. J Clin Oncol 2000. Lancet 1998. Niedzwiecki D. and oral cyclophosphamide in advanced breast cancer. 85(1):104-111. et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. N Engl J Med 2000.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. et al: Adjuvant cyclophosphamide. Palangie T. 8. Richel DJ. Cancer 1999. May 17. 10. et al: Safety and efficacy of outpatient treatment with CPT-11 plus bolus folinic acid/5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer. and fluorouracil in node-positive breast cancer. fluorouracil. Moehler M. PubMed Article: http://www. 15. Martinez-Villacampa M.nejm. Zanke C. 345(18):1351-1352. Seymour M. Frye DK. Hoffmann T. O'Connell MJ et al: Recommendation for caution with irinotecan. Available at: http://www. Moliterni A. NEJM early release notice posted. et al: Triplet combination with irinotecan plus oxaliplatin thomsonhc. Kerr DJ. 352:515-521. van der Wall E. Van Cutsem E. Smith TL.ncbi. 18(16):2938-2947. Raymond E. Rahman ZU. 9. Aranda E.25/10/12 Drug details . Anticancer Drugs 2003. & Kohne C-H: Toxicity of irinotecan in patients with colorectal cancer (editorial). 17.nih. et al: Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy. N Engl J Med 2001.ncbi. Sargent DJ. 20(2):251-257. Lippman ME: High-dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer. et al: Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. 13. 14.MICROMEDEX® 2. et al: Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol 2009. Bonadonna G. Anon: Drugs of choice for cancer chemotherapy..nlm. Lancet 2003.nlm.org/content/sargent/1. methotrexate..gov/. 12.

14:729-736. Chang D. Levi F. J Clin Oncol 2002. El-Taani H. Nitti D. et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Lancet 1998. et al: Intravenous azidothymidine with fluorouracil and leucovorin: a phase I-II study in previously untreated metastatic colorectal cancer patients. et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Boisdron-Celle M. Aranda E. 33. 30. J Clin Oncol 1996. Diaz-Rubio E.MICROMEDEX® 2. 20:585-592. 29. 26. Danesi R. Gamelin E. Parriani D. Schramm H.infusion fluorouracil and leucovorin as fist-line treatment in metastatic colorectal cancer: a multicenter phase II trial. 16:1470-1478. Chase JL. 32A:1719-1726. J Clin Oncol 1998. 14:234-238. 23. J Clin Oncol 1998. Bismuth H.25/10/12 Drug details . Sugarbaker PH. Di Costanzo F.0 plus continuous. 25. 20(11):2651-2657. Muller H-H. thomsonhc. World J Surg 1996. 79:1100-1105. et al: Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. Dargenio F. 228(6):756-762. 32. 22. ASCO Annual Meeting [abstr LBA3500 and oral presentation]. Beerblock K. Cervantes A. Lorusso V. Cancer 1997. Ann Surg 1998. 9:727-731. Andre T. 16(1):301-308. Ann Oncol 1998. Schellinx MET. 27. Comella P. Wieand HS. Am J Surg 1996. 31. Kuebler JP. Falcone A. et al: Bimonthly high dose leucovorin and 5-fluorouracil 48-hour continuous infusion in patients with advanced colorectal carcinoma.IntermediateToDocumentPrintLink 271/317 . 24. Rinaldi Y. Davidson BS. Ann Surg 1996. Rougier P. et al: Double biochemical modulation of 5-fluorouracil by methotrexate and levo-folinic acid in the treatment of advanced digestive tract malignancies. Wolmark N. 2005.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Eur J Cancer 1996. 172:244-247. 224:509-522. Adam R. Sahmoud T. et al: Alternating floxuridine and 5-fluorouracil hepatic arterial chemotherapy for colorectal liver metastases minimizes biliary toxicity. Izzo F. et al: Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. 21. et al: A phase II trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: results of NSABP protocol C-07. 28. Delva R. Anon: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. et al: Hydroxyurea may increase the activity of fluorouracil plus folinic acid in advanced gastrointestinal cancer: phase II study. 351:1677-1681. et al: Peritoneal carcinomatosis from adenocarcinoma of the colon. et al: Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. Cancer Invest 1996. Palmieri G. Lorenz M.

Kahn MJ. Oncology 2000. 38. Ann Surg Oncol 2000. and C-04).IntermediateToDocumentPrintLink 272/317 . 35.. Mounedji-Boudiaf L. 43.. Min JS. 17(11):3553-3559. N Engl J Med 2004. 42. J Clin Oncol 2001.gov/.long term results and evaluation of the indicators of health-related quality of life. fluorouracil. Laurie JA. et al: A prospective randomized trial comparing intravenous 5fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. J Natl Cancer Inst 1998.nlm. Becker H. Marsoni S. J Clin Oncol 1999. 40. PubMed Article: http://www.. Bryant J.risk colon cancer. Andre T.gov/. thomsonhc. 16(1):295-300. 350(23):2343-2351. 39. et al: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four national surgical adjuvant breast and bowel project adjuvant studies (C-01. O'Connell MJ. Wolmark N. J Clin Oncol 1999. 46. 7(9):674-679. Loffler T. 37. 41. Sauer R.nih.ncbi. Fountzilas G. J Clin Oncol 1998. Strahlenther Onkol 2001. 15:246-250.. et al: Oxaliplatin. Wieand S. and leucovorin as adjuvant treatment for colon cancer. Anon: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. Boni C. et al: GIVIO-SITAC 01: A randomized trial of adjuvant 5fluorouracil and folinic acid administered to patients with colon carcinoma .nlm. Zaniboni A.. Mamounas E. Kim NK. Rockette H. Mailliard JA. et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer.nih. and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. C-03. Bermann A. Labianca R. Fietkau R. 82(11):2135-2144. 45. 4:173-181. et al: Prospective randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. 19:1787-1794. Smith R. et al: Fluorouracil and leucovorin with or without interferon alfa2a as adjuvant treatment. et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. et al: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol C05. Zisiadis A.MICROMEDEX® 2. et al: Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. O'Connell MJ.ncbi. Wittekind C. leucovorin.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.0 34. et al: Clinical trial to assess the relative efficacy of fluorouracil and leucovorin. Wolmark N. and fluorouracil. 90(23):1810-1816. 351(17):1731-1740. C-02.25/10/12 Drug details . fluorouracil and levamisole. 36. J Clin Oncol 1999. Porschen R. 44. Kahn M. PubMed Abstract: http://www. 58:227-236. N Engl J Med 2004. 17(5):1349-1355. 17(5):1356-1363. Wolmark N. Sauer R. in patients with high. Hohenberger W. Cancer 1998. J Clin Oncol 1997. Dafni U. et al: Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. Park JK. Mamounas E.

Aventis Pharmaceuticals Inc. 73:549-552. et al: Adjuvant chemotherapy after gastric resection in nodepositive cancer patients: a multicentre randomised study. Bridgewater. 55. Tsavaris NB. 49. Isselbacher KJ. 79:1767-1775. O'Connell MJ. PA. et al: Treatment of patients with advanced gastric carcinoma with combination of etoposide plus oral tegafur modulated by uracil and leucovorin. New York. Petroni GR. 47. Philadelphia. Chemotherapy 1996a. docetaxel intravenous solution. & Fleming TR: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Moertel CG. 53:64-67. Product Information: TAXOTERE(R) intravenous solution. de Leonardis V. 56. 78:211-216. et al: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. Cullinan SA. 53. 51. 15:2030-2039. Kosmidis P. Leichman L. 1989. 58. 1990. Kosmidis P. 48. and mitomycin with no treatment in operable gastric cancer. et al (Eds): Harrison's Principles of Internal Medicine. 42:220-226. Tentas K. Neri B.MICROMEDEX® 2. epirubicin. mitomycin C and leucovorin in advanced gastric carcinoma: a randomized trial. Oncology 1996. O'Connell MJ. Mort D. 74:1651-1654. McGraw-Hill Book Company. MD Anderson Hospital and Tumor Institute at Houston. 19:517-521. JAMA 1985. 60. 52. Br J Cancer 1996. Tsavaris N. 1993. et al: A randomized trial comparing adjuvant fluorouracil. 3rd. DeVita VT. N Engl J Med 1994. & Maughan TS: Epirubicin. 57. Braunwald E. et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. Melcher AA. et al: Systemic chemotherapy for gastric carcinoma followed by postoperative intraperitoneal therapy: a final report. & Rosenberg SA (Eds): Cancer: Principles & Practice of Oncology. 54.. 2006. Am J Clin Oncol 1996. Feliu J. Cancer 1996. 50. et al: 5-Fluorouracil. NJ. Garcia-Giron C. epirubicin. Pharmacy Bulletin.25/10/12 Drug details . Kodera Y. Crookes P. Anon: Chemotherapy and antibiotic fluid standardizations and fluid minimums. Tentas K. J Clin Oncol 1997.IntermediateToDocumentPrintLink 273/317 . 331:502-507. Martenson JA. Wieand HS. and mitomycin C versus 5fluorouracil. Petersdorf RG. 253:2061-2067. Baron MG. Romano S. thomsonhc.0 Oncol 2001. 12th. Leichman CG. NY. Murase M. 59. Hellman S.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. Kondo K. Tepper JE. Br J Cancer 1996. et al: Feasibility study on protracted infusional 5-fluorouracil and consecutive low-dose cisplatin for advanced gastric cancer. cisplatin and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro-oesophageal cancer. epirubicin. Cancer 1997. 19:1787-1794. JB Lippincott Co. pp Vol 11.

Bassi C. 65. Hudes GR. Maru Y. Rougier P. et al: Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies. 230(6):776-782. et al: Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an EORTC GITCCG study. Gebbia V. and interferonalpha in the treatment of patients with metastatic or recurrent gastric carcinoma. 64. 304(10):1073-1081. Pozzo C. PubMed Article: http://www. PubMed Abstract: http://www. 32A(8):1310-1313. 6S-leucovorin. 67. et al: Hepatic arterial infusion of 5-fluorouracil for liver metastases from pancreatic carcinoma: results from a pilot study. PubMed Abstract: http://www. J Clin Oncol 1997. J Surg Oncol 1989. An Eastern Cooperative Oncology Group Study (E5292). et al: A phase II study of 5-fluorouracil.. 350(12):1200-1210. 8:445-448. et al: A phase II study of 5-fluorouracil. et al: Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5-fluorouracil. adriamycin. Eur J Cancer 1996. 40:177-181. Neoptolemos JP. leucovorin. Hoogenraad WJ. high dose levofolinic acid and oral hydroxyurea on a weekly schedule. 66. Cancer 1999. 78:1300-1307.nih.. and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer. JAMA 2010.nih. 85(2):290-294. Lipsitz S. Sahmoud T..nlm.. et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.Drug details . cisplatin. 72. Cancer 1996. Meropol NJ. 71. Neoptolemos JP. Jeekel J. Cancer 1998. N Engl J Med 2004.MICROMEDEX® 2. Quebbeman E. Yoshino M. 82(8):1460-1467.0 61. Hepatogastroenterology 2001. 15(11):3313-3319. Stocken DD.ncbi. Barone C.ncbi. leucovorin.nih. Freiss H. Am J Clin Oncol 1997. Alessandroni P. 70. Lokich JJ: Optimal schedule for 5-fluorouracil chemotherapy... 274/317 . 69.nlm.ncbi.nlm. Klinkenbijl JH. Holroyde C. et al: Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil. Labianca R. Hansen R. Ausman R.. Majello E. Stocken DD. 68. et al: Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: results in 91 patients.gov/.gov/.gov/. Vaughn DJ. Ann Surg 1999.ncbi. Cascinu S. Grem J. 62. glutathione. et al: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Testa A. Corsi DC. et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.. and ciplatin (FLAP) for metastatic gastric and gastroesophageal junction adenocarcinoma: a Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community Oncology Research Program Trial. Am J Clin Oncol 1985. 20:242-246. 48:208-211. Furuse J. 63.nlm. Wagener DJT.gov/.nih. epi-doxorubicin. PubMed Article: http://www.

Carnaghi C. solution.0 73. Nutley. Hepatogastroenterology 1996. Muchmore JH.25/10/12 Drug details . Roche Laboratories. CA. 2002.gov/. Product Information: EFUDEX(R) topical cream. 36:236-238. 82. 43:346-355. Roche Laboratories. 74. Carter RD.. and epirubicin in the treatment of patients with neuroendocrine tumors.. et al: Pilot study of continuous-infusion 5-fluorouracil. Nuzzo A. ICN Pharmaceuticals Inc. Pfeiffer C. Available at http://www. 77. Okada S. fluorouracil topical cream. Wadler S. 83. 85. Costa Mesa. Martenson JA. Int J Radiat Oncol Biol Phys 1997. J Am Acad Dermatol 1997. Berwyn. Burch PA. Cancer 1998. 76. flourouracil. fluorouracil cream.nlm.MICROMEDEX® 2.nccn. 25:665-667. Am J Clin Oncol 1996.ncbi. Abbruzzese J. Lalli A. Product Information: Fluoroplex(R)..ncbi.nlm. Preslan JE. 86.pdf (cited 6/24/2002). Swaminathan R..nih. Tokuuye K. 79. et al: Chemotherapy for disseminated actinic keratoses with 5fluorouracil and isotretinoin. Product Information: Efudex(R). solution.. Product Information: Carac(R). et al: Phase II trial of prolonged continuous infusion of 5fluorouracil and interferon-alpha in patients with advanced pancreatic cancer: Eastern Cooperative Oncology Group Protocol 3292. et al: 5-fluorouracil.org/physician_gls/PDF/pancreatic. et al: Randomized trial of 5-fluorouracil and high-dose folinic acid with or without alpha-2B interferon in advanced colorectal cancer. & Vamvakias G: One-week treatment with 0. PubMed Abstract: http://www. Cancer 1997. fluorouracil. Sparano JA. 2005. thomsonhc. long-term study. PubMed Article: http://www. Bajetta E. Dermik Laboratories Inc.gov/. Recchia F. 2003. Ishii H. 84. Kligman AM. et al: Regional chemotherapy with hemofiltration: a rationale for a different treatment approach to advanced pancreatic cancer. Lipsitz S. 19:546-551. vehicle-controlled. Benson AB et al: National Comprehensive Cancer Network Practice guidelines in oncology . Sander CA.Pancreatic adenocarcinoma v. 37:615-618. 79:1516-1520.IntermediateToDocumentPrintLink 275/317 .1. J Am Acad Dermatol 1991. Pearlman DL: Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses. 83(2):372-378. et al: Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma. and upper-abdominal radiation therapy in patients with locally advanced residual or recurrent upper gastrointestinal or extrapelvic colon cancer. 19:301-304. 81. J Drugs Dermatol 2006. Jorizzo J.. Am J Clin Oncol 1996.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double-blind.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. PA.nih. 78. 5(2):133-139. dacarbazine. 75. oral leucovorin. 1997. 80. 1995. Rimassa L. NJ. NJ. Weiss J. Nutley. Tempero M.

. 92.ncbi.nih. 97. 15:1063-1070. Kaba SE. et al: Arterial infusion of 5-fluorouracil as a treatment for carcinoma of the prostate. 14:3121-3125. La Monica G..gov/.0 87. 82(12):2321-2325. 14:2311-2315. Patt YZ.. leucovorin. 89. et al: Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710. 158:368-372. and carboplatin in patients with unresectable biliary tree carcinoma. Lipsitz SR. Dahan L. 140:987-988.gov/. 5-fluorouracil. cisplatin. 112:114-119. Br J Dermatol 1999. 63:183-188. 16(4):1351-1361. mitomycin. 99.MICROMEDEX® 2.gov/. Sanz-Altamira PM.nih. 35:745-749. Int J Radiat Oncol Biol Phys 1996. 118:928-930. and radiotherapy vs fluorouracil. J Clin Oncol 1996. 62:2071-2076. et al: Phase II trial of intravenous fluorouracil and subcutaneous interferon alfa-2b for biliary tract cancer. Baggerly JT Jr. et al: A phase II trial of 5-fluorouracil. Ellis PA. J Clin Oncol 1997. Cancer Treat Rep 1978. Doci R. Reymann F: Treatment of basal cell carcinoma of the skin with 5-fluorouracil ointment: a 10-year follow-up study.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. PubMed Article: http://www. and Levamisole combined with radiotherapy. Winter KA. et al: Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients.nlm. et al: Fluorouracil. Bonnetain F. Hoque A. 88. and cisplatin for patients with anal cancer (E4292): an eastern cooperative oncology group study. Nevin JE.nlm.gov/.. Shelley WB & Wood MG: Nodular superficial pigmented basal cell epitheliomas. Levin VA. 98. Rougier P. PubMed Abstract: http://www. Wagner H. Cancer 1998. Lundbeck F & Christophersen IS: Phase II study of adriamycin. Melnick I. et al: BCNU-5-fluorouracil combination therapy for recurrent malignant brain tumors. 100.nih. Hill A. Ajani JA. 93. Arch Dermatol 1982. 90.. Zucali R. thomsonhc. Jenkins RL. and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.ncbi. Pischer TL. 96. Hoffman WF. et al: Initial results of a phase II trial of high dose radiation therapy. cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours.IntermediateToDocumentPrintLink 276/317 . Jones DV. Ferrante K. Cancer Treat Rep 1979. Dermatologica 1979. PubMed Abstract: http://www. 31:1594-1598. Kyritsis AP. J Clin Oncol 1996. Gunderson LL.. Norman A.ncbi. 94. 5-fluorouracil. 91.25/10/12 Drug details . JAMA 2008.nlm. Eur J Cancer 1995. et al: TPDC-FuHu chemotherapy for the treatment of recurrent metastatic brain tumors. 299(16):1914-1921. Endocr Relat Cancer 2009.nih. Stone N & Burge S: Bowen's disease of the leg treated with weekly pulses of 5% fluorouracil cream. PubMed Article: http://www. Hess K. 95. J Urol 1974..nlm. et al: Epirubicin.ncbi.. Martenson JA.

106. Blessing JA. 17(6):529-533.gov/. et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281.nih. et al: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group Study. Bundy BN. Lin JC. Look KY.nlm. PubMed Article: http://www.ncbi. Korantzis A.nlm. 84:268-272. 17(5):1339-1348.nlm. J Clin Oncol 1984..ncbi. 105.nih.nlm.. PubMed Article: http://www. Shueng PW.ncbi.nih.. Int J STD AIDS 2000. Ahmad SA.gov/.. 108. et al: Concurrent 5-fluorouracil. Sause W.nih. J Clin Oncol 1999. thomsonhc.. 53(4):240-243. PubMed Abstract: http://www. PubMed Abstract: http://www..ncbi.MICROMEDEX® 2. Whitney CW. Yeatts RP. Moertel CG . et al: Treatment of men with flat (FC) or acuminata (CA) condylomata with interferon alpha-2a. Syed TA.. et al: High complete response rate of concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the uterine cervix. Cardamakis E. Am J Clin Oncol 1996. et al: Management of intravaginal warts in women with 5fluorouracil (1%) in vaginal hydrophilic gel: a placebo-controlled double-blind study. Engelbrecht NE. Relakis K..com/micromedex2/librarian/PFDefaultActionId/evidencexpert...gov/. Angeli CD. Lavin PT . PubMed Article: http://www. Jan JS. Jen YM.nih. Gallup DG.. PubMed Abstract: http://www.gov/.nlm.25/10/12 Drug details . Gynecol Oncol 1996. Eur J Gynaecol Oncol 1996. Midena E. 111.gov/. 61:101-108.0 101. et al: 5-Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Curry CD.. Br J Ophthalmol 2000. Br J Vener Dis 1977.nlm.ncbi. 109. 103.ncbi.. Ho ESC.nlm. Wallin J: 5-Fluorouracil in the treatment of penile and urethral condylomata acuminata. Engstrom PF . 107. Qureshi ZA.ncbi..ncbi. Sun W .gov/. et al: A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. Hsu WL.gov/.. Ophthalmology 2000.. 19:439-441.nih.gov/. PubMed Abstract: http://www.gov/.ncbi.gov/.nih.. Lipsitz S . 23(22):4897-4904. and radiotherapy in stage IIIB cervical cancer.nlm. 19:263-267.IntermediateToDocumentPrintLink 277/317 . et al: Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil.. 2(11):1255-1259. Am J Clin Oncol 1996.nih. 11(6):371-374.. PubMed Abstract: http://www. 102. 104.nih. Catalano P . PubMed Article: http://www. J Clin Oncol 2005.nlm. daily low-dose cisplatin. Valenti M.nih.. et al: Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. PubMed Article: http://www.ncbi. 107:2190-2195.nlm. 110.

Cancer 1989. Haynes H. et al: Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. mitomycin C. Herskovic A. McCluskey P. Am J Ophthalmol 1997. 117. Mora JS.. 118. 115. Nguyen N. Ann Surg 1996. 124. Shaer B. Hay JM. Pouliquen X. fluorouracil. Bhalla K. Levard H. recombinant interferon-alpha-2b. 120. Am J Ophthalmol 2000. . et al: Phase II trial of paclitaxel. Pasha MA. 114. et al: Randomized. . and cisplatin for patients with metastatic or regionally advanced carcinoma of the esophagus. 116. Chang M. et al: Trabeculectomy with intraoperative sponge 5-fluorouracil. Iwach AG. 107:1822-1828. Stamper RL. Cancer 1996. Liebmann JE. and concurrent radiation therapy with and without esophogectomy for esophageal carcinoma. . 19(2):305-313. O'Connor DJ. Jacobson J. controlled study of low-dose 5fluorouracil in primary trabeculectomy. Cancer 1996. Theodossiou C. .. Belyea DA. 78:30-34. Wadler S. Stewart FM. 5-fluorouracil. Am J Ophthalmol 1996a. J Clin Oncol 1998. 223:127-133. Chaudhry IA. Ophthalmology 2000. et al: 5-fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus: a multicenter randomized trial. 123. 130:700-703. 119. et al: Late onset of sequential multifocal bleb leaks after glaucoma filtration surgery with 5-fluorouracil and mitomycin C. 124:40-45. Turrisi A. 113. et al: Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060. Urba SG. Kim J. Orringer MB. Ophthalmology 1996. interferon-alpha-2a. 78:1851-1856. Towler HMA. Anon: Five-year follow-up of the fluorouracil filtering surgery study. and cisplatin as neoadjuvant chemotherpay for locally advanced esophageal carcinoma. 125. et al: Cisplatin. Reviewers' responses to Hematologic and Oncologic Disease Advisory Panel Memo #9 of 1/30/97. Reviewers' responses to Hemotologic and Oncologic Disease Advisory Panel Memo #26 of 8/28/89.. & Schwayder T: Topical tretinoin and 5-fluorouracil in the treatment of linear verrucous epicermal nevus. 103:963-970. 64:622628. . Hahn SS. 43:129-132. 122. 121. J Clin Oncol 2001. and cisplatin in patients with advanced carcinoma of the esophagus.112. et al: Phase II clinical trial with 5-fluorouracil.. leucovorin. 77:2432-2439. 121:349-366. Ilson DH. et al: Long-term follow-up of trabeculectomy with intraoperative 5-fluorouracil for uveitis-related glaucoma. et al: Phase II trial of 5-fluorouracil. Temeck BK. Beitler JJ. Cancer 1996. 126. J Am Acad Dermatol 2000. Ajani J. Harkins BJ. Poplin EA. Dan JA. 16(5):1826-1834.

Lewin AA. Pappagallo GL. Semin Oncol 1991. DeVita VT. Weichselbaum RR. 1983. San Francisco. CA. Sridhar KS. 8:241-247. Ciancaglini M. methotrexate. The American Cancer Society Inc. Gonzalez-Baron J. Hellman S. 130. 2001. Rubin P (Ed): Clinical Oncology A Multidisciplinary Approach. Abitbol AA. Am J Clin Oncol 1990. 112:167-172. 129. Eye 1998. May 12-15.0 glaucoma filtration surgery with 5-fluorouracil and mitomycin C. 127. R91-11.CA. GA. Maor M et al: Phase III trial to preserve the larynx: induction chemotherapy and radiotherapy vs concurrent chemotherapy and radiotherapy vs radiotherapy. Anon: Drugs of choice for cancer chemotherapy. Wolf GT: Discussion: Phase III trial to preserve the larynx . Atlanta. 128. 131. 18:34-48. Andry G. 135. GA. 137. Dodion PF. 6th. 3rd. Vokes E. Paccagnella A. USA. 139. thomsonhc. Fink DJ. American Cancer Society.MICROMEDEX® 2. et al: Response and toxicity of cisplatin and 120-h 5fluorouracil infusion in pretreated and untreated patients with advanced epidermoid cancer of the head and neck. intergroup trial R91-11. Recloux P. & Murphy GP (Eds): American Cancer Society Textbook of Clinical Oncology. 134. bleomycin and vincristine (CABO) in patients with stage III and IV squamous cell carcinoma of the head and neck. Carpineto P. 124:40-45. Dreyfuss AI. Berkey B. Atlanta. et al: Neoadjuvant chemotherapy with cisplatin. et al: Hyperfractionated radiation therapy and 5-fluorouracil. Clark JR. Inc. fluorouracil. et al: Delayed post-operative use of 5-fluorouracil as an adjunct in medically uncontrolled open angle glaucoma. 15:568-574. Wright JE. Segati R. 35:43-50. 1989. Tomas M. JB Lippincott Company.com/micromedex2/librarian/PFDefaultActionId/evidencexpert. San Francisco. 2001. Presented at the 37th Annual Meeting of the American Society of Clinical Oncology. Vincente J. Mastropasqua L. J Clin Oncol 1990. 132. Fink DJ. 138.25/10/12 Drug details . 133. May 12-15. Philadelphia. & Rosenberg SADeVita VT. Ann Intern Med 1990. Am J Clin Oncol 1990. 12:701-706. USA. et al: Induction of chemotherapy with cisplatin. Clark JR & Dreyfuss AI: The role of cisplatin in treatment regimens for squamous cell carcinoma of the head and neck. Eur J Surg Oncol 1989. 1991. 13:194-198. PA. Holleb AI. et al: Continuous infusion high-dose leucovorin with 5Fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Presented at the 37th Annual Meeting of the American Society of Clinical Oncology. Forastiere A. Hellman S. and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis. 136. & Murphy GPHolleb AI. 140. et al: Phase II trial of cisplatin and tegafur (Ftorafur) as initial therapy in squamous-cell carcinoma of the head and neck.intergroup trial.IntermediateToDocumentPrintLink 279/317 . Med Lett Drugs Ther 1993. Schilsky RL. & Rosenberg SA (Eds): Cancer: Principles & Pr