Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma.

Preclinical models in an ovarian cancer cell line (A2780) demonstrate synergistic activity with the combination of gemcitabine and cisplatin compared to either single agent alone. Platinum resistance is related to expression of excision repair proteins, one of which (ERCC-1) has been identified as playing a critical role in the synergy of gemcitabine and cisplatin. We evaluated the cisplatin and gemcitabine regimen in patients with platinum refractory and multidrug refractory ovarian and peritoneal carcinoma. Gemcitabine (750 mg/m(2)) was administered intravenously over 30 min followed by cisplatin (30 mg/m(2)) on Days 1 and 8 every 21 days. Day 8 therapy was canceled for an absolute neutrophil count <1000/mm(3) or platelet count <75,000/mm(3). Sequential dose reductions of gemcitabine to 600, 400, and 300 mg/m(2) were prescribed in the event of canceled therapy, neutropenic sepsis, or severe thrombocytopenia (platelets <20,000/m(3)). Thirty-six platinum- and paclitaxel-resistant patients were studied. Thirty-five were evaluable for response, of which 6 had progressed on gemcitabine as a single agent. Fifteen of the patients responded (42.9%, 95% CI 28.0-59.1%). Eleven were partial clinical responses and 4 were complete clinical responses, with 4 of the 6 patients who had failed gemcitabine as a single agent responding. Among the responding patients the median response duration was 11 months (range 4-14 months). For all patients the progression-free interval was 6 months (range 1-14 months). The median survival was 12 months. The combination of gemcitabine and cisplatin is active in patients who are platinum resistant. Additionally, activity is demonstrated even in patients who have previously been resistant to gemcitabine.