Irinotecan in Epithelial Ovarian Cancer

ABSTRACT: Ovarian cancer, the second most common gynecologic malignancy, accounts for approximately 14,000 deaths annually in the United States. Disease relapse after primary treatment, which consists mainly of surgery followed by platinum-based therapy, occurs in more than 60% of ovarian cancer patients overall, and in more than 80% of those diagnosed initially with advanced-stage disease. Responses to second-line chemotherapy agents range from 15% to 25%, and are usually partial responses of short duration. Irinotecan (CPT-11, Camptosar), a camptothecin derivative that inhibits topoisomerase I, is undergoing assessment for the treatment of ovarian cancer. Preclinical studies demonstrated antitumor activity in ovarian cancer. Early phase I or II trials showed response rates of 20% to 25% in patients with recurrent or refractory disease, with some responses noted in the relatively chemoresistant mucinous and clear cell tumors. Irinotecan has also been studied in combination regimens, most commonly irinotecan plus cisplatin. In a phase II trial of irinotecan plus cisplatin in platinum-sensitive or -resistant patients, response rates were 75% and 33%, respectively. Irinotecan seems to be relatively well tolerated; dose-limiting toxicities appear to be diarrhea, nausea and vomiting, and leukopenia/neutropenia. [ONCOLOGY 16(Suppl 5):29-31, 2002]

Ovarian cancer is the second most common gynecologicmalignancy, accounting for approximately 23,400 cases annually in the UnitedStates.[1] Although it is only the fifth most common cancer among women in theUnited States, its importance is far out of proportion to its incidence becauseit is the most lethal of gynecologic cancers. Approximately 13,900 women diefrom ovarian cancer annually in the United States.[1]

Because no effective screening method exists for ovarian cancer, more than70% of women are diagnosed when the cancer has already spread beyond the ovary.Standard treatment for the majority of patients with epithelial ovarian cancerconsists of primary surgery followed by platinum-based chemotherapy. The currentstandard regimen is the combination of paclitaxel and carboplatin(Paraplatin).[2]

Survival rates for patients with stage III and IV epithelial ovarian cancerare approximately 15% to 20% and less than 5%, respectively. Therefore, morethan 60% of patients with ovarian cancer, regardless of stage, and more than 80%of those with advanced-stage epithelial ovarian cancer, will have diseaserelapse following primary treatment. In general, recurrent ovarian cancer isincurable, 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 ofclinicopathologic factors. One of the strongest predictive factors is the lengthof time from completion of primary chemotherapy to relapse.[3-6] Thisobservation has led to definitions of platinum sensitivity and platinumresistance.[7]

Currently, conventional chemotherapeutic agents constitute the predominantoption for secondary therapy. However, in the setting of platinum-resistantovarian cancer, response rates associated with the most active agents, includingtopotecan (Hycamtin),[8-10] liposomal doxorubicin (Doxil),[11,12] gemcitabine(Gemzar),[13,14] vinorelbine (Navelbine),[15-17] and oral etoposide,[18] rangefrom 15% to 25%. Most responses are partial and not durable. Therefore, aconcerted effort to identify new active agents—both chemotherapeutic andnonchemotherapeutic—against epithelial ovarian cancer is justified.

Irinotecan Chemotherapy in Ovarian Cancer

Irinotecan is a derivative of camptothecin and belongs to a class ofchemotherapeutic agents that inhibit topoisomerase I. Topoisomerase I is aprotein with enzymatic activity that relaxes supercoiled double-strand DNA,thereby permitting DNA replication and RNA transcription.[19] Clinicaldevelopment of irinotecan began in Japan in the 1980s. Subsequent preclinicalstudies demonstrated that it had antitumor activity in ovarian cancer.[20-23] O’Mearaand Sevin found that the median effective doses of irinotecan were significantlylower than clinically achievable peak plasma concentrations in 7 of 12 freshovarian carcinoma specimens, and 11 of 12 specimens showed sensitivity to theactive metabolite SN-38.[22]

Single-Agent Irinotecan Studies

Early clinical trials of irinotecan in ovarian cancer patients were conductedalmost exclusively in Japan. In 1991, Takeuchi et al reported results of a phaseII trial of irinotecan in 15 patients with recurrent ovarian cancer.[24] Threedrug 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 andtwo partial responses, for an overall response rate of 20%. Significanttoxicities were reported among the 30 patients in the study, which also includedcervical and uterine cancer patients. Leukopenia occurred in 30% of patients,anemia in 20%, and nausea and vomiting in 13%. Subsequently, the sameresearchers reported results of a late phase II study in which 55 patients withovarian cancer received irinotecan in one of two schedules: 100 mg/m² weekly(regimen I) or 150 mg/m² every 2 weeks (regimen II).[25] Thirteen partialresponses were observed, for a response rate of 24%. A total of 24% of patientsreceiving regimen I and 14% receiving regimen II responded. Major toxicitiesagain included leukopenia in 57%, anemia in 25%, and diarrhea in 19% ofpatients.

At the American Society of Clinical Oncology annual meeting in 1997, Sugiyamaand colleagues reported results of a phase II study of irinotecan in 52 patientswith refractory ovarian cancer.[26] Patients were randomly assigned to one oftwo dose schedules: 100 mg/m² weekly (regimen I, 27 patients) or 150 mg/m² every2 weeks (regimen II, 25 patients). Response rates were 29.6% for regimen I and16% for regimen II. The authors noted that responses occurred among patientswith mucinous and clear cell tumors, which are known to be relativelychemoresistant. The dose-limiting toxicity was leukopenia, which was observed in57% of patients. Grade 3 or worse diarrhea was noted in 19.2% of patients.

A phase II study of irinotecan alone in patients with platinum-resistantepithelial ovarian cancer was presented at the American Society of ClinicalOncology annual meeting in 2001.[27] That study has now been completed, and amanuscript has been submitted for publication.

Irinotecan in Combination Chemotherapy for Ovarian Cancer

Irinotecan has also been studied in combination with other chemotherapy drugsin ovarian cancer patients. Shimizu et al reported results of a trial ofirinotecan plus mitomycin (Mutamycin) in 10 patients with newly diagnosed clearcell cancer of the ovary.[28] Irinotecan at 140 mg/m² was administered on days1, 15, and 29, and mitomycin at 7 mg/m² intraperitoneally (IP) on days 1, 15,and 29. Treatment cycles were repeated every 4 weeks. The authors observed a 60%response rate in this chemoresistant tumor type, with four complete respondersand two partial responders.

The most commonly studied irinotecan combination has been irinotecan pluscisplatin. Adachi et al conducted a phase II study of irinotecan plus cisplatinin 10 patients with newly diagnosed clear cell cancer of the ovary.[29] Dosesincluded irinotecan at 60 mg/m² on days 1, 8, and 15, and cisplatin at 70mg/m²IV on day 1 (three patients) or 75 mg/m² IP on day 1 (seven patients). Theoverall response rate was 20%, with one complete response and one partialresponse. Toxicities included grade 3 leukopenia in 70% and grade 3 diarrhea in10% of patients.

Sugiyama et al reported results of a phase II trial in which 25 patients withrecurrent ovarian cancer received the irinotecan/cisplatin combination.[30]Doses were irinotecan at 50 to 60 mg/m² on days 1, 8, and 15, and cisplatin at50 to 60 mg/m² on day 1. Four of the 25 patients were platinum-sensitive and 21were platinum-resistant. The overall response rate was 40%, with a completeresponse rate of 8%. When subgroups were considered, the response rate forplatinum-sensitive patients was 75%, and the response rate forplatinum-resistant patients was 33%. Again, the authors noted patients withclear cell or mucinous tumors among responders. The median duration of responsewas 5.5 months. Grade 3 or 4 neutropenia was observed in 55% of cycles and 64%of patients, and grade 3 or 4 diarrhea was noted in only 3% of cycles and 4% ofpatients.

In another study of the irinotecan/cisplatin combination, 30 patients withrecurrent ovarian cancer received irinotecan at 50 to 60 mg/m² on days 1, 8, and15, and cisplatin at 60 mg/m² on day 1.[31] The response rate was 60%, with twocomplete responses and 16 partial responses. The study included 12platinum-sensitive and 18 platinum-resistant patients. Apparently, the responserate was 60% in both subgroups.

Conclusion

In summary, irinotecan has moderate activity and acceptable toxicity inpatients with recurrent epithelial ovarian cancer. Although data suggest thatthe weekly irinotecan schedule is associated with a superior response ratecompared with the other schedules, no randomized data are available to supportthis. Other well-designed confirmatory trials of irinotecan are needed.Dose-limiting toxicities appear to be diarrhea, nausea and vomiting, andleukopenia/neutropenia. However, the bone marrow toxicity of irinotecan appearsto be significantly less than that associated with topotecan. Furthermore,gastrointestinal effects have been tolerable for most patients when managed witha combination of supportive care and dose reduction.

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