Reviewers: Kenneth Blank, MD
Source: Journal of Clinical Oncology Vol. 16, No. 12, p. 3720 1998
The treatment of patients with metastatic breast cancer is challenging, with the roles of chemotherapy, endocrine therapy and radiation therapy evolving. The benefit of chemotherapy is based on retrospective reviews comparing patients who received chemotherapy versus historical controls. There has never been a prospective trial demonstrating a survival advantage to chemotherapy in the setting of metastatic breast cancer and for ethical reasons, it is unlikely such a trial will ever occur. The next logical question concerns which chemotherapuetic agents to use and whether one agent is as effective as combination chemotherapy (two or more agents). To answer this question, several randomized prospective trials have been performed which on the balance have failed to demonstrate a survival benefit to combination chemotherapy over single-agent therapy. A report from Helsinki University published in the December issue of the Journal of Clinical Oncology adds important data to this issue. This report examined quality of life as well as survival in patients with metastatic breast cancer receiving either single agent or combination chemotherapy.
Three hundred and three patients were enrolled in this perspective study. All patients were females with pathologically proven invasive breast cancer and either histologic or clinical evidence of metastatic breast cancer. Women were excluded if they were older than seventy-one, if they had received anthracycline chemotherapy (eg. Doxorubicin/Adriamycin) already, or if they were taking simultaneous endocrine therapy. Patients were randomized to either combination chemotherapy or single agent chemotherapy. Women assigned to the single agent arm received weekly epirubicin while those assigned to the combination chemotherapy arm received three chemotherapy agents every twenty-two days. The drug regimen in the combination arm consisted of cyclophosphamide, epirubicin and 5-flourouracil (CEF).
The design of this study was unique in that patients who failed epirubicin were continued on a second-line single agent medication and patients who failed CEF chemotherapy were salvaged with two more agents. Specifically, patients failing epirubicin were placed on monthly mitomycin, while those failing CEF were dosed with mitomycin and vinblastine once per month.
Patient accrual began in July 1991 and ended April 1996. Three hundred and three patients were enrolled, 150 of whom were randomized to receive CEF chemotherapy and 153 to epirubicin. Nine patients were considered ineligible based mostly on age or prior treatments. The two arms were well balanced with respect to a host of clinical and pathologic variables including age, performance status, estrogen receptor status, histology and time from diagnosis to detection of distant metastases. Quality of life was measured by the Rotterdam Symptom checklist. This tool measures 30 items that assesses for daily activities and psychological and physical distress.
No significant difference in survival or time to progression was found between the two study arms. The median survival time on the combination arm and on the single agent arm were 18 and 16 months, respectively. Time to progression was 10 months in the combination arm versus 8 months in the single agent arm. Toxicity was greater in patients receiving multiple agents. Total hair loss occurred in 80% of patients on CEF, while the majority of patients on single agent therapy had no or slight hair loss. Severe nausea was significantly more common in CEF patients, as was severe anemia. These toxicities led to a difference in quality of life. There was no difference in psychological distress between the two arms; however, women receiving single agents had less physical distress, and less days of incapacity. When asked to rate the therapy as easy or difficult, more patients on the combination arm reported the therapy to be difficult.
This is the first modern study comparing monotherapy to multi-agent chemotherapy as both the first and second-line regimen in patients with metastatic breast cancer. The finding of similar survival and disease free progression in both arms may partly be explained by dose reductions in the combination arm made necessary by toxicity. For example, patients receiving epirubicin as a single agent dosed at 20mg/m2 weekly had no dose reductions compared to nearly half the patients in the combination chemotherapy arm who had dose reductions while receiving epirubicin every twenty-two days at 60mg/m2. In summary single agent epirubicin followed by single agent mitomycin offered similar survival and provided better quality of life compared to a multi-agent regimen.