Mitoxantrone combined with paclitaxel as salvage therapy for platinum-refractory ovarian cancer: laboratory study and clinical pilot trial.
This report describes preclinical and early clinical investigations of the mitoxantrone/paclitaxel combination (NT) for patients with platinum-refractory ovarian cancer. The preclinical activity of NT was studied ex vivo, evaluating native tumor specimens with the ATP tumor chemosensitivity assay. Of 24 tumors tested, 20 (83%) were sensitive to NT, whereas 7 (29%) responded to mitoxantrone and 8 (33%) responded to paclitaxel. In the majority of tumors assayed (19 of 24), potentiating or major independent effects between both agents were found. Subsequently, a clinical pilot trial of NT was initiated for patients with platinum-refractory ovarian cancer. Patients had failed one to four (median, two) prior chemotherapy regimens. In 11 cases, NT was administered every three weeks with 8 mg/m2 mito-xantrone and 180 mg/m2 paclitaxel (NT-I). Seven patients were treated biweekly with 6 mg/m2 mitoxantrone and weekly with 100 mg/m2 paclitaxel (NT-II). During 92 NT courses, myelosuppression with leucopenia, anemia, and thrombocytopenia was the limiting toxicity, occurring more frequently with NT-II. No patient required hospitalization due to any life-threatening complication. Five complete and nine partial remissions were observed with both NT-I and NT-II, accounting for an overall 78% response rate, with a median progression-free survival of 40 weeks. One patient showed early progression during therapy. Currently, three patients (NT-I, two; NT-II, one) have died due to progressive relapsed ovarian cancer, so that the median overall survival is not reached after a median follow-up of 40.5+ weeks. Both schedules were found to be equal in terms of response rate and overall survival. NT is highly active and practical for salvage treatment of ovarian cancer. NT-II may be preferred due to both clinical activity and patients' acceptance. However, NT-I seems to be a less myelotoxic alternative. Both schedules warrant further clinical investigation.