Topotecan/Doxil Studied as Second-Line Ovarian Cancer Therapy

NEW YORK—Liposomal doxorubicin (Doxil) may be essentially equivalent to topotecan (Hycamtin) as second-line therapy for ovarian cancer, but the combination of the two may have more promise than either agent alone, according to preliminary results of a phase I study.

Franco Muggia, MD, director of medical oncology, New York University (NYU) School of Medicine, reported results suggesting that some patients have "very long responses" on liposomal doxorubicin plus topotecan. "From our preliminary results, one might expect that the response rates with the combination will exceed those of either drug alone," he said at the Chemotherapy Foundation Symposium XIX (abstract 31).

Liposomal doxorubicin alone has been characterized in a large, randomized trial as a suitable treatment option in recurrent epithelial ovarian carcinoma. This is because of its favorable safety profile, convenient dosing, and efficacy comparable to topotecan, which has been studied extensively in recurrent disease.

Similar Response Rates

In this phase III study of 474 patients with recurrent epithelial ovarian carcinoma, the two agents showed similar overall response rates and median overall survival times. Liposomal doxorubicin was superior to topotecan in overall survival time (median, 108 weeks vs 71.1 weeks, P = .008), while there was a survival trend in favor of topotecan for the platinum-refractory patients (Gordon AN et al: J Clin Oncol 19:3312-3322, 2001).

Several points about the study are interesting in light of ongoing investigations looking at dual-topoisomerase inhibition in the second-line setting.

Dr. Muggia noted that both topotecan and liposomal doxorubicin have response rates over 25% in platinum-sensitive patients. The curves for progression-free survival and overall survival for the two agents vary, despite similar medians. This fact suggests that continued therapy with liposomal doxorubicin might improve the two extremes of the survival curves, he said.

Liposomal doxorubicin may have an advantage over topotecan in platinum-sensitive patients, as shown in the phase III trial results.

The two agents have nonoverlapping toxicities (major dose-limiting toxicities are myelosuppression for topotecan, and skin toxicity and mucositis for liposomal doxorubicin). "The lack of neurotoxicity could render the combination an attractive regimen to develop for second-line therapy," Dr. Muggia said.

The NYU Study

In the 20-patient phase I study at NYU, liposomal doxorubicin was given at one of two intravenous doses every 28 days along with 14 to 21 days of topotecan as a continuous, low-dose infusion (oral topotecan was used later).

For seven patients who received intravenous liposomal doxorubicin plus intravenous topotecan, there were two complete responses and one partial response, while three patients had prolonged stable disease (greater than 6 months).

Among the 13 patients who received intravenous liposomal doxorubicin and oral topotecan, there was one partial response and six patients who had stable disease for 6 months or more (median, 11.5 months). All of the responding
patients were platinum resistant, Dr. Muggia reported.

Dose-limiting toxicities included neutropenia and thrombocytopenia. The recommended phase II dose was topotecan 0.4 mg/m² for 14 days plus liposomal doxorubicin 40 mg/m² every 28 days. Some patients had unacceptable gastrointestinal toxicity on oral topotecan, Dr. Muggia said.

Future phase III trials must specifically address whether a liposomal doxorubicin-topotecan combination would have an advantage over other combinations or sequential single agents, he added.