Dose Finding Study for Combination Treatment with Topotecan and Gemcitabine of Patients with Recurrent Ovarian Cancer after Failure of First-Line Chemotherapy with Paclitaxel and Platinum

Abstract

Objective: Topotecan and gemcitabine have shown mono-activity against different solid tumors including recurrent ovarian cancer after failure of platinum- and paclitaxel-containing therapies. Both drugs affect DNA replication, topotecan additionally inhibits the DNA repair process. Efficacy profiles and different mechanisms of action make the combination of both drugs a promising regimen. Therefore the following dose-finding study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of this combination. Based on the monotherapy schedules topotecan was given on day 1–5, and gemcitabine on day 1 + 8 every 21 days. Patients and Methods: Patients with histologically proven ovarian cancer who relapsed after platinum- and paclitaxel-containing therapy were enrolled. 3 different dose levels were investigated. No individual dose escalation or primary use of cytokines were allowed. Results: 23 patients were enrolled, 50% were pretreated with at least 2 platinum-containing therapies; 80 courses were analyzed for toxicity. Thrombocytopenia and leucopenia were the major DLTs. The MTD for phase II trials is 0.50 mg/m² topotecan and 800/600 mg/m² gemcitabine. In this dose level only one therapy-related non-hematological adverse event >grade 2 (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in 6 and stable disease in 4 out of 12 evaluable patients. Median survival was 15.3 (95% CI: 13.2–28.6) months. Conclusion: The results of this phase I study demonstrate the feasibility and tolerability of this new combination in heavily pretreated patients. Based on these results a phase II study was initiated to evaluate the efficacy of this regimen.

Topotecan in Platinum-Resistant Epithelial Ovarian Cancer

“…In these trials, response rates ranged from 19 to 33% in platinum-sensitive recurrent ovarian cancer, whereas response rates ranged from 12 to 23% in platinum-resistant recurrent ovarian cancer, and stable disease was reported in 21-61% of patients, with a duration of response ranging from 18 weeks to 11 months. There are several regimens combining topotecan and other chemotherapy agents like ifosfamide and gemcitabine in patients with advanced ovarian cancer refractory to or relapsing after platinum compound-based chemotherapy [23,24] . In these studies, response rates ranged from 40 to 50% with signifi cantly more toxicity as in combination regimens compared to topotecan monotherapy, and effect of combination regimens on survival is not known.…”

Medikamentöse Therapie des Ovarialkarzinomrezidivs

“…Vielmehr wurde durch den zusätz-lichen Einsatz einer weiteren Substanz, wie beispielsweise Anthrazyklin zu Paclitaxel, eine höhere Knochenmarkstoxizität erzeugt [5]. Weitere Kombinationen von Topotecan, Gemcitabin oder pegyliertem liposomalem Doxorubicin wurden untersucht [10,23]. Obwohl diese Regime weniger toxisch erscheinen, sind sie bezüg-lich ihres Nebenwirkungsprofils den Monotherapien unterlegen.…”

Treatment of recurrent disease: randomized trials of monotherapy versus combination chemotherapy

“…However, the combination of paclitaxel + anthracyclin was more myelotoxic. Other doublets with new agents such as topotecan, gemcitabine, and pegylated liposomal doxorubicin have been developed (12–15) . Although these new combinations are being presented as tolerable regimens, the observed toxicity is higher than monotherapy, and their application in a nonselected platinum‐resistant population cannot be recommended as yet, until conclusive data from comparative trials have been obtained.…”