Researchers in Recurrent/Resistant Epithelial Ovarian Cancer Test Irinotecan

HOUSTON, Texas—David M. Gershenson, MD, painted a bleak picture of current treatment for advanced ovarian cancer and suggested that new agents such as topoisomerase inhibitors should be studied further in clinical trials. Dr. Gershenson said that although CA-125 and transvaginal ultrasound are used for screening, they have limited efficacy, with the result that over 70% of ovarian cancers have already spread beyond the ovary by the time they are detected.

"These advanced stages have an 80% to 90% response rate to current therapy, but they nearly all relapse, and 5-year survival is only about 15%," he said. He is professor and chairman of the Department of Gynecologic Oncology at the University of Texas M. D. Anderson Cancer Center in Houston, Texas.

Dr. Gershenson updated the data from a phase II, single-agent irinotecan (Camptosar) trial he presented earlier this year at the American Society for Clinical Oncology (ASCO) annual meeting. This protocol evaluated the efficacy of irinotecan in patients who had recurrent epithelial ovarian cancer.

"We found that irinotecan has moderate activity and acceptable toxicity in patients with epithelial ovarian cancer. Response rates were well within the range reported for the commonly accepted drugs used for refractory ovarian cancer," Dr. Gershenson reported.

Followed Japanese Studies

"There is a suggestion from Japanese studies that a weekly schedule might be more effective than biweekly or every three weeks schedules, but none of these ideas have been tested in randomized trials in ovarian cancer. Clearly, we need to pursue the use of irinotecan, and we need confirmatory and well-controlled trials," Dr. Gershenson said.

The M. D. Anderson trial followed a number of small Japanese phase II studies. The first was a phase II trial of 15 patients with recurrent ovarian cancer that reported a 20% response rate including one complete response (CR). The major toxicities were leukopenia, anemia, and nausea and vomiting. A subsequent study from the same research group included 55 ovarian cancer patients treated either with irinotecan 100 mg/m² weekly or 150 mg/m² every 2 weeks. Partial responses occurred in 13 of 55 patients (23.6%). "There was a suggestion that the response rate was better for the weekly schedule, 24% vs 14% for the biweekly schedule," Dr. Gershenson said. The major toxicities were leukopenia (57%), anemia (25%), and diarrhea (19%).

Dr. Gershenson said that irinotecan has also produced promising results in chemo-resistant clear-cell cancers when combined with intraperitoneal mitomycin-C (Mutamycin) or with intraperitoneal cisplatin (Platinol) in pilot studies.

M. D. Anderson Protocol

The M. D. Anderson phase II trial included 31 women with metastatic, platinum-resistant epithelial ovarian cancer (n=30) or primary peritoneal cancer (n=1). "All patients had either progressed on first-line chemotherapy, which typically included paclitaxel (Taxol) and carboplatin (Paraplatin), or had progressed within 6 months of completion of platinum-based chemotherapy," Dr. Gershenson said. Patients could have had only one prior chemotherapy regimen.

The starting dose was irinotecan 300 mg/m² given intravenously over 90 minutes every 3 weeks. The minus-one dose level was 250 mg/m², and all elderly patients were started at this dose level.

Twenty-one of 31 patients had papillary serous carcinomas. The median age was 57 with a range of 38 to 74 years of age. Dr. Gershenson said that 29 patients are now evaluable for both response and toxicity. Two patients dropped out because of severe diarrhea after one cycle of therapy and were evaluable for toxicity only.

"Using intent-to-treat analysis, we found that 5 of 31 patients responded, or 16%. If we look at just the 29 patients who were evaluable for response, the response rate was 17%. All except one of these were partial responses," Dr. Gershenson said. "This certainly falls within the range of acceptable efficacy for other drugs used in refractory ovarian cancer, including topotecan (Hycamtin), gemcitabine (Gemzar), docetaxel (Taxotere), and oral etoposide (VePesid)."

CA-125 Levels Are Reduced

Twenty-two patients had elevated CA-125 tumor marker levels at the beginning of chemotherapy, and irinotecan treatment reduced CA-125 levels by at least 50% in 7 of these patients. "There was also a very high rate of stable disease, almost 50%," Dr. Gershenson said.

Duration of response ranged from 5 to 44 weeks, and duration of stable disease ranged from 6 to 43 weeks. "We have completed accrual on this study, but one patient is still receiving treatment. She is a partial responder at more than 5 weeks," Dr. Gershenson said.

Dose reductions were required in 16/31 patients (52%). Six were elderly patients who were started at the lower level, and 10 had reductions due to toxicity.

Dose limiting toxicities were diarrhea, nausea and vomiting, and leukopenia. "All patients had alopecia. Sixteen had grade 3 fatigue. Two had neutropenic fevers. Grade 3 or 4 diarrhea occurred in 29% of the patients. About one third had grade 3 nausea, and about 10% had grade 3 vomiting, but this regimen was reasonably well tolerated," Dr. Gershenson said. He emphasized that confirmatory, well-controlled trials are needed.