QUINIDINE AS A RESISTANCE MODULATOR OF EPIRUBICIN IN ADVANCED BREAST-CANCER - MATURE RESULTS OF A PLACEBO-CONTROLLED RANDOMIZED TRIAL

Purpose: To evaluate the effect of quinidine, a putative modulator of P-glycoprotein-mediated drug resistance, on the response rate and toxi city profile of epirubicin in patients with advanced breast cancer. Pa tients and Methods: Between 1989 and 1992, 223 eligible patients were randomized in double-blind fashion to receive epirubicin 100 mg/m(2) b y intravenous (IV) bolus and prednisolone 25 mg orally twice daily, al ong with either placebo or quinidine (250 mg) capsules, taken for 4 da ys before and 2 days after chemotherapy. Treatment was continued for a maximum of eight courses. Results: Ten eligible patients did not comp lete the first cycle of treatment. Of the remaining patients, 106 in t he placebo arm received 619 courses of treatment, and 107 in the quini dine arm received 612 courses. The median cumulative dose of epirubici n in both arms was 600 mg/ m(2) The median quinidine level (measured b efore epirubicin administration in 288 courses) was 5.5 mu mol/L; at t his concentration, the drug partially reverses anthracycline resistanc e in multidrug-resistant (MDR) breast carcinoma cells in vitro. There were no statistically significant differences in hematologic or gastro intestinal toxicity between the two arms. The response rate in the pla cebo arm war 44% (6% complete remission [CR], 38% partial remission [P R]), and in the quinidine arm was 43% (4% CR, 39% PR). Surviving patie nts have been monitored for a median time of 74 weeks, and there is no significant difference in the overall or progression-free survival be tween the two arms. The median survival times were 59 weeks for placeb o and 47 weeks for quinidine patients. The estimated relative death ra te (quinidine/placebo) was 1.2 (P =.247; 95% confidence interval [CI], 0.88 to 1.63). Conclusion: Quinidine at this dose does not significan tly alter toxicity profile, response rate, or survival after epirubici n chemotherapy in patients with advanced breast cancer. This may be du e to ineffective modulation of P-glycoprotein by quinidine or the lack of expression of mdr-1 in a sufficient proportion of cells in these t umors, or alternative mechanisms underlying resistance to epirubicin. (C) 1994 by American Society of Clinical Oncology.