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A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer
S E Bates1, B Meadows, B R Goldspiel
1National Institutes of Health, Bethesda, MD 20892.
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.
Insights
Amiodarone, an oral P-glycoprotein (Pgp) antagonist, showed limited efficacy in reversing drug resistance in refractory breast cancer due to significant gastrointestinal toxicities. Pgp expression accelerated treatment failure, suggesting its role in resistance.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- P-glycoprotein (Pgp) expression is implicated in multidrug resistance (MDR) in various cancers, including refractory breast cancer.
- Chemotherapeutic agents like doxorubicin and vinblastine are often less effective in Pgp-expressing tumors.
Purpose of the Study:
- To evaluate the efficacy of oral amiodarone as a Pgp antagonist in combination with chemotherapy for refractory breast cancer.
- To assess the relationship between Pgp expression and treatment response and toxicity.
Main Methods:
- A pilot study involving 33 patients with refractory breast cancer treated with infusional doxorubicin or vinblastine and oral amiodarone.
- Tumor biopsies were performed to assay Pgp expression using immunohistochemical staining.
- Patients received chemotherapy cycles with amiodarone initiated from the second cycle.
Main Results:
- Partial responses were observed in 9 of 33 patients. Some responses occurred before amiodarone administration, suggesting potential benefit from the infusional chemotherapy schedule.
- Pgp expression was detected in 9 of 21 evaluable tumor samples and was associated with accelerated time to treatment failure.
- The primary toxicity was gastrointestinal (nausea, vomiting, anorexia, diarrhea) in 21 patients, attributed to amiodarone.
Conclusions:
- Oral amiodarone, despite being a Pgp antagonist, demonstrated limited success in reversing chemotherapy resistance in refractory breast cancer.
- Amiodarone's significant gastrointestinal toxicity profile makes it unsuitable as a drug resistance-reversing agent in this context.
- Pgp expression is a significant factor contributing to treatment failure in refractory breast cancer.