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(Drug information on paclitaxel) and carboplatin(Drug information on carboplatin) (Paraplatin).
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 resistance.
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(Drug information on doxorubicin) (Doxil),[11,12] gemcitabine(Drug information on gemcitabine) (Gemzar),[13,14] vinorelbine (Navelbine),[15-17] and oral etoposide(Drug information on 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(Drug information on 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 patients.