Extensive preclinical work has demonstrated the efficacy of
irinotecan (CPT-11 [Camptosar]) against many cancer cell lines and
human tumor xenografts. In addition, numerous phase I clinical trials
have included case reports of responses in different tumor types.
Minor, partial, and/or complete responses to varying schedules of
irinotecan have been reported in patients with cancers of the head
and neck, esophagus, stomach, pancreas, liver, colon/rectum, kidney,
lymph nodes, ovary, and uterine cervix.[1-8] These papers also have
described responses in sarcoma, melanoma, acute and chronic leukemia,
mesothelioma, and cancers of unknown primary site. Isolated cases are
helpful in the design of future phase II trials but, of course, need
to be interpreted with caution.
Most of the phase II and III trials of irinotecan have been conducted
in patients with colorectal and other gastrointestinal, non-small-cell
lung, and cervical cancers. These trials are discussed in other
articles in this monograph. This article discusses the limited number
of studies of irinotecan in other diseases. Specifically, phase II
trials in lymphoma, leukemia, breast, pancreas, ovarian, and
small-cell lung cancers are presented.
As will become evident from this discussion, the information gleaned
from such preliminary work is subject to many limitations. The number
of patients enrolled in the studies is small, and often patients with
different disease histologies, stages, and number of prior treatments
are included, thereby diluting the reproducibility of the results
even further. In many of the early Japanese trials, two or sometimes
more dosing regimens are employed in the same trial. When response or
toxicity information is eventually reported, rates are based on
numbers of patients evaluable rather than number of patients
enrolled. Many patients, either because of advanced disease and/or
extreme toxicity, are not included in the efficacy analysis.
Most of the trials discussed in this article have been published in
abstract form only, itself a limitation on the amount of information
that can be presented. When several publications appear in the same
year with similar but not identical lists of authors, one cannot be
sure whether two separate trials are being summarized or whether the
same study is being updated with additional patient numbers. Finally,
response duration or length of survival often is not presented,
limiting the value of the information that is included.
Despite these drawbacks, which are fairly typical of preliminary
data, these studies contain some interesting information. They appear
to show a broad range of clinical activity of irinotecan. These
studies leave much room open for further study to discover the
precise diseases in which the drug may be useful and in which combinations.
Several phase I trials hinted that irinotecan has clinical activity
against the lymphomas; these included one complete response in a
patient with previously treated non-Hodgkins lymphoma who
received 500 mg/m² every 3 weeks. Often, such publications
did not provide precise details about disease histology, previous
treatment, response duration, and survival. A few phase II trials,
conducted in Japan, were limited in that they involved patients with
several histologic types and degrees of prior therapy. Two previously
published trials included patients with both non-Hodgkins
lymphoma and Hodgkins disease, and one of these studies also
included patients with acute leukemias. (With regard to the latter
study, the lymphoma patients will be discussed here and the leukemia
patients, in the following section.)
Ohno et al described a series of 29 patients with non-Hodgkins
lymphoma and 3 with Hodgkins disease enrolled at 14 Japanese
institutions between December 1987 and October 1989. This study
population included 3 patients with follicular lymphoma, 2 with
diffuse small-cell lymphoma, 7 with diffuse medium-cell lymphoma, 2
with diffuse mixed large- and small-cell lymphoma, 10 with diffuse
large-cell lymphoma, 4 with lymphoblastic lymphoma, and 1 with an
immunoblastic lymphoma. The Hodgkins disease patients were not
characterized by subtype. Although not specifically mentioned in the
study, it can be assumed that all of the patients were pretreated, as
10 were characterized as primarily refractory and 21 as both relapsed
In the initial treatment phase of the study, patients were randomly
assigned to 200 mg/m² of irinotecan every 3 to 4 weeks (schedule
A) or 40 mg/m² for 5 days every 3 to 4 weeks (schedule B). An
interim analysis showed no response to the first dosing regimen and
early relapses (ie, before recovery of normal hematopoietic cells) in
patients given the second regimen. Subsequent patients, therefore,
were randomized to 40 mg/m² of irinotecan for 3 days every week
(schedule C) or 20 mg/m² twice daily for 7 days every 3 to 4
weeks (schedule D).
Results by histology are detailed in Table
1 and by schedule in Table 2.
Overall response rates were 24% in the non-Hodgkins group
(four complete and three partial responses) and 33% in those with
Hodgkins disease (one partial response in three patients).
Toxicities were predictable, with myelo- suppression, diarrhea,
nausea, vomiting, and anorexia being the most common.
The authors concluded that a single monthly dose of irinotecan was
ineffective for these diseases and that only divided doses given
daily (for 3 or 7 days) produced responses. These conclusions are
consistent with the theoretical notion that a mechanism of action
dependent on cell proliferation would require more frequent dosing.
A follow-up phase II study in lymphoma, conducted by the same group,
was published in 1992. This phase II study enrolled 59 patients
(56 evaluable for toxicity and 51 for efficacy) who were treated with
the prior studys schedule C, 40 mg/m² of irinotecan for 3
days repeated weekly. Again, multiple histologies were included, with
44 patients described as having non-Hodgkins lymphoma, 8 having
adult T-cell leukemia/lymphoma (ATLL), and 4 having Hodgkins
disease. The patients appear to have been heavily pretreated, and had
fairly good Eastern Cooperative Oncology Group (ECOG) performance status.
In the non-Hodgkins group, 8 complete and 15 partial responses
were recorded (44%); no responses were noted in the Hodgkins
group. Interestingly, there was a 50% response rate (four partial
responses) in the ATLL group. The regimen was reasonably well
tolerated in this trial.
The results of this trial were updated by Ota et al in 1994. Of
79 patients with lymphoma, 66 completed treatment. The overall
response rate was 42% (95% confidence interval [CI], 30% to 54%),
including nine complete responses in patients with non-Hodgkins
lymphoma and no responses in the four individuals with Hodgkins
disease. The ATLL subgroup of NHL patients (reported separately in
another publication) had a response rate of 39% (one complete
response, four partial responses).
Irinotecan Combined With Carboplatin
The Japanese study group conducted a phase I/II trial in which
carboplatin (Paraplatin) was added to irinotecan. Irinotecan was
given at a dose of 20 mg/m² for 3 days every week (with dose
escalation planned), and carboplatin dose was fixed at 300 mg/m²
on day 1. The first dose level was declared to be the maximum
tolerated dose (MTD). In the eight patients treated at that level,
the response rate was 25%, which was clearly not superior to the
response rate achieved with irinotecan alone. As a result, the
regimen was not pursued further.
The limited studies conducted to date (Table
3) suggest evidence of irinotecans activity against a
number of lymphoma subtypes, albeit with numbers too small to answer
questions with sufficient statistical power. No trials have examined
the irinotecan dosing regimens currently approved for other diseases
in the United States and Europe. Controlled investigations in
patients with similar lymphoma subtypes and amounts of prior therapy
should clarify the role of irinotecan, alone and in combination, in lymphoma.
1. Mori K, Ohnishi T, Yokoyama K, et al: A phase I study of
irinotecan and infusional cisplatin for advanced non-small-cell lung
cancer. Cancer Chemother Pharmacol 39:327-332, 1997.
2. Abigerges D, Chabot GG, Armand JP, et al: Phase I and
pharmacologic studies of the camptothecin analog irinotecan
administered every 3 weeks in cancer patients. J Clin Oncol
3. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and
pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-1-piperidino)-1-piperidino]
carbonyloxycamptothecin (CPT-11) administered as a ninety-minute
infusion every 3 weeks. Cancer Res 54:427-436, 1994.
4. Taguchi T, Wakui A, Hasegawa K, et al: Phase I clinical study of
CPT-11. Research Group of CPT-11. Jpn J Cancer Chemother 17:115-120, 1990.
5. Clavel M, Extra JM, Abigerges D, et al: French phase I studies of
CPT-11 using 3 different schedules of administration. Ann Oncol
3(suppl 5): 50, 1992.
6. Gandia D, Armand JP, Chabot GG, et al: Phase I study of the new
camptothecin analog CPT-11 administered every 3 wk (abstract). Proc
Am Assoc Cancer Res 33:A1560, 1992.
7. Clavel M, Mathieu-Boue A, Dumortier A, et al: Phase I study of
CPT-11 administered as a daily infusion for 3 consecutive days
(abstract). Proc Am Assoc Cancer Res 33:A1568, 1992.
8. Culine S, de Forni M, Extra JM, et al: Phase I study of the
camptothecin analog CPT-11, using a weekly schedule (abstract). Proc
Am Soc Clin Oncol 11:A263, 1992.
9. Merrouche Y, Extra J-M, Abigerges D, et al: High dose-intensity of
irinotecan administered every 3 weeks in advanced cancer patients: A
feasibility study. J Clin Oncol 15:1080-1086, 1997.
10. Ohno R, Okada K, Masaoka T, et al: An early phase II study of
CPT-11: A new derivative of camptothecin, for the treatment of
leukemia and lymphoma. J Clin Oncol 8:1907-1912, 1990.
11. Tsuda H, Takatsuki K, Ohno R, et al: A late phase II trial of a
potent topoisomerase I inhibitor, CPT-11, in malignant lymphoma
(abstract). Proc Am Soc Clin Oncol 11:316, 1992.
12. Ota K, Ohno R, Shirakawa S, et al: Late phase II clinical study
of irinotecan hydrochloride (CPT-11) in the treatment of malignant
lymphoma and acute leukemia: The CPT-11 Research Group for
Hematological Malignancies. Jpn J Cancer Chemother 21:1047-1055, 1994.
13. Tsuda H, Takatsuki K, Ohno R, el al: Treatment of adult T-cell
leukaemia-lymphoma with irinotecan hydrochloride (CPT-11): CPT-11
Study Group on Hematological Malignancy. Br J Cancer 70:771-774, 1994.
14. Tobinai K, Hotta T, Saito H, et al: Combination phase I/II study
of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or
refractory non-Hodgkins lymphoma: CPT-11/Lymphoma Study Group.
Jpn J Clin Oncol 26:455-460, 1996.
15. Kawato Y, Furuta T, Aonuma M, et al: Antitumor activity of a
camptothecin derivative CPT-11 against human tumor xenografts in nude
mice. Cancer Chemother Pharmacol 28:192-198, 1991.
16. Clavel M, Mathieru-Boue A, Dumortier A, et al: Phase I study of
CPT-11 administered as a daily infusion for 3 consecutive days
(abstract). Proc Am Assoc Cancer Res 33:262, 1992
17. Taguchi T, Yoshida Y, Izuo M, et al: An early phase II study of
CPT-11 (irinotecan hydrochloride) in patients with advanced breast
cancer. Jpn J Cancer Chemother 21:83-90, 1994.
18. Taguchi T, Tominaga T, Ogawa M, et al: A late phase II study of
CPT-11 (irinotecan) in advanced breast cancer: CPT-11 Study Group on
Breast Cancer. Jpn J Cancer Chemother 21:1017-1024, 1994.
19. Bonneterre J, Pion JM, Adenis A, et al: A phase II study of a new
camptothecin analogue CPT-11 in previously treated advanced breast
cancer patients (abstract). Proc Am Soc Clin Oncol 12:94, 1993.
20. Sakata Y, Wakui A, Nakao K, et al: A late phase II study of
irinotecan (CPT-11), in advanced pancreatic cancer (abstract). Proc
Am Soc Clin Oncol 12:211, 1993.
21. Wagener DJ, Verdonk HE, Dirix LY, et al: Phase II trial of CPT-11
in patients with advanced pancreatic cancer: An EORTC early clinical
trials group study. Ann Oncol 6:129-132, 1995.
22. Shimada Y, Rothenberg M, Hilsenbeck SG, et al: Activity of CPT-11
(irinotecan hydrochloride), a topoisomerase I inhibitor, against
human tumor colony-forming units. Anticancer Drug 5:202-206, 1994.
23. Kawato Y, Furuta T, Aonuma M, et al: Antitumor activity of a
camptothecin derivative, CPT-11 against human tumor xenografts in
nude mice. Cancer Chemother Pharmacol 28:192-198, 1991.
24. Takeuchi S, Takamizawa H, Takeda Y, et al: Clinical study of
CPT-11, camptothecin derivative, on gynecological malignancy
(abstract). Proc Am Soc Clin Oncol 10:189, 1991.
25. Takeuchi S, Takamizawa H, Takeda Y, et al: An early phase II
study of CPT-11 in gynecologic cancers: Research Group of CPT-11 in
Gynecologic Cancers. Jpn J Cancer Chemother 18:579-584, 1991.
26. Takeuchi S, Dobashi K, Fujimoto S, et al: A later phase II study
of CPT-11 on uterine cervical cancer and ovarian cancer: Research
Group of CPT-11 in Gynecologic Cancers. Jpn J Cancer Chemother
27. Sugiyama T, Nishida T, Ookura N, et al: Is CPT-11 useful as a
salvage chemotherapy for recurrent ovarian cancer (abstract)? Proc Am
Soc Clin Oncol 16:378a, 1997.
28. Sugiyama T, Nishida T, Kataoka A, et al: Combination of
irinotecan hydrochloride (CPT-11) and cisplatin as a new regimen for
patients with advanced ovarian cancer. Acta Obstet Gynecol Jpn
29. Sugiyama T, Nishida T, Ushijima K, et al: Irinotecan
hydrochloride (CPT-11) combined with cisplatin (CDDP) in patients
with relapsed or metastatic ovarian cancer (abstract). Proc Am Soc
Clin Oncol 15:291, 1996.
30. Shimizu Y, Umezawa S, Hasumi K: Combination of CPT-11 (CPT) with
mitomycin-C (MMC) is active for clear cell adenocarcinoma of the
ovary (OCA) which is intrinsically CDDP-resistant (abstract). Proc Am
Soc Clin Oncol 15:282, 1996.
31. Kajino T, Higuchi M, Hata K, et al: Combination therapy with
irinotecan and CBDCA for patients in terminal stage of ovarian
carcinoma. Jpn J Cancer Chemother 23:115-117, 1996.
32. Negoro S, Fukuoka M, Niitani H, et al: Phase II study of CPT-11,
new camptothecin derivative, in small-cell lung cancer (SCLC)
(abstract). Proc Am Soc Clin Oncol 10:241, 1991.
33. Negoro S, Fukuoka M, Niitani H, et al: A phase II study of
CPT-11, a camptothecin derivative, in patients with primary lung
cancer: CPT-11 Cooperative Study Group. Jpn J Cancer Chemother
34. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative
of camptothecin for the treatment of refractory or relapsed
small-cell lung cancer. J Clin Oncol 10:1225-1229, 1992.
35. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly
intravenous infusions of CPT-11, a new derivative of camptothecin, in
the treatment of advanced non-small-cell lung cancer. J Natl Cancer
Inst 83:1164-1168, 1991.
36. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study of
CPT-11, a new derivative of camptothecin, for previously untreated
non-small-cell lung cancer. J Clin Oncol 10:16-20, 1992.
37. Le Chevalier T, Ibrahim N, Chomy P, et al.: A phase II study of
irinotecan (CPT-11) in patients (pts) with small-cell lung cancer
(SCLC) progressing after initial response to first-line chemotherapy
(CT) (abstract). Proc Am Soc Clin Oncol 16:450a, 1997.
38. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of irinotecan
(CPT-11) and etoposide (E) with G-CSF in advanced lung cancer
(abstract). Proc Am Soc Clin Oncol 12:A331, 1993.
39. Fujiwara Y, Yamakido M, Fukuoka M, et al: Phase II study of
irinotecan (CPT-11) and cisplatin (CDDP) in patients with small-cell
lung cancer (SCLC) (abstract). Proc Am Soc Clin Oncol 13:335, 1994.