New Strategies for Treating Ovarian Cancer

NEW YORK—Two new strategies for treating advanced ovarian cancer may improve the outlook for this difficult to treat disease. Early data from trials of repeating and sequential doublets of cisplatin (Platinol)-based drug combinations have shown encouraging results, according to presentations at the Chemotherapy Foundation Symposium XVII.

Robert A. Nagourney, MD, adjunct associate professor, University of California, Irvine, and medical and laboratory director, Rational Therapeutics Inc., Long Beach, California, reported on trials of gemcitabine (Gemzar) and cisplatin delivered in repeating doublets in women with relapsed ovarian cancer. Gemcitabine has been shown to be active against ovarian cancer, with a 20% response rate in patients with advanced disease when used as a single agent.

Using the Ex Vivo Apoptotic (EVA) assay, designed to measure drug-induced cell death in tumor cells, Dr. Nagourney’s group selected 24 heavily pretreated and drug-refractory ovarian cancer patients with tumors sensitive to the gemcitabine and cisplatin combination. They received cisplatin 30 mg/m² plus gemcitabine 600 to 750 mg/m² administered on days 1 and 8, with cycles repeated every 21 days.

Dr. Nagourney reported that objective responses were observed in 12 of the 24 patients, with 7 (29%) achieving a complete response and 5 (21%) a partial response. Stable disease was seen in 4 patients (17%). The duration of response ranged from 1 to 17 months, with a median of 9 months.

Dr. Nagourney called the regimen both tolerable and active, even in women for whom single-agent therapy with cisplatin or gemcitabine had failed. As such, he said, “it is an attractive alternative to current regimens.” A phase II trial of the regimen is ongoing, he added.

Sequential Doublets

Despite high initial response rates, advanced epithelial ovarian cancer is subject to rapid relapse. Even with the addition of paclitaxel (Taxol) to platinum-based chemotherapy, the cure rate is in the single digits, Paul J. Hoskins, MD, clinical assistant professor, British Columbia Cancer Agency, Vancouver, said at the symposium.

Dr. Hoskins reported on attempts to improve on the outcome of first-line cisplatin/paclitaxel therapy with the addition of a sequential doublet of cisplatin/topotecan (Hycamtin). “Giving the three drugs together,” Dr. Hoskins said, “causes significant myelotoxicity, and strategies to avoid that, including the use of G-CSF [Neupogen], are themselves problematic.”

In a study of 44 previously untreated women with advanced epithelial ovarian cancer, 50 mg/m² of cisplatin was given on day 1, followed by topotecan 0.75

mg/m2 on days 1 through 5. Patients received four 21-day cycles. That sequence was followed by 135 mg/m² of paclitaxel given over 24 hours on day 1 and 75 mg/m² of cisplatin on day 2; again there were four 21-day cycles.

Dr. Hoskins explained that the sequencing of the individual chemotherapy agents within the doublets was crucial. Cisplatin given before topotecan is synergistic, although it is more myelotoxic. Paclitaxel given before cisplatin is more active than the reverse order.

The response rate was based on CT scanning. Of 37 evaluable patients, 62% showed a response after the first sequence and 78% after completion of the total regimen. Progression over the total regimen was seen in 5% of 41 patients evaluable for progression. Median time to progression was 16 months.

“Nonhematologic toxicity was minimal. Myelotoxicity was high, but of short duration,” Dr. Hoskins said. Because the myelotoxicity was noncumulative, it did not prevent treatment delivery.

Based on these encouraging results, the National Cancer Institute of Canada is planning a phase III study with a slightly modified regimen, replacing cisplatin with carboplatin (Paraplatin) in the second (paclitaxel) sequence and using a paclitaxel dose of 175 mg/m² given over 3 hours.