A PILOT-STUDY OF AMIODARONE WITH INFUSIONAL DOXORUBICIN OR VINBLASTINE IN REFRACTORY BREAST-CANCER

Increasing evidence suggests that P-glycoprotein (Pgp) expression can mediate drug resistance in refractory breast cancer. We studied 33 pat ients with refractory breast cancer enrolled in a pilot study of oral amiodarone as a Pgp antagonist given in combination with infusional do xorubicin or vinblastine. Whenever possible, tumors were biopsied and Pgp expression was assayed, Patients received either 60 mg/m(2) doxoru bicin over 96 h or 8.5 mg/m(2) vinblastine over 120 h by continuous in travenous infusion. Beginning with the second cycle of chemotherapy, 6 00-800 mg amiodarone was given orally each day. Patients who experienc ed toxicity due to amiodarone but were responding to chemotherapy were placed on quinidine, Partial responses were observed in 9 of 33 patie nts on study and were sometimes observed after the first cycle of chem otherapy, before amiodarone was given, suggesting that some patients m ay have responded to treatment because of the infusional schedule. Tox icities were primarily the known side effects of the antineoplastic ag ents and of amiodarone, The major amiodarone toxicity was gastrointest inal, with nausea, vomiting, anorexia, or diarrhea being noted in 21 p atients. Biopsy samples were obtained from 29 patients acid in 21 case s, viable tumor tissue was present and the results were interpretable. Of the 21 samples, 9 had Pgp expression as determined by immunohistoc hemical staining; 12 were considered negative. The presence of Pgp exp ression was associated with an acceleration of the time to treatment f ailure. Whereas normal-tissue toxicities related to the combination of a Pgp antagonist with chemotherapy were not observed, amiodarone was associated with too many untoward effects to be utilized as a drug res istance-reversing agent.