Ovarian cancer is the second most common gynecologic
malignancy, accounting for approximately 23,400 cases annually in the United
States. Although it is only the fifth most common cancer among women in the
United States, its importance is far out of proportion to its incidence because
it is the most lethal of gynecologic cancers. Approximately 13,900 women die
from ovarian cancer annually in the United States.
Because no effective screening method exists for ovarian cancer, more than
70% of women are diagnosed when the cancer has already spread beyond the ovary.
Standard treatment for the majority of patients with epithelial ovarian cancer
consists of primary surgery followed by platinum-based chemotherapy. The current
standard regimen is the combination of paclitaxel and carboplatin
Survival rates for patients with stage III and IV epithelial ovarian cancer
are approximately 15% to 20% and less than 5%, respectively. Therefore, more
than 60% of patients with ovarian cancer, regardless of stage, and more than 80%
of those with advanced-stage epithelial ovarian cancer, will have disease
relapse following primary treatment. In general, recurrent ovarian cancer is
incurable, partly because of the relative inefficacy of salvage therapy.
Patients with recurrent ovarian cancer are not a homogeneous group. To date,
the probabilities of responsiveness and outcome are related to a variety of
clinicopathologic factors. One of the strongest predictive factors is the length
of time from completion of primary chemotherapy to relapse.[3-6] This
observation has led to definitions of platinum sensitivity and platinum
Currently, conventional chemotherapeutic agents constitute the predominant
option for secondary therapy. However, in the setting of platinum-resistant
ovarian cancer, response rates associated with the most active agents, including
topotecan (Hycamtin),[8-10] liposomal doxorubicin (Doxil),[11,12] gemcitabine
(Gemzar),[13,14] vinorelbine (Navelbine),[15-17] and oral etoposide, range
from 15% to 25%. Most responses are partial and not durable. Therefore, a
concerted effort to identify new active agentsboth chemotherapeutic and
nonchemotherapeuticagainst epithelial ovarian cancer is justified.
Irinotecan is a derivative of camptothecin and belongs to a class of
chemotherapeutic agents that inhibit topoisomerase I. Topoisomerase I is a
protein with enzymatic activity that relaxes supercoiled double-strand DNA,
thereby permitting DNA replication and RNA transcription. Clinical
development of irinotecan began in Japan in the 1980s. Subsequent preclinical
studies demonstrated that it had antitumor activity in ovarian cancer.[20-23] O’Meara
and Sevin found that the median effective doses of irinotecan were significantly
lower than clinically achievable peak plasma concentrations in 7 of 12 fresh
ovarian carcinoma specimens, and 11 of 12 specimens showed sensitivity to the
active metabolite SN-38.
Early clinical trials of irinotecan in ovarian cancer patients were conducted
almost exclusively in Japan. In 1991, Takeuchi et al reported results of a phase
II trial of irinotecan in 15 patients with recurrent ovarian cancer. Three
drug schedules were used, including 100 mg/m² weekly, 150 mg/m² every 2 weeks,
and 200 mg/m² every 3 to 4 weeks. The authors reported one complete response and
two partial responses, for an overall response rate of 20%. Significant
toxicities were reported among the 30 patients in the study, which also included
cervical and uterine cancer patients. Leukopenia occurred in 30% of patients,
anemia in 20%, and nausea and vomiting in 13%. Subsequently, the same
researchers reported results of a late phase II study in which 55 patients with
ovarian cancer received irinotecan in one of two schedules: 100 mg/m² weekly
(regimen I) or 150 mg/m² every 2 weeks (regimen II). Thirteen partial
responses were observed, for a response rate of 24%. A total of 24% of patients
receiving regimen I and 14% receiving regimen II responded. Major toxicities
again included leukopenia in 57%, anemia in 25%, and diarrhea in 19% of
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA
Cancer J Clin 51:15-36, 2001.
2. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of
cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III
epithelial ovarian cancer: A Gynecologic Oncology Group trial (abstract). Proc
Am Soc Clin Oncol 18:1373a, 1999.
3. Blackledge G, Lawton F, Redman C, et al: Response of patients in phase II
studies of chemotherapy in ovarian cancer: Implications for patient treatment
and the design of phase II trials. Br J Cancer 59:650-653, 1989.
4. Gershenson DM, Kavanagh JJ, Copeland LJ, et al: Re-treatment of patients
with recurrent epithelial ovarian cancer with cisplatin-based chemotherapy.
Obstet Gynecol 73:798-802, 1989.
5. Markman M, Reichman B, Hakes T, et al: Responses to second-line
cisplatin-based intraperitoneal therapy in ovarian cancer: Influence of a prior
response to intravenous cisplatin. J Clin Oncol 9:1801-1805, 1991.
6. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of
the ovary with cisplatin or carboplatin following initial treatment with these
compounds. Gynecol Oncol 36:207-211, 1990.
7. Markman M, Hoskins W: Responses to salvage chemotherapy in ovarian cancer:
A critical need for precise definitions of the treated population (editorial). J
Clin Oncol 10:513-514, 1992.
8. Kudelka AP, Tresukosol D, Edwards CL, et al: Phase II study of intravenous
topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J
Clin Oncol 14:1552-1557, 1996.
9. Creemers GJ, Bolis G, Gore M, et al: Topotecan, an active drug in the
second-line treatment of epithelial ovarian cancer: Results of a large European
phase II study. J Clin Oncol 14:3056-3061, 1996.
10. Swisher EM, Mutch DG, Rader JS, et al: Topotecan in platinum- and
paclitaxel-resistant ovarian cancer. Gynecol Oncol 66:480-486, 1997.
11. Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal
doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity
modification by liposomal encapsulation. J Clin Oncol 15:987-993, 1997.
12. Gordon AN, Granai CO, Rose PG, et al: Phase II study of liposomal
doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J
Clin Oncol 18:3093-3100, 2000.
13. Friedlander M, Millward MJ, Bell D, et al: A phase II study of
gemcitabine in platinum pre-treated patients with advanced epithelial ovarian
cancer. Ann Oncol 9:1343-1345, 1998.
14. Lund B, Hansen OP, Theilade K, et al: Phase II study of gemcitabine
(2´,2´-difluorodeoxycytidine) in previously treated ovarian cancer patients. J
Natl Cancer Inst 86:1530-1533, 1994.
15. Bajetta E, Di Leo A, Biganzol L, et al: Phase II study of vinorelbine in
patients with pretreated advanced ovarian cancer: Activity in platinum-resistant
disease. J Clin Oncol 14:2546-2551, 1996.
16. Gershenson DM, Burke TW, Morris M, et al: A phase I study of a daily × 3
schedule of intravenous vinorelbine for refractory epithelial ovarian cancer.
Gynecol Oncol 70:404-409, 1998.
17. Burger RA, DiSaia PJ, Roberts JA, et al: Phase II trial of vinorelbine in
recurrent and progressive epithelial ovarian cancer. Gynecol Oncol 72:148-153,
18. Rose PG, Blessing JA, Mayer AR, et al: Prolonged oral etoposide as
second-line therapy for platinum-resistant and platinum-sensitive ovarian
carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 16(2):405-410, 1998.
19. Zhang H, Wang JC, Liu LF: Involvement of DNA topoisomerase I in
transcription of human ribosomal RNA genes. Proc Natl Acad Sci USA 85:1060-1064,
20. Jansen WJM, Kolfschoten GM, Erkelens CAM, et al: Anti-tumor activity of
CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. Int J
Cancer 73:891-896, 1997.
21. Kano Y, Akutsu M, Tsunoda S, et al: In vitro schedule-dependent
interaction between paclitaxel and SN-38 (the active metabolite of irinotecan)
in human carcinoma cell lines. Cancer Chemother Pharmacol 42:91-98, 1998.
22. O’Meara AT, Sevin BU: In vitro sensitivity of fresh ovarian carcinoma
specimens to CPT-11 (irinotecan). Gynecol Oncol 72:143-147, 1999.
23. Jonsson E, Dhar S, Jonsson B, et al: Differential activity of topotecan,
irinotecan and SN-38 in fresh human tumour cells but not in cell lines. Eur J
Cancer 36:2120-2127, 2000.
24. Takeuchi S, Takamizawa Y, Takeda Y, et al: An early phase II study of
CPT-11 for gynecologic cancer. Gan To Kagaku Ryoho (Jpn J Cancer Chemother)
25. Takeuchi S, Dobashi K, Fujimoto S, et al: A late phase II study of CPT-11
on uterine cervical cancer and ovarian cancer. Gan To Kagaku Ryoho (Jpn J Cancer
Chemother) 18:1681-1689, 1991b.
26. Sugiyama T, Nishida T, Ookura N, et al: Is CPT-11 useful as a salvage
chemotherapy for recurrent ovarian cancer? Proc Am Soc Clin Oncol 16:378a, 1997.
27. Bodurka-Bevers D, Levenback C, Wolf J, et al: A phase II trial of
irinotecan (CPT-11) in patients with metastatic epithelial ovarian cancer (EOC)
or peritoneal cancer (PC). Proc Am Soc Clin Oncol 20:217a, 2001.
28. Shimizu Y, Umezawa S, Hasumi K: Successful treatment of clear cell
adenocarcinoma of the ovary (OCCA) with a combination of CPT-11 and mitomycin.
Gan To Kagaku Ryoho (Jpn J Cancer Chemother) 5:587-593, 1996.
29. Adachi S, Ogasawara T, Yamasaki N, et al: A pilot study of CPT-11 and
cisplatin for ovarian clear cell adenocarcinoma. Jpn J Clin Oncol 29:434-437,
30. Sugiyama T, Yakushiji M, Nishida T, et al: Irinotecan (CPT-11) combined
with cisplatin in patients with refractory or recurrent ovarian cancer. Cancer
Lett 128:211-218, 1998.
31. Kigawa J, Takahashi M, Minagawa Y, et al: Topoisomerase-I activity and
response to second-line chemotherapy consisting of camptothecin-11 and cisplatin
in patients with ovarian cancer. Int J Cancer 84:521-524, 1999.