A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer

Abstract

Increasing evidence suggests that P-glycoprotein (Pgp) expression can mediate drug resistance in refractory breast cancer. We studied 33 patients with refractory breast cancer enrolled in a pilot study of oral amiodarone as a Pgp antagonist given in combination with infusional doxorubicin or vinblastine. Whenever possible, tumors were biopsied and Pgp expression was assayed. Patients received either 60 mg/m2 doxorubicin over 96 h or 8.5 mg/m2 vinblastine over 120 h by continuous intravenous infusion. Beginning with the second cycle of chemotherapy, 600-800 mg amiodarone was given orally each day. Patients who experienced toxicity due to amiodarone but were responding to chemotherapy were placed on quinidine. Partial responses were observed in 9 of 33 patients on study and were sometimes observed after the first cycle of chemotherapy, before amiodarone was given, suggesting that some patients may have responded to treatment because of the infusional schedule. Toxicities were primarily the known side effects of the antineoplastic agents and of amiodarone. The major amiodarone toxicity was gastrointestinal, with nausea, vomiting, anorexia, or diarrhea being noted in 21 patients. Biopsy samples were obtained from 29 patients and in 21 cases, viable tumor tissue was present and the results were interpretable. Of the 21 samples, 9 had Pgp expression as determined by immunohistochemical staining; 12 were considered negative. The presence of Pgp expression was associated with an acceleration of the time to treatment failure. 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 resistance-reversing agent.

ATP binding cassette transporters and drug resistance in breast cancer.

“…By comparison, the response rate to an alternative second-line chemotherapy in patients already exposed to doxorubicin is about 21% (Henderson 1987). Ries & Dicato (1991) Anthracycline-resistant patients 16 Dox, Vcr + verapamil RR = 3/16 Mross et al (1993) Randomized 48 Epirub ± verapamil No difference in RR and survival Thurlimann et al (1995) Cross-over 14 Eprib + R-verapamil RR = 2/14** Taylor et al (1997) Cross-over 27 CVAD + verapamil and RR = 5/27 quinine Lehnert et al (1998) Cross-over 23 Epirub + R-verapamil RR = 4/23 Warner et al (1998) Cross-over 20 Anthracycline + R-verapamil RR = 2/20 Belpomme et al (2000) Anthracycline-resistant patient 99 Vds/FU RR = 5/47 Vds/FU + verapamil RR = 14/42*** Bates et al (1995) Patients generically refractory 33 Dox or Vbl + amiodarone RR = 9/33 to chemotherapy van Kalken et al (1991) Cross-over 5 Epirub or Dox + bepridil RR = 0/5 Wishart et al (1994) Randomized 213 Epirub and No difference in RR Prdnsl + quinidine and survival Toppmeyer et al (2002) Cross-over 35 Paclitaxel + biricodar RR = 4/35 Murren et al (1996) Anthracycline-refractory patients 16 Vbl + trifluoperazine RR = 1/6 RR, response rate. *First-line: anticancer agents; second line: MDR1-reversing agent.…”

“…Another MDR1 − reversing agent, biricodar, when added to paclitaxel, obtained a partial response in 4/35 (11%) patients with locally advanced or metastatic disease refractory to paclitaxel (Toppmeyer et al 2002). A study by Bates et al (1995) reported a 27% (9/33) response rate to amiodarone (chemosensitizer) in combination with doxorubicin or vinblastine. However, patients in this study were selected for a generic resistance to chemotherapy, as opposed to a specific resistance to respectively doxorubicin and vinblastine.…”

Downregulation of mdr-1 expression by 8-Cl-cAMP in multidrug resistant MCF-7 human breast cancer cells.

“…P-glycoprotein has been demonstrated in human breast cancer cells selected in vitro for drug resistance (5), and the protein has been observed in breast cancer samples (1,2,6). Expression is typically found in previously treated breast cancers and less often in untreated breast cancer (2,3,7). The present studies were undertaken to determine whether P-glycoprotein expression could be modulated in multidrugresistant human breast cancer cells.…”

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

“…In a recently reported study, 1 out of 16 patients with metastatic breast cancer refractory to vinblastine alone had a partial response upon the addition of trifluoperazine (Murren et al, 1996). Other chemosensitizer studies in metastatic breast cancer were not designed in a manner that allows assessment of chemosensitizer activity (Ries and Dicato, 1991;Budd et al, 1993;Bates et al, 1995). The dose of epirubicin and its response rate in the present study were similar to the negative randomized trials of quinidine and racemic verapamil (Mross et al, 1993a;Wishart et al, 1994).…”

“…In a meta-analysis of all the original studies of MDRl/P-gp detection in clinical breast cancers, the proportion of MDRI/P-gp-positive tumours was around 40% (Trock et al, 1997). The results, however, have been highly variable (Goldstein et al, 1989;Merkel et al, 1989;Wishart et al, 1990;Sanfilippo et al, 1991;Verrelle et al, 1991;Wallner et al, 1991;Bates et al, 1995;Linn et al, 1995;Murren et al, 1996;Trock et al, 1997). One reason for the discrepant data seems to be the different sensitivity and specificity of the various detection methods used in these studies (Beck et al, 1996;Broxterman et al, 1996).…”