Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer

Abstract

Purpose : A controversy exists regarding whether it is safe to delay radiation therapy until the completion of chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Within the context of two concurrent randomized clinical trials we had the opportunity to evaluate outcomes for patients who received breast irradiation after completing different durations of chemotherapy. Methods and Materials : From July 1986 to April 1993 the International Breast Cancer Study Group (IBCSG) Trial VI randomly assigned 1554 pre/perimenopausal node-positive breast cancer patients to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for either three consecutive courses on months 1–3, or six consecutive courses on months 1–6, both with or without reintroduction CMF, IBCSG Trial VII randomly assigned 1266 postmenopausal node-positive breast cancer patients to receive tamoxifen for 5 years, or tamoxifen for 5 years with three cycles of CMF, both with or without three courses of delayed CMF. Both trials allowed a choice of mastectomy, or breast-conserving surgery plus radiation therapy, and both were stratified by type of surgery. Radiotherapy was delayed until the initial block of CMF was completed; 4 or 7 months after surgery for pre/perimenopausal patients, and 2 or 4 months after surgery for postmenopausal patients. Over both trials, 718 neglible patients elected to receive breast-conserving surgery plus radiation therapy: 433 on Trial VI, and 285 on Trial VII. Four-year actuarial total failure rates (failure at any site), risks of developing distant metastases (DM at any time during conservation), an overall survival (OS) were estimated using the Kaplan-Meier method. To avoid potential bias due to competing causes of failure, only patients who could be followed for at least 4 years (enrolled prior to July 1, 1990) were used to evaluate the patterns of first relapse site. Crude percents of local failure with or without other sites (LF), distant metastases including regional nodal failure (DM/RNF), or other first events (second primaries/death without recurrence) were estimated for each treatment group. For this report, an intent to treat analysis was performed at a median follow-up of 48 months. Results : No differences were found in the 4-year actuarial total failure rates, risks of developing distant metastases, and overall survival among the two radiotherapy groups of each study. The cumulative incidence of types of first failure and the 4-year crude rates showed no treatment differences in the patterns of site of first event. Estimates for the 4-year crude percent of local failures were 8 and 9% for pre/perimenopausal patients who had radiation therapy at 4 or 7 months after surgery, and 3 and 6% for postmenopausal patiens who had radiation therapy at 2 months or 4 months after surgery. Conclusions : For node positive patients receiving breast-conserving surgery followed by radiation therapy, the incidence of breast recurrence in the conserved ipsilateral breast within 4 years was between 8 and 9% for pre/perimenopausal patients and between 3 and 6% for postmenopausal patients. After 48 months of median follow-up, administering radiation therapy after three or six cycles of CMF for pre/perimenopausal women, or after no cycles or three cycles of CMF for postmenopausal women does not influence overall efficacy or local control in this series.