A Phase II Study of Weekly Docetaxel and Topotecan in Patients With Platinum-Resistant, Recurrent Epithelial Ovarian Cancer

Each year more than 28,000 women are diagnosed with epithelial ovarian cancer (EOC). Over 70% of these women will present with advanced (stage III, IV) disease. The current treatment for newly diagnosed advanced EOC involves cytoreductive surgery followed by chemotherapy. The standard chemotherapy in the primary setting is a combination of a taxane; either paclitaxel or docetaxel and a platinum agent; either cisplatin or carboplatin. Although high initial responses are seen with these primary therapies, most will recur. Salvage chemotherapy thus becomes the mainstay of treatment for many patients with this disease. The goals of salvage therapy are to maximize tumor response while maintaining quality of life with minimal toxicity. As a consequence, there are a number of agents that have been studied in this recurrent setting with significant antitumor activity. Two such novel agents, topotecan and docetaxel are the basis of this phase I, II study.

Patients can be grouped into prognostic categories based on their responses to primary therapy. Those with persistent disease or recurrence within 6 months of treatment are deemed platinum resistant and those achieving a greater than 6 month progression free interval are deemed platinum sensitive. This distinction is important because those that are platinum sensitive have an improved overall survival and higher response rates to salvage chemotherapy. The magnitude of this response increases with an increasing progression free interval. The response of these patients to reintroducing either platinum or paclitaxel has been established. Thigpen et. al. showed a 44% overall response rate(ORR) to paclitaxel infused over 24 hours in 16 patients with a platinum free interval of greater than or equal to 6 months. Kavanagh et. al. demonstrated a 21% partial response rate (PR) to the reintroduction of carboplatin after taxane treatment in 26 patients with a 12-month platinum-free intraval following platinum-refractory ovarian cancer.

Topotecan has been shown to have similar activity as paclitaxel as a second line therapy with non-cross resistance. Topotecan is usually administered in a daily infusion over 30 minutes in doses of 1.5 mg/m2/d x 5 consecutive days every 21 days. In an effort to decrease toxicity and maintain response rates, weekly schedules of topotecan have been explored. Homesley et. al. conducted a phase I trial with single agent weekly topotecan evaluating dosages from 1.5 to 6 mg/m2/wk. The recommended phase II dosage for weekly topotecan was determined to be 4 mg/m2/wk. Dose limiting toxicities consisted of 70 non-hematologic events in 32 of 35 evaluable patients, primarily consisting of grade 1 or 2 chronic fatigue (16%) and gastrointestinal (nausea and vomiting [23%]) with the majority (80%) being grade 1 in severity. Dose limiting myelotoxicity and thrombocytopenia were not an issue at the weekly dosages evaluated in this trial. Morris and colleagues at Wayne State University are currently studying weekly topotecan in platinum sensitive patients and have reported a 40% partial response rate with 35% having stable disease. Myelotoxicity was infrequent and included grade 3 or 4 neutropenia in 1.1% and grade 3 anemia in 1.8%. Nonhematologic toxicity included grade 3 fatigue in 17% of patients.

Abu-Rustum et. al. conducted a phase I trial of weekly paclitaxel (60 -100 mg/m2 over 1-hour) in platinum resistant patients (n = 18 patients, recommended phase II dose 80 mg/mg/wk). Dose limiting toxicity was defined as two or more patients with treatment delay or grade 3 toxicity at the same dose level. Treatment was delayed in 2 of 3 patients at the 100 mg/m2 dose level due to ANC < 1500. In addition they reviewed Memorial Sloan Kettering's previous data with weekly paclitaxel (60 to 100 mg/m2/wk) in platinum resistant patients and found an overall response rate (either documented tumor shrinkage or decrease in serum CA-125 levels) of 28% (ORR in 13 of 45 patients). In a follow up phase II trial, Markman et. al. reported a 25% objective response rate in 13 of 51 platinum resistant patients (4 by decreasing CA-125 and 9 by 50% reduction in tumor volume). Only 1% (13 of 887 dosages) required a dose modification due to toxicity with weekly paclitaxel at 80 mg/m2/wk. Weekly paclitaxel is an active second-line regimen and is generally well tolerated.

In advanced, platinum-refractory ovarian cancer, docetaxel administered every 3 weeks has demonstrated substantial single-agent efficacy with response rates ranging from 24% to 40% and an overall survival of 8 to 10.4 months. Neutropenia was the predominant Grade 3 /4 toxicity, followed by fluid retention, hypersensitivity reactions and diarrhea.