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2226 only one test and do not return the following year; therefore, sole
reliance on fecal screening tests is not recommended. A digital
rectal examination is a part of the physical examination in which
an anorectal mass could possibly be palpable. Barium enema
with radiography permits the visualization of the entire colon
and may visualize late-stage cancers. This option can, however,
miss important precancer lesions.14 A barium enema provides
another screening option for patients in whom colonoscopy has
failed or is contraindicated.
Endoscopic screening for colorectal cancer includes either
flexible sigmoidoscopy or colonoscopy. Flexible sigmoidoscopy
allows for examination of the sigmoid colon and rectum only,
where about 60% of all colorectal cancers are identified. The
advantages of sigmoidoscopy are that no sedation is required, a
simple preparation (two Fleet enemas) is used, and it can be per-
formed in various settings. Patients may choose flexible sigmoi-
doscopy over colonoscopy if they do not want to go under seda-
tion or undergo an extensive bowel preparation. Sigmoidoscopy
has been shown to reduce incidence and mortality caused by dis-
tal colorectal cancer by 60% to 80%.15,16 A colonoscopy examines
the entire colon and offers the ability to remove polyps and obtain
biopsy samples during the procedure.
For a photo of a pedunculated polyp, go to
http://thepoint.lww.com/AT10e.
Because cancerous lesions detected by any of the other tests
will ultimately necessitate an examination by colonoscopy, it
is considered the gold standard. A relatively new method known
as CT colonography provides two- and three-dimensional images
of the colon. As with endoscopic procedures, it requires complete
bowel preparation to remove feces from the intestine.
For a patient handout for colonscopy
preparation, go to http://thepoint.
lww.com/AT10e.
This screening test has the ability to detect 90% of polyps
Section 17
that are 10 mm or larger in diameter.17 If suspicious lesions are
visible, biopsies would be obtained in a separate procedure (e.g.,
colonoscopy), and this represents a limitation to CT colonogra-
phy. CEA is a tumor marker that has been evaluated as a screening
tool, but its primary utility is in monitoring response to treat-
ment, and not screening.
Neoplastic Disorders
The American Cancer Society, the US Multi-Society Task
Force on Colorectal Cancer, and the American College of Radi-
ology have jointly published screening recommendations for the
early detection of colorectal cancer.13 According to their rec-
ommendations any man or woman at average risk of develop-
ing colorectal cancer should begin screening at age of 50 years
(Table 95-1). Patients at average risk of developing colorectal
cancer will not have genetic predisposition or history of a family
member with colorectal cancer. In addition, patients in this cate-
gory will have no history of polyps, previous history of colorectal
cancer, inflammatory bowel disease, chronic ulcerative colitis, or
Crohn’s colitis.
O.B. is a 35-year-old woman with a first-degree relative with
a diagnosis of colon cancer at the age of 68. It is less likely she
would develop colorectal cancer through a hereditary syndrome
because her father was diagnosed after the age of 50. She does,
however, have nearly double the life time risk of developing
colorectal cancer because a first-degree relative had colorectal
cancer.18 Because O.B.’s father had colorectal cancer diagnosed
November 16, 2011 19:23
TA B L E 9 5 - 1
American Cancer Society Screening Recommendation for
Colorectal Cancer by Age and Risk
Average Risk Begin screening at age of 50 years
Annual DRE and FOBT/FIT (stool DNA test,
interval uncertain) and one of the
following:
– Sigmoidoscopy every 5 years
– CT colonography every 5 years
– Colonoscopy every 10 years
– Barium enema every 5 years
Family History Begin screening at age of 40 years or 10 years
younger from first-degree relative
colorectal cancer diagnosis
Hereditary HNPCC Begin screening at age of 20–25 years or
10 years younger from first-degree relative
colorectal cancer diagnosis
FAP Begin screening at age of 10–12 years
IBD, CUC, or CC Begin screening at 8–15 years after diagnosis
CC, Crohn’s colitis; CT, computed tomography; CUC, chronic ulcerative colitis;
DRE, digital rectal examination; FAP, familial adenomatous polyposis; FIT, fecal
immunochemical test; FOBT, fecal occult blood test; HNPCC, hereditary
nonpolyposis colon cancer; IBD, inflammatory bowel disease.
at or above the age of 60, she is at increased risk for developing
the disease and should consider initiating a colorectal screening
program at the age of 40.13
Clinical Presentation
CASE 95-2
QUESTION 1: B.R. is a 66-year-old white man who was in his
usual state of health until recently, when he decided to visit
his general practitioner owing to progressively worsening
gastrointestinal symptoms including abdominal cramping
and changing bowel habits. He admits to also having some
blood in his stool at times, which he attributes to his hem-
orrhoids. His family history is notable for a paternal uncle
with gastric cancer. He occasionally drinks alcohol and has
never smoked nor used illicit or recreational drugs. On phys-
ical examination he is a well-nourished, well-developed man
who is afebrile, alert and oriented, and in no apparent dis-
tress. He has no palpable masses and no hepatomegaly, and
his abdomen is soft and nontender with normal active bowel
sounds. The rest of his review of systems is unremarkable.
His performance status is excellent. He does have a history
of type II diabetes mellitus and hypercholesterolemia, which
are both controlled on his current medication regimen. Vital
signs and laboratory values obtained are as follows:
Blood pressure, 108/71 mm Hg
Heart rate, 95 beats/minute
Respiratory rate, 18 breaths/minute
White blood cell (WBC) count, 4.8 × 103 cells/μL
Hemoglobin, 11.6 g/dL
Hematocrit, 35.1%
Platelet count, 208 × 103 cells/μL
Total bilirubin, 0.3 mg/dL
Serum creatinine, 0.8 mg/dL
Blood urea nitrogen, 15 mg/dL
Alkaline phosphatase, 61 international units/L
Lactate dehydrogenase, 366 international units/L
Albumin, 4.2 g/dL
Hemoglobin A1C, 6.2%
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Are any of the symptoms that B.R. is exhibiting associ-
ated with colorectal cancer?
Although the symptoms B.R. is describing are nonspecific
in nature, the changes in bowel habits in addition to the blood
in his stools are symptoms associated with the development of
colorectal cancer. Given his age, symptoms, and lack of prior
cancer screening, additional workup is warranted with one of the
screening modalities mentioned earlier in this chapter, preferably
colonoscopy.
CASE 95-2, QUESTION 2: If B.R. did have colon or rectal
cancer, could it be diagnosed with CEA alone?
CEA was first described in 1965. It was detected in fetal colon
and colon adenocarcinoma; therefore CEA was named carci-
noembryonic antigen.19 It is a tumor marker that is detected in
the blood. It has been suggested that CEA may act as an adhesion
molecule that facilitates malignant colon cancer cell interaction
with healthy tissue and promotes tumor dissemination.19 It has a
high specificity (87%) for detecting occult colorectal cancer, but
very low sensitivity (36%). Therefore, it is not a good diagnostic
tool for B.R. It has been suggested that CEA values increase as
the disease stage increases. Therefore, stage IV colorectal cancer
patients are more likely to present with higher concentrations
of CEA compared with stage II patients. In addition, a higher
proportion of patients with advanced stages presents with ele-
vated CEA compared with earlier stages. One study used a CEA
threshold of 5 mg/mL, and it showed that 3%, 25%, 45%, and
65% of patients had Dukes stage A, B, C, and D colorectal cancer
at this threshold, respectively.20 Also, a CEA level greater than
5 mg/mL before surgery is a poor prognostic indicator.21 There-
fore, CEA levels are routinely recommended during diagnostic
and presurgery workup. The CEA is primarily used to monitor
for the recurrence of disease after treatment. About 80% of recur-
rences are identified by CEA monitoring.22 Healthy smokers are
likely to have twice the CEA level compared with nonsmokers.
Administration of 5 -fluorouracil (5 -FU)–containing therapy can
cause false elevation of CEA without disease progression.
Chemotherapy for Localized
Colorectal Cancer
ADJUVANT THERAPY
CASE 95-2, QUESTION 3: After a colonoscopy, B.R. is found
to have a moderately differentiated adenocarcinoma of the
colon lying 18 cm from the anal verge invading through
the muscularis propria with lymphovascular invasion and
involvement of 8 of 25 regional lymph nodes. A CT scan
of his chest, abdomen, and pelvis shows no evidence of
metastatic disease. A baseline CEA level of 8.0 ng/mL (nor-
mal range, 0–3.0 ng/mL for nonsmokers and 0–6.0 ng/mL
for smokers) is reported. After surgical resection, would B.R.
benefit from adjuvant chemotherapy? Which chemotherapy
agents or regimen gives B.R. the best chance to avoid a
future recurrence?
B.R. has extensive lymph node involvement, and this means he
has stage IIIC disease (Table 95-2), which places him at a high risk
of recurrence; therefore, he should receive adjuvant chemother-
apy after surgery. The goal of adjuvant therapy is to eradicate
any residual, undetectable disease left behind after surgery and
to reduce his risk of recurrence.
November 16, 2011 19:23
Historically, 5 -FU combined with leucovorin was consid- 2227
ered the standard chemotherapy for adjuvant treatment of stage
III colon cancer. Leucovorin stabilizes the binding of an active
metabolite of 5 -FU known as fluorodeoxyuridine monophos-
phate to its intracellular target thymidylate synthase, ultimately
enhancing the cytotoxicity of 5 -FU. Single-agent capecitabine,
an oral prodrug of 5 -FU, offers convenient administration and
is as effective as intravenous (IV) bolus 5 -FU modulated with
leucovorin.23 Because the enzyme involved in the final conver-
sion of capecitabine to 5 -FU is expressed more prominently in
cancerous cells compared with healthy cells, further biomodu-
lation of capecitabine to enhance activity with leucovorin is not
required. At present, single-agent therapy is typically considered
for patients with a poor performance status or those who are
unable to tolerate or possess a contraindication to combination
therapy. Combinations of irinotecan with 5 -FU have been stud-
ied but are not currently recommended for use in the adjuvant
setting owing to the lack of survival benefit and an increase in
treatment-related morbidity.24–26
A combination of 5 -FU and oxaliplatin is considered the cur-
rent standard of care in the adjuvant setting for patients with
stage III disease, as several landmark trials have shown this strat-
egy can improve diseasefree survival and reduce the relative risk
of disease recurrence by 20% to 23%.27,28 There are several 5 -FU
and oxaliplatin regimens used in clinical practice. The choice is
based on differences in toxicity and convenience because these
regimens use different administration strategies for 5 -FU. For
example, some regimens with 5 -FU administer the drug for
a short 10- to 30-minute bolus infusion, whereas others spec-
ify a much longer continuous infusion, spanning several days.
5 -FU has a very short half-life and must be metabolically acti-
vated; therefore, infusing the drug for a prolonged period results
in greater formation of the active metabolite and, theoretically,
greater antitumor effect. The shorter infusion, however, is more
convenient for the patient and caregiver.
The toxicity profiles vary according to the length of infusion.
Efforts to reduce adverse effects observed with continuous infu-
sions have resulted in the evolution of multiple dosing strategies
collectively referred to as FOLFOX regimens.
Chapter 95
For an audio file explaining the FOLFOX
acronym and evolution of the FOLFOX
regimen, go to http://thepoint.lww.com/
AT10e.
Each is considered equally effective, differing only in toxic-
ity patterns. Adjuvant capecitabine combined with oxaliplatin
Colorectal Cancer
(Xeloda) (XELOX) has recently been evaluated in patients with
stage III disease, and has also proven to be safe and effective in
this setting.29 A list of commonly used adjuvant regimens is pre-
sented in Table 95-3. Combination therapy in the form of FLOX,
XELOX, or FOLFOX should be considered for B.R., noting that
a FOLFOX regimen is often clinically recommended based on a
superior tolerability profile.
The initial cycle of B.R.’s adjuvant chemotherapy should
begin approximately 4 to 6 weeks after his surgery and continue
for a total of 6 months.
ADVERSE EFFECTS OF 5-FU AND OXALIPLATIN
CASE 95-2, QUESTION 4: B.R. is scheduled to receive a
modified FOLFOX6 (mFOLFOX6) regimen in the adjuvant
setting. What potential adverse effects should B.R. be made
aware of before receiving this regimen? Are any dose-
limiting side effects associated with this therapy? Are there
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TA B L E 9 5 - 2
Colorectal Cancer Staging

T, N, M Definitions
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial or invasion of lamina propriaa
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into pericolorectal tissues
T4a Tumor penetrates to the surface of the visceral peritoneumb
T4b Tumor directly invades or is adherent to other organs or structuresb ,c
Regional Lymph Nodes (N)d
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–3 regional lymph nodes
N1a Metastasis in one regional lymph node
N1b Metastasis in 2–3 regional lymph nodes
N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
N2 Metastasis in 4 or more regional lymph nodes
N2a Metastasis in 4–6 regional lymph nodes
N2b Metastasis in 7 or more regional lymph nodes
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to one organ or site (for example, liver, lung, ovary, nonregional node)
M1b Metastases in more than one organ or site or the peritoneum

Anatomic Stage/Prognostic Groups

Stage T N M Dukese MACe

0 Tis N0 M0 — —
I T1 N0 M0 A A
T2 N0 M0 A B1
IIA T3 N0 M0 B B2
IIB T4a N0 M0 B B2
IIC T4b N0 M0 B B3
IIIA T1–T2 N1/N1c M0 C C1
T1 N2a M0 C C1
IIIB T3–T4a N1/N1c M0 C C2
T2–T3 N2a M0 C C1/C2
T1–T2 N2b M0 C C1
Section 17

IIIC T4a N2a M0 C C2

T3–T4a N2b M0 C C2
T4b N1–N2 M0 C C3
IVA Any T Any N M1a — —
IVB Any T Any N M1b — —

NOTE: cTNM is the clinical classification, pTNM is the pathologic classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (for
Neoplastic Disorders

example, ypTNM). Patients who have a complete pathologic response are ypT0N0cM0, which may be similar to Stage Group 0 or I. The r prefix is to be used for those
cancers that have recurred after a diseasefree interval (rTNM).
a
Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the
muscularis mucosae into the submucosa.
b
Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic
examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other
organs or structures by virtue of extension beyond the muscularis propria (that is, a tumor on the posterior wall of the descending colon invading the left kidney or lateral
abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
c
Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be
pT1-4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion,
whereas the PN site-specific factor should be used for perineural invasion.
d
A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent
discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive
nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the Site-Specific Factor category Tumor Deposits (TD).
e
Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic groups, as is Dukes C (any T N1 M0 and any T N2 M0). MAC is the modified Astler-Coller
classification.
Used with the permission of the American Joint Committee on Cancer (AJCC). Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Seventh
Edition (2010) published by Springer-Verlag, New York, www.springer.com
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TA B L E 9 5 - 3
Select Regimens Used in the Treatment of Localized Colon and Rectal Cancersa

Regimen Name Dosing of Chemotherapy Agents Cycle Description

Colon and Rectal Adjuvant Regimens

Roswell Park Leucovorin 500 mg/m2 IV for 2 hours; Cycle length = 56 days
One hour after starting the leucovorin administer: Repeat × 3 cycles
5 -Fluorouracil 500 mg/m2 IV bolus
Administered on days 1, 8, 15, 22, 29, and 36, followed by 2 weeks off
Mayo Clinic Leucovorin 20 mg/m2 IV bolus daily on days 1–5; Cycle length = 28 days
5 -Fluorouracil 425 mg/m2 IV bolus daily on days 1–5 Repeat × 6 cycles
Simplified Infusional Leucovorin 400 mg/m2/d IV for 2 hours on day 1 Cycle length = 14 days
Biweekly 5 -FU/LVb 5 -Fluorouracil 400 mg/m2 IV bolus on day 1, then Repeat × 12 cycles
5 -Fluorouracil 1,200 mg/m2/d IVCI × 2 days (total 2,400 mg/m2 IVCI for 46–48 hours)
Capecitabine Capecitabine 1,000–1,250 mg/m2/d PO BID days 1–14 Cycle length = 21 days
Repeat × 8 cycles
FLOX Leucovorin 500 mg/m2 IV for 2 hours; Cycle length = 56 days
One hour after starting the leucovorin administer: Repeat × 3 cycles
5 -Fluorouracil 500 mg/m2 IV bolus
Administered on days 1, 8, 15, 22, 29, and 36
Oxaliplatin 85 mg/m2 IV for 2 hours
Administered on days 1, 15, and 29
FOLFOX4 Oxaliplatin 85 mg/m2 IV for 2 hours day 1 Cycle length = 14 days
Leucovorin 200 mg/m2/d IV for 2 hours on days 1 and 2 Repeat × 12 cycles
5 -Fluorouracil 400 mg/m2/d IV bolus on days 1 and 2
5 -Fluorouracil 600 mg/m2/d IVCI for 22 hours on days 1 and 2
mFOLFOX6 Oxaliplatin 85 mg/m2 IV for 2 hours day 1 Cycle length = 14 days
Leucovorin 350–400 mg/m2/d IV for 2 hours on day 1 Repeat × 12 cycles
5 -Fluorouracil 400 mg/m2 IV bolus on day 1, then
5 -Fluorouracil 1,200 mg/m2/d IVCI × 2 days (total 2,400 mg/m2 IVCI for 46–48 hours)
XELOXc Capecitabine 1,000 mg/m2 PO BID days 1–14 Cycle length = 21 days
Oxaliplatin 130 mg/m2 IV every 21 days Repeat × 8 cycles
Rectal Regimens Combined With Radiation

Infusional 5 -FU 5 -Fluorouracil 225–300 mg/m2 IVCI Daily throughout radiation

or
Monday–Friday throughout
radiation
Capecitabine Capecitabine 825 mg/m2 PO BID Daily throughout radiation
or

Chapter 95
Monday–Friday throughout
radiation
a
Disclaimer: Please consult specific regimen protocol for exact dosing recommendation.
b
Recommended as an option in NCCN guidelines.
c
Not in current NCCN recommendations, but data are available supporting its use in stage III disease.
BID, twice daily; 5 -FU, 5 -fluorouracil; IV, intravenous; IVCI, intravenous continuous infusion; LV, leucovorin; NCCN, National Comprehensive Cancer Network; PO, orally.
Colorectal Cancer

administration is associated with more severe palmar-plantar ery-

any preventive measures that can be taken to limit the sever-
throdysesthesia or hand-foot syndrome (HFS)
ity of these adverse effects?

The goal of therapy in this setting is a cure; therefore, clini-
cians typically try to remain aggressive and limit chemotherapy
dose reductions or delays while trying to maintain an acceptable
toxicity profile. Although generally considered mild, there are a
number of chemotherapy-related toxicities that may occur dur-
ing adjuvant therapy or after its completion. Because B.R. will
receive a combination of 5 -FU and oxaliplatin in the adjuvant
setting, the toxicities of these agents should be discussed before
initiation of therapy.
The toxicity of 5 -FU will vary depending on its dose, route,
and schedule of administration. At doses used in the treatment of
colorectal cancer, bolus administration is associated with more
severe neutropenia and mucositis whereas continuous infusion
For a narrated PowerPoint presentation with
photos of HFS and information about its
incidence, prevention, and treatment, go to
http://thepoint.lww.com/AT10e.
HFS is managed primarily with supportive-care measures
such as the application of topical moisturizers in addition to tem-
porary withdrawal of fluorouracil-based therapy to allow time
to heal. Once the wound has healed or decreased in its severity,
fluorouracil-based therapy is often resumed at a reduced dose.
Severe neutropenia is typically managed with chemotherapy
dose reductions or delays, and in some cases clinicians may use
daily administration of granulocyte colony-stimulating factors
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2230 such as filgrastim or sargramostim until recovery of a patient’s
absolute neutrophil count. Severe mucositis is uncommon, but
mild symptoms can be managed with supportive-care measures
such as mild narcotic pain medications or mouthwashes that con-
tain a local anesthetic such as lidocaine. Strategies for preventing
this complication are also important and include stressing the
importance of good oral hygiene and avoidance of harsh sub-
stances, which may irritate the oral mucosa or inhibit saliva pro-
duction, such as alcohol, alcohol-based mouthwashes or rinses,
spicy foods, and anticholinergic medications. As is the case with
many fluorinated pharmaceutical agents, 5 -FU causes photo-
sensitivity, which may result in mild to severe sunburns after sun
exposure. Therefore, during his adjuvant therapy, B.R. should
avoid prolonged exposure to direct sunlight and use a sun block
of SPF-15 or higher during outdoor activities.
If oral capecitabine were chosen to substitute for the IV for-
mulation of 5 -FU, the differences with regard to toxicity should
be explained. Capecitabine undergoes enzymatic conversion to
5 -FU in the tumor and is usually given daily for 14 days; there-
fore, it has a similar toxicity profile to continuous infusion 5 -FU.
However, it is usually associated with a greater incidence and
severity of HFS and diarrhea compared with continuous infu-
sions. Often the decision of which fluorouracil-based therapy to
choose is multifactorial owing to the nuances of clinical practice.
Potential factors that play a role in the agent chosen can include,
but are not limited to, toxicity differences, institutional resources
(pump availability, etc.), insurance coverage, and patient prefer-
ence. Additional factors that could influence the selection of a
capecitabine-based regimen include the presence of renal impair-
ment and relevant drug–drug interactions, particularly concomi-
tant warfarin use.
Oxaliplatin is the newest member of the platinum family of
antineoplastics, and it offers a different antitumor profile and
resistance pattern than cisplatin or carboplatin. Of the three
agents, oxaliplatin is highly active against colorectal tumors.
Myelosuppression, primarily neutropenia and thrombocytope-
nia, and neurotoxicity are dose-limiting toxicities associated with
its use.30 Oxaliplatin causes an acute, reversible neuropathy con-
sisting of either paresthesias or dysesthesias and in some instances
muscle spasms. One particular phenomenon that is distressing
for patients is an involuntary laryngopharyngeal dysesthesia that
Section 17
can create the sensation of an inability to swallow or breathe.
The acute phenomenon is reported to occur in greater than 90%
of patients receiving oxaliplatin.28,31 Although our understand-
ing of the event is limited, it is known to be triggered by direct
contact with anything cold. This sensitivity to cold as well as
the aforementioned reactions generally occur within minutes of
Neoplastic Disorders
receiving the infusion and can persist up to 7 days. Avoidance
of cold objects, including the eating or drinking of cold foods
and beverages, should be emphasized to B.R. after each dose of
oxaliplatin. The use of gloves, socks, and scarves can also be rec-
ommended, especially in cold weather. B.R. should be reassured
that the intensity of this reaction diminishes daily after treatment
and usually resolves within a week. Delayed neurotoxicity may
also occur and is potentially irreversible. This chronic neuropathy
is a cumulative, dose-dependent effect. It initially develops in the
distal extremities and slowly progresses in a glove and stocking
distribution pattern. It is typically characterized by a persistent
sensation of numbness, tingling, or burning in the extremities.
Hypersensitivity reactions have also been observed with oxali-
platin use, but the appearance of the reaction is arbitrary in that
it can manifest with any dose, and although it usually occurs dur-
ing the infusion, delayed reactions are possible. The severity of
these allergic reactions can range from mild itching or flushing
to anaphylaxis. After a reaction, mild cases are often managed
November 16, 2011 19:23
through premedication with antihistamines or corticosteroids
(e.g., diphenhydramine 50 mg IV or orally with or without hydro-
cortisone 50 mg 15 minutes before oxaliplatin IV) in addition
to prolonging the infusion of oxaliplatin. More-severe reactions
generally warrant discontinuation of the drug; however, there
are reports in which desensitization protocols have been used
successfully, allowing for continued administration.32,33 Regard-
less of what is chosen, this strategy accompanies all subsequent
doses of oxaliplatin.
The primary role of chemotherapy in this setting is to reduce
the risk of relapse and prolong diseasefree survival by eradicating
residual, undetectable disease. A total of 6 months of adjuvant
therapy is considered the current standard of care after surgery
with curative intent (12 cycles of an every 2-week regimen like
FOLFOX, or 8 cycles of an every 3-week strategy like single-agent
capecitabine) owing in large part to data from select adjuvant
trials as well as the results obtained after multivariate analyses
of these trials. In short, the truly optimal duration for any given
patient in this setting is unknown because the patients are tech-
nically diseasefree after their resection.
PERIPHERAL NEUROPATHY
CASE 95-2, QUESTION 5: After eight cycles of adjuvant
therapy, B.R. begins complaining of a constant numbness
and tingling in the toes on his left foot that is not interfer-
ing with his daily activities but is described as more of a
nuisance. Which drug is most likely responsible for this, and
what course of action should be taken?
The timing of the symptoms that B.R. is experiencing is indica-
tive of the cumulative toxicity oxaliplatin exerts on peripheral sen-
sory nerves. As explained earlier, the severity of this condition
can worsen with continued doses of oxaliplatin and is not readily
reversible; therefore, it is imperative that clinicians and patients
work together to minimize its negative impact on various activi-
ties of daily living such as buttoning a shirt, walking up or down
stairs, or realizing whether one’s foot is actually touching the
brake pedal as the car approaches a red light. The incidence of
delayed neurotoxicity causing functional impairment has been
reported to exceed 15% after cumulative doses of 780 mg/m2 .31
Early evidence suggested that use of IV infusions of calcium and
magnesium with oxaliplatin attenuates the acute symptoms and
perhaps delays the onset and intensity of the chronic manifes-
tations of this neurotoxicity.34 Controversy as to whether this
strategy is practical in the adjuvant setting exists because of con-
cerns of decreased tumor response rates and other measures of
effectiveness. Another strategy uses a “stop-and-go” approach to
limit exposure to oxaliplatin while retaining its antitumor effects
and has been shown to be beneficial in delaying the develop-
ment of peripheral neuropathy.35 In this approach, oxaliplatin
is withdrawn from therapy in patients with metastatic disease
and is reinitiated when disease progression is noted. However,
this strategy was used in patients with metastatic disease, and
although effective, it is impractical in the adjuvant setting.
Because B.R. has completed 8 of a planned 12 cycles of his
adjuvant therapy and because his symptoms just started, are
confined to one extremity, and are not interfering with his daily
activities, the reaction would be graded as relatively mild in its
severity at this point. He will likely benefit most from continued
administration of oxaliplatin at a reduced dosage with diligent
monitoring of his neuropathy. Several small trials have been con-
ducted to evaluate the effectiveness of certain pharmaceutical
agents in the management of chemotherapy-induced peripheral
neuropathy. These trials have focused on either the prevention or