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CANCER INVESTIGATION
Vol. 21, No. 5, pp. 682–689, 2003

ORIGINAL ARTICLE

Cisplatin and Irinotecan (CPT-11) for Peritoneal Mesothelioma

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Duc Thanh Le, Michael Deavers, Kelly Hunt, Anais Malpica,

and Claire F. Verschraegen*

Departments of Gynecologic Medical Oncology, General Surgery, and Pathology,

The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

ABSTRACT

Peritoneal mesothelioma is a rare malignancy that is seen in patients exposed to asbestos or in

young women with no known exposure to asbestos. The clinical features of the disease are
For personal use only.

similar in these two groups, and include peritoneal carcinomatosis, ascites, thrombocytemia,
systemic symptoms (fever and night sweats), and hypercoagulability. There is no known
curative therapy for this disease. Cisplatin has activity in 25% of patients. Mesothelial cells
are known to contain high levels of carboxylesterase, a key enzyme in the activation of
Irinotecan (CPT-11) to SN-38. This retrospective review of our experience in combining
cisplatin 50 or 60 mg/m2 IV or i.p. on day 1 with CPT-11 50 or 60 mg/m2 IV on day 1, 8, and
15. Courses were repeated every 4 weeks £ 6. If i.p. administration of cisplatin were feasible,
it was the preferred route. Response to treatment was based on RECIST criteria.
Fourteen men and 3 women, median age 62 years (35– 76 years) and median PS 1 (0 – 2)
were treated. Median number of courses was two for nonresponders and six for responders.
The overall response rate was 24%, but 76% of patients improved on treatment. Median
survival is not reached. Grade $ 2 side effects included anemia (n 5 6), neutropenia (n 5 3),
nausea/vomiting ðn 5 4Þ; and constipation ðn ¼ 2Þ: Grade 1 side effects were fatigue,
anorexia, weight loss, alopecia, diarrhea, neuropathy, and gastric reflux. There were no grade
$ 3 hematologic toxicities.
The combination of cisplatin and CPT-11 is well tolerated and has clinical benefits in
patients with peritoneal mesothelioma.

Key Words: Mesothelioma; Topoisomerase inhibitors; Intraperitoneal therapy.

*Correspondence: Claire Verschraegen, M.D., University of New Mexico, Division of Hematology Oncology, 900 Camino de Salud
NE, Albuquerque, NM 87131-5636, USA; Fax: 505-272-2841; E-mail: cverschraegen@salud.onm.edu.

682

DOI: 10.1081/CNV-120023766 0735-7907 (Print); 1532-4192 (Online)

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Cisplatin and CPT-11 for Peritoneal Mesothelioma
INTRODUCTION
Malignant mesothelioma is a lethal disease, with a
median survival of 6 – 12 months for pleural involvement
and 10 –20 months for peritoneal disease. Surgery and
radiotherapy play a very limited role in therapy, and
treatment is usually palliative. Systemic chemotherapy
as a single agent or combination of drugs has been used
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since the 1980s, but no effective standard regimen for
mesothelioma has emerged. The best responses seem to
be obtained following intraperitoneal (i.p.) infusion of
platinum and its analogs.[1 – 3]
Many studies have tested the combination of cisplatin
with irinotecan (CPT-11), a semisynthetic derivative of
camptothecin in various malignancies. These studies
reported that CPT-11 in combination with cisplatin had
definite activity in lung, gastrointestinal, and gynecologic
cancers. The combination is usually well tolerated, with
acceptable myelosuppression and rare treatment-related
diarrhea.[4 – 8] Activity has been noted in patients with
pleural mesothelioma, when intravenous (IV) cisplatin
and CPT-11 were used.[9] These results encouraged us to
For personal use only.
retrospectively evaluate our experience with the combi-
nation of i.p. or IV cisplatin and IV irinotecan for patients
with malignant peritoneal mesothelioma. The immediate
objectives were (1) to determine the clinical response and
the survival of the patients, and (2) to evaluate the toxicity
of this combination.
PATIENTS AND METHODS
Patient Population
The medical records of patients with histopatholo-
gically documented peritoneal malignant mesothelioma
treated between 1999 and 2001 with cisplatin and
irinotecan were reviewed. Patient characteristics that
were coded were performance status; presence of night
sweats; bone marrow, hepatic, and renal functions;
platelet count; history of prior malignancies; concurrent
medical conditions; prior cancer treatments with
chemotherapy, immunotherapy, radiotherapy, or any
other investigational medications; and prior surgeries for
mesothelioma.
Pretreatment and Follow-up Studies
Evaluation before each treatment consisted of a
complete history and a physical examination with
documentation of all measurable disease. Zubrod’s
683
performance status, weight, and concurrent nonmalig-
nant disease and therapy were noted. All relevant
information regarding drug dosages, tumor response,
laboratory examinations, and treatment-related toxicities
were recorded. Routine blood work consisted of a
complete blood count with differential and platelet
counts, a blood chemistry profile, electrolytes including
magnesium, and CA-125 or other tumor markers, as
necessary. Complete blood count, platelet count, and
differential count were performed weekly. Computed
tomography was used to evaluate measurable disease,
and repeated after 2 to 3 courses and at the completion of
6 courses.
Treatment
If clinically and anatomically feasible, a subcu-
taneous or transcutaneous catheter was inserted through
the abdominal wall. Prior to infusion of cisplatin, as
much peritoneal fluid as possible was removed. Cisplatin
at a dose of 60 (untreated patients) or 50 mg/m2
(pretreated patients) in a liter of normal saline was
administered intraperitoneally over 2 hr on day 1 if the
abdominal cavity was free of adhesions. The same dose
of cisplatin would be administered intravenously, if a
peritoneal catheter could not be inserted. All patients
were given ondansetron (8 mg IV) and dexamethasone
(20 mg IV) 1 hour prior to the start of the cisplatin
infusion, and ondansetron (8 mg IV) at the completion of
chemotherapy. Pre- and posttreatment IV hydration was
given to patients with each cisplatin infusion. Mannitol
(40 g) was given intravenously during the infusion of
cisplatin. During each i.p. treatment of cisplatin, the
position of the patient was rotated every 20 min to supine
position, right decubitus, left decubitus, reverse Trende-
lenburg position, and prone position, to fully saturate all
surfaces of the peritoneal cavity.
One hour after the completion of the cisplatin
infusion, irinotecan 60 or 50 mg/m2 was administered
intravenously. Irinotecan was infused concurrently with
the posthydration. The premedication consisted of
diphenhydramine (25 mg IV) and atropine (0.5 mg
subcutaneously) to be administered 30 min prior to
irinotecan. The same dose of irinotecan was repeated on
days 8 and 15 of a 28-day cycle. A maximum of 6 cycles
were given every 4 weeks, provided that there was no
documentation of progressive disease and all toxicities
from prior courses had reverted. Irinotecan was held if
the absolute granulocyte count (AGC) , 1,500/mm3 and
platelets , 100,000/mm3. Skipped doses because of side
effects were not rescheduled.
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684 Le et al.

Assessment of Response Table 1. Patient characteristics.

An assessment of tumor response was made based Characteristica No. of patients

on clinical examination and imaging studies. Response Age (years)
was evaluated according to the RECIST criteria.[10] Median (range) 62 (35 – 76)
However, the dimension that was measured was the Gender
greatest thickness of the omental cake. For isolated tumor Male 14
masses, the longest diameter was measured. Resolution Female 3
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of ascites was also evaluated and recorded, as was Asbestos exposure

improvement in performance status. Response duration Yes 4
was measured from the time of response until evidence of No 8
Unknown 5
progression of disease.
Performance status (Zubrod scale)
0 8
1 6
Evaluation of Toxicity 2 3
Weight loss
Toxicity was evaluated for each course of therapy. Yes 7
Data were analyzed for evidence of cumulative toxicity No 10
in patients who received repeated doses of therapy. All Night sweats
toxicities encountered during the study were evaluated Yes 3
No 14
according to the National Cancer Institute Common
Primary site
Toxicity Criteria (NCI CTC) version 2 grading system
For personal use only.

Peritoneal 16
(0 – 4), dated 1/30/98. Pleural 1
Pathological subtype
Epithelial 12
RESULTS Mixed 1
Not classified 4
Between August 1999 and May 2001, 17 patients Prior therapy
with peritoneal mesothelioma received the combination S þ CT þ RT 1
of cisplatin and CPT-11. Patient characteristics are S þ CT þ H 2
S þ CT þ I 1
summarized in Tables 1 and 2. Sixteen patients had
S þ CT 3
primary peritoneal mesothelioma and only 1 patient had I 1
onset of the disease in the pleura. The patients ranged in S 6
age from 35 to 76 years (median age, 62 years), with No prior therapy 3
male patients outnumbering female patients 14 to 3. A
a
history of asbestos exposure was found in 4 male S, Surgery; CT, chemotherapy; RT, radiotherapy;
patients, whereas in 5 others it was unknown. The H, hormonotherapy; I, immunotherapy.
median performance status prior to therapy was 1 (range,
0– 2). Weight loss greater than 10% was seen in 7

Table 2. Pretreatment laboratory values.

Tests Mean (range)

CA-125 107.6 U/mL (7.0– 478.8)

No patients with CA-125 . 35 U/mL 9
Hemoglobin 12.3 g/dL (9.2– 15.0)
No men with hemoglobin ,14.0 g/dL 11
No women with hemoglobin , 12 g/dL 1
White blood cells 8.3 £ 103/mL (3.5 – 17.0)
Platelets 425 £ 103/mL (184 –843)
3
No patients with thrombocytosis (. 400 £ 10 /mL) 8
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Cisplatin and CPT-11 for Peritoneal Mesothelioma 685

Table 3. Treatment. Table 5. Treatment toxicity.

Treatment No. of patients Grade

No. of cycles Toxicity 1 2 3 Percentage $grade 2

1 1
2 4 Granulocytopenia 5 3 0 18
3 3 Anemia 7 6 0 36
5 1 Thrombocytopenia 0 0 0
Nausea 5 3 0 18
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6 8
Cisplatin administration Vomiting 3 1 1a 12
i.p.a 8 Anorexia 5 0 0
IVb 8 Gastric reflux 1 0 0
i.p. þ IV 1 Diarrhea 2 0 0
Constipation 0 2 0 12
a
i.p., Intraperitoneal. Rectal bleeding 1 0 0
b
IV, Intravenous. Fatigue 9 0 0
Neurotoxicity 2 0 0
Hearing loss 1 0 0
patients and night sweats were noted in 3 patients. Weight loss 3 0 0
Twelve patients (70%) had epithelial mesothelioma, 1 Alopecia 3 0 0
had mixed sarcomatous and epithelial forms, and 4 had a
In one patient with partial bowel obstruction.
mesothelioma otherwise not specified. Eight patients had
received prior chemotherapy. None of the prior regimens
For personal use only.

contained irinotecan. Five of the patients who received

prior chemotherapy were exposed to platinum [1 to
cisplatin, 1 to carboplatin, 2 to a liposomal platin (L-
NDDP), and 1 to both cisplatin and L-NDDP]. Two
patients had received hormonal therapy and 2 patients
had received immunotherapy, 1 with interferon and 1
with FLT-3 ligand, a monocyte-stimulating factor.
The patient with pleural mesothelioma had received
radiation to the chest.
A total of 71 cycles of treatment were administered
to the 17 patients. Eight of the patients completed
the planned 6 cycles. The median number of cycles per
patient was 5 (mean, 4.2). Eight patients received
cisplatin intraperitoneally and 8 intravenously.
One patient received cisplatin intraperitoneally for 5
cycles and intravenously during the sixth cycle (Table 3).
Partial responses were observed in 4 patients (24%).
Of 6 patients with ascites, 2 had complete resolution of
the ascites, and for the other 4, the rate of ascites
reaccumulation slowed significantly. The amount of
disease remained stable in 9 patients (52%). Four patients
had progression of disease after two courses (24%)
(Table 4).
Side effects are shown in Table 5. Granulocytopenia
and anemia were the main hematologic toxicities. Three
and 5 patients experienced grade 2 and 1 granulocyto-
penia, respectively. Six patients had grade 2 anemia and
7 had grade 1. No thrombocytopenia was noted.
Vomiting was rare and managed by antiemetic regimens.
One patient had grade 3 emesis and required hydration
and IV antiemetic agents several days after IV cisplatin
therapy. Grade 2 nausea occurred in 3 patients and grade
1 in 5. Two patients had grade 2 constipation. Grade 1
toxicities were fatigue, anorexia, weight loss, alopecia,
diarrhea, neuropathy, and gastric reflux. One patient had
a partial hearing loss after the sixth cycle of treatment.
No patients required a dose reduction.
Eleven patients are alive. Median survival has not
been reached. Duration of response for responders was
36 weeks (range, 5þ – 47þ weeks), and for patients with
stable disease, 26 weeks (range, 4þ – 44þ weeks) (Fig. 1).

DISCUSSION
Table 4. Response to treatment.

Response category No. of patients The low incidence of peritoneal mesothelioma in

the United States prevents the conduct of randomized
Partial response 4 trials. There is no known curative treatment for
Stable disease 9
extensive disease and the role of surgery has yet to be
Progressive disease 4
defined. Exploratory laparotomy has often been
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686
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Figure 1. Probability of survival of all patients.
necessary to obtain adequate tissue to provide an
accurate histologic diagnosis. More recently, tissue
can often be obtained by laparoscopy. Aggressive
surgical procedures with a high morbidity rate, and 2-
year survival rates of 10% to 37% and 5-year survival
rates of # 10%,[11] have lead many investigators to
conclude that an aggressive surgical approach does not
prolong the overall survival of patients.[11,12] How-
ever, Sugarbaker and colleagues reported excellent
For personal use only.
results after aggressive surgical debulking, followed
by chemotherapy and radiotherapy.[13] Most patients
will require systemic chemotherapy during the course
of the disease. Randomized studies of surgery vs.
chemotherapy have not been performed.
Radiotherapy alone does not prolong the survival of
patients with malignant mesothelioma. The median
survival in radiotherapy studies is about 10 months. This
is not significantly different from the natural course of
the disease.[14] Radiotherapy, however, remains an
important modality in controlling pain and can be used
as a palliative measure.[15]
Most studies of systemic chemotherapy in mesothe-
lioma have included small numbers of patients. Many
trials of single-agent or combination chemotherapy have
been reported; however, a drug of choice for the
treatment of mesothelioma has not been identified. The
most effective agents include doxorubicin, cisplatin,[16]
gemcitabine,[17] onconase,[18] L-NDDP,[2] and more
recently, pemetrexed.[19] Cisplatin or platinum analogs
show antitumor activity and synergism with other
drugs.[20 – 23] In one study, the combination of cyclopho-
sphamide, doxorubicin, and cisplatin yielded a 30%
remission rate in one study of 23 patients with
unresectable or metastatic malignant mesothelioma.[24]
However, the overall median survival was only 60
weeks, not significantly different from that reported for
patients treated with supportive care only.[24]
Peritoneal mesothelioma is an ideal disease on which
to perform studies of i.p. chemotherapy administration
Le et al.
because many patients have disease isolated to the
peritoneal cavity and many patients present with ascites, a
clinical situation that is optimal for peritoneal therapy.[25]
Alberts et al. demonstrated a potential advantage of
cisplatin when administered intraperitoneally in patients
with stage III ovarian cancer and residual tumor masses of
2 cm or less.[26] The estimated median survival was
significantly longer in the group receiving i.p. cisplatin
(49 months; 95% CI, 42– 56) than in the group receiving
IV cisplatin (41 months; 95% CI, 34 –47). The risk of
death was lower in the i.p. group than in the IV group
(hazard ratio, 0.76; 95% CI, 0.61– 0.96; P ¼ 0:02).
Moderate-to-severe tinnitus, clinical hearing loss, and
neuromuscular toxic effects were significantly more
frequent in the IV group. These findings raise the question
of whether i.p. administration of cisplatin may confer a
survival advantage with fewer toxic effects in patients
with histologic types of peritoneal carcinomatosis other
than ovarian cancer. There have been no randomized
studies of i.p. chemotherapy administration in patients
with peritoneal mesothelioma, and the impact of tumor
burden is unknown. Table 6 lists studies of i.p.
chemotherapy in this patient population.
The activity of topoisomerase-I inhibitors is
synergistic with platinum.[27] Nakano et al. tested the
efficacy and toxicity of a combination of cisplatin and
CPT-11 (60 mg/m2 for each drug) in patients with
malignant pleural mesothelioma and characterized the
pharmacokinetic profiles of CPT-11 and its active
metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38).
Of 15 previously untreated patients with malignant
pleural mesothelioma, four partial responses (response
rate of 26.7%) with a median response duration of 25.9
weeks and two regressions of evaluable disease (overall
response rate of 40%) were observed. The median
survival time after chemotherapy was 28.3 weeks, and
the median time to treatment failure was 22.1 weeks.
The 1-year survival rate for all patients was 38.5%.
Toxicity was mild, and there were no treatment-related
deaths. Grade 3 leukopenia occurred in 3 patients
(20%), and grade 1 or 2 diarrhea occurred in 3 patients
(20%). There was no excessive toxicity in patients with
large pleural effusions compared with those without
pleural effusions. CPT-11 and SN-38 were detected in
the pleural fluid 1 hr after IV administration. The
maximum concentrations of CPT-11 and SN-38 in the
pleural fluid compared with the corresponding plasma
values were 36.5% and 75.8%, respectively. The
combination of cisplatin and CPT-11 had definite
activity against malignant pleural mesothelioma and
was well tolerated. The IV administration of CPT-11
produced adequate distribution of CPT-11 and its active
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Cisplatin and CPT-11 for Peritoneal Mesothelioma 687

Table 6. Studies of i.p. chemotherapy for peritoneal mesothelioma.

No. of Clinical
Authors patients Drugs assessmenta Comments Ref.

Vlasveld 4 Mitoxantrone or platinum 1 CR, 1 PR, 1 Low-volume disease [31]

NC, 1 PD
Markman et al. 19 Cisplatin þ mitomycin C Median survival: 9 months; 2 Catheter failure [1]
pts alive at 5 years after 4 – 6 courses
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Langer et al. 10 Cisplatin (200 mg/m2) CR: 1 of 4 pts Chemotherapy given [32]
þ etoposide (65 – 290 mg/m2) after debulking
NC: 1 of 4 pts
PD: 2 of 4 pts
a
CR, Complete response; PR, partial response; NC, no change; PD, progressive disease; pts, patients.

metabolite SN-38 into the pleural fluid, and allowed a
high concentration of the more active SN-38 to make
contact with mesothelioma cells in the thoracic cavity.[9]
In our experience, the combination of cisplatin
# 60 mg/m2 on day 1 and CPT-11 # 60 mg/m2 on day 1,
8, and 15 of a 28 day-cycle is well tolerated and induces
For personal use only.
In conclusion, the combination of IV irinotecan and
i.p. or IV cisplatin is very safe and has a modest activity
in patients with peritoneal mesothelioma. A comparison
of this regimen with a gemcitabine- or pemetrexed-based
combination is warranted.

remission in diseases involving the peritoneal cavity,

such as appendiceal carcinoma (signet ring cell type and
mucinous type), pseudomyxoma peritonei, malignant
mixed mullerian tumor of the ovary, cervical cancer, and
mesothelioma. Complete remissions have been observed
in signet ring cell carcinoma and malignant mixed
mullerian tumor.[28] Partial remissions have been
observed in all cancer types. The toxicity profile has
been well tolerated, mainly with grade 2 nausea and
vomiting, and fatigue. Diarrhea has not been observed at
these doses. Gastrointestinal toxicity is related to the
dose and has been found to be minimal at doses below
70 mg/m2.[29] Hematologic toxicity has been minimal at
these doses, although the schedule was designed to
minimize these effects. With higher doses, it would be
necessary to skip some of the weekly administration of
the CPT-11 and this would be counterproductive given
the mechanism of action of this class of agent.[30]
Our retrospective study analyzed the combination
of irinotecan administered intravenously and cisplatin
administered intraperitoneally if feasible, otherwise
intravenously. No complete responses were observed
in this patient population. However, partial remissions
and stable disease with reduction in ascites production
and improvement in performance status were observed
in 13 patients (76%). In this combination, treatment
was well tolerated by most patients and no toxicity-
related deaths occurred. The predominant side effect
was nausea and emesis. Hematopoietic toxicity was
not significant.
REFERENCES
1. Markman, M.; Kelsen, D. Efficacy of cisplatin-based
intraperitoneal chemotherapy as treatment of malignant
peritoneal mesothelioma. J. Cancer Res. Clin. Oncol.
1992, 118 (7), 547– 550.
2. Verschraegen, C.; Mansfield, P.; Feig, B.; Steger, M.; Wu,
Q.; MacLean, D.; Siddik, Z.; Perez-Soler, R.; Hu, W.;
Kudelka, A.; Kavanagh, J.; Khokhar, A. Phase I study of
an intraperitoneal liposomal cisplatin analog l-nddp for
treatment of peritoneal carcinomatosis. Proc. Annu. Meet.
Am. Soc. Clin. Oncol. 1999, 18, A1405.
3. Mintzer, D.M.; Kelsen, D.; Frimmer, D.; Heelan, R.;
Gralla, R. Phase II trial of high-dose cisplatin in patients
with malignant mesothelioma. Cancer Treat. Rep. 1985,
69 (6), 711–712.
4. Noda, W.; Nishiwaki, Y.; Kawahara, M.; Negoro, S.;
Sugiura, T.; Yokoyama, A.; Fukuoka, M.; Mori, K.;
Watanabe, K.; Tamura, T.; Yamamoto, S.; Saijo, N.
Irinotecan plus cisplatin compared with etoposide plus
cisplatin for extensive small-cell lung cancer. New Engl.
J. Med. 2002, 346 (2), 85 – 91.
5. Adachi, S.; Ogasawara, T.; Yamasaki, N.; Shibahara, H.;
Kanazawa, R.; Tsuji, Y.; Takemura, T.; Koyama, K. A
pilot study of CPT-11 and cisplatin for ovarian clear cell
adenocarcinoma. Jpn. J. Clin. Oncol. 1999, 29 (9),
434– 437.
6. Boku, N.; Ohtsu, A.; Shimada, Y.; Shirao, K.; Seki, S.;
Saito, H.; Sakata, Y.; Hyodo, I. Phase II study of a
combination of irinotecan and cisplatin against metastatic
gastric cancer. J. Clin. Oncol. 1999, 17 (1), 319– 323.
 MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
688
7. Ilson, D.H.; Saltz, L.; Enzinger, P.; Huang, Y.;
Kornblith, A.; Gollub, M.; O’Reilly, E.; Schwartz,
G.; DeGroff, J.; Gonzalez, G.; Kelsen, D.P. Phase II
trial of weekly irinotecan plus cisplatin in advanced
esophageal cancer. J. Clin. Oncol. 1999, 17 (10),
3270– 3275.
8. Sugiyama, T.; Yakushiji, M.; Noda, K.; Ikeda, M.;
Kudoh, R.; Yajima, A.; Tomoda, Y.; Terashima, Y.;
Takeuchi, S.; Hiura, M.; Saji, F.; Takahashi, T.; Umesaki,
Cancer Invest Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/02/14
N.; Sato, S.; Hatae, M.; Ohashi, Y. Phase II study of
irinotecan and cisplatin as first-line chemotherapy in
advanced or recurrent cervical cancer. Oncology 2000, 58
(1), 31 – 37.
9. Nakano, T.; Chahinian, A.P.; Shinjo, M.; Togawa, N.;
Tonomura, A.; Miyake, M.; Ninomiya, K.; Yamamoto,
T.; Higashino, K. Cisplatin in combination with
irinotecan in the treatment of patients with malignant
pleural mesothelioma: a pilot phase II clinical trial and
pharmacokinetic profile. Cancer 1999, 85 (11),
2375 –2384.
10. Lederman, G.S.; Recht, A.; Herman, T.; Osteen, R.;
Corson, J.; Antman, K.H. Combined modality treatment
of peritoneal mesotheliomas. NCI Monogr. 1988, 6,
321 –322.
For personal use only.
11. Ma, G.Y.; Bartlett, D.L.; Reed, E.; Figg, W.D.; Lush,
R.M.; Lee, K.B.; Libutti, S.K.; Alexander, H.R.
Continuous hyperthermic peritoneal perfusion with
cisplatin for the treatment of peritoneal mesothelioma.
Cancer J. Sci. Am. 1997, 3 (3), 174– 179.
12. Sebbag, G.; Yan, H.; Shmookler, B.M.; Chang, D.;
Sugarbaker, P.H. Results of treatment of 33 patients with
peritoneal mesothelioma. Br. J. Surg. 2000, 87 (11),
1587 –1593.
13. Ball, D.; Cruickshank, D. The treatment of malignant
mesothelioma of the pleura: review of a 5-year
experience, with special reference to radiotherapy. Am.
J. Clin. Oncol. 1990, 13, 4 – 9.
14. Gordon, W.; Antman, K.; Greenberger, J.; Weichsel-
baum, R.; Chaffey, J. Radiation therapy in the manage-
ment of patients with mesothelioma. Int. J. Rad. Oncol.
Biol. Phys. 1982, 8, 19– 25.
15. Taub, R.N.; Antman, K.H. Chemotherapy for malignant
mesothelioma. Semin. Thor. Cardiovasc. Surg. 1997, 9
(4), 361– 366.
16. Kindler, H.L.; Millard, F.; Herndon, J.E., II. Vogelzang,
N.J.; Suzuki, Y.; Green, M.R. Gemcitabine for malignant
mesothelioma: a phase II trial by the Cancer and
Leukemia Group B. Lung Cancer 2001, 31 (2– 3),
311 –317.
17. Taub, R.; Keohan, M.L.; Vogelzang, N.J.; Costanzi, J.;
Chun, H.; Mittelman, A.; Panella, T.; McCachren, S.;
Puccio, C.; Shogen, K.; Fine, R.; Mikulski, S.M. Phase
II trial of onconase (onc) in patients (pts) with
advanced malignant mesothelioma (mm): analysis of
survival. Proc. Annu. Meet. Am. Soc. Clin. Oncol.
1999, 18, A2021.
Le et al.
18. Le Chevallier, T. Multi-targeted antifolate therapy for
non-small cell lung cancer and mesothelioma. Anti
Cancer Drugs 2001, 12 (3), 21 –25.
19. Tsunoda, T.; Tanimura, H.; Hotta, T.; Tani, M.; Iwahashi,
M.; Ishimoto, K.; Tanaka, H.; Matsuda, K.; Yamaue, H. In
vitro augmentation of antitumor effect in combination
with CPT-11 and CDDP for human colorectal cancer.
J. Surg. Oncol. 2000, 73 (1), 6 –11.
20. Kanzawa, F.; Nishio, K.; Fukuoka, K.; Fukuda, M.;
Kunimoto, T.; Saijo, N. Evaluation of synergism by a
novel three-dimensional model for the combined action of
cisplatin and etoposide on the growth of a human small-
cell lung-cancer cell line, SBC-3. Int. J. Cancer 1997, 71
(3), 311– 319.
21. Goldwasser, F.; Valenti, M.; Torres, R.; Kohn, K.W.;
Pommier, Y. Potentiation of cisplatin cytotoxicity by 9-
aminocamptothecin. Clin. Cancer Res. 1996, 2 (4),
687– 693.
22. Albain, K.S.; Swinnen, L.J.; Erickson, L.C.; Stiff, P.J.;
Fisher, S.G.; Fisher, R.I. Cytotoxic synergy of cisplatin
with concurrent hydroxyurea and cytarabine: summary of
an in vitro model and initial clinical pilot experience.
Sem. Oncol. 1992, 19 (3 Suppl 9), 102– 109.
23. Shin, D.; Fossella, F.; Umawasdi, T. Prospective study of
combination chemotherapy with cyclophosphamide,
doxorubicin, and cisplatin for unresectable or metastatic
malignant peritoneal mesothelioma. Cancer 1995, 76,
2230– 2236.
24. Markman, M. Intraperitoneal chemotherapy: a rational
approach to overcome drug resistance. In Clinical
Management of the Drug resistant Cancer Patient: New
Options in Clinical Oncology; Nagourney, R.A., Sheikh,
K.M.,Eds.; Memorial Medical Center Foundation: Long
Beach, CA, 1991; 85 – 105.
25. Alberts, D.S.; Liu, P.Y.; Hannigan, E.V.; O’Toole, R.;
Williams, S.D.; Young, J.A.; Franklin, E.W.; Clarke-
Pearson, D.L.; Malviya, V.K.; DuBeshter, B. Intraper-
itoneal cisplatin plus intravenous cyclophosphamide
versus intravenous cisplatin plus intravenous cyclopho-
sphamide for stage III ovarian cancer. N. Eng. J. Med.
1996, 335 (26), 1950– 1955.
26. Takiyama, I.; Terashima, M.; Ikeda, K.; Kawamura, H.;
Sasaki, N.; Hayakawa, Y.; Ishida, K.; Saito, K.
Remarkable synergistic interaction between camptothecin
analogs and cisplatin against human esophageal cancer
cell lines. Proc. Annu. Meet. Am. Assoc. Cancer Res.
1997, 38, A101.
27. Verschraegen, C.; Le, D.; Kudelka, A.; Kavanagh, J.;
Hunt, K.J. Cisplatin and irinotecan for peritoneal
mesothelioma. Proc. Am. Soc. Clin. Oncol. 2001, 20,
A2110.
28. Azevedo, P.; Verschraegen, C.F.; Kavanagh, J.J.;
Kudelka, A.P.; Freedman, R.S.; Lu, K.; Deavers, M.T.
Malignant mixed mesodermal tumor of the ovary treated
with a cisplatin-irinotecan combination: case report. Eur.
J. Gynaecol. Oncol. 2001, 22 (5), 319– 321.
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Cisplatin and CPT-11 for Peritoneal Mesothelioma 689

29. Verschraegen, C.F.; Levy, T.; Kudelka, A.P.; Llerena, E.;
Ende, K.; Freedman, R.S.; Edwards, C.L.; Hord, M.;
Steger, M.; Kaplan, A.L.; Kieback, D.; Fishman, A.;
Kavanagh, J.J. Phase II study of irinotecan in prior
chemotherapy-treated squamous cell carcinoma of the
cervix. J. Clin. Oncol. 1997, 15 (2), 625– 631.
30. Balat, O.; Verschraegen, C. Topoisomerase I inhibitors in
gynecologic cancers. Expert Opin. Investig. Drugs 1995,
4, 1217– 1230.
Cancer Invest Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/02/14
For personal use only.
31. Vlasveld, L.T.; Gallee, M.P.; Rodenhuis, S.; Taal, B.G.
Intraperitoneal chemotherapy for malignant peritoneal
mesothelioma. Eur. J. Cancer 1991, 27 (6), 732– 734.
32. Langer, C.J.; Rosenblum, N.; Hogan, M.; Nash, S.;
Bagchi, P.; LaCreta, F.P.; Catalano, R.; Comis, R.L.;
O’Dwyer, P.J. Intraperitoneal cisplatin and etoposide in
peritoneal mesothelioma: favorable outcome with a
multimodality approach. Cancer Chemother. Pharmacol.
1993, 32 (3), 204– 208.