SAN FRANCISCOCancer and Leukemia Group B (CALGB) 9082 has failed in its second analysis to show a survival benefit for intensive therapy and transplant in primary breast cancer patients with multiple positive axillary lymph nodes. Nevertheless, outcomes in the 785-patient study, which compared high-dose and intermediate-dose consolidation chemotherapy with alkylating agents, are superior to outcomes achieved in studies of standard-dose therapy alone, William P. Peters, MD, PhD, said on behalf of investigators in the study, which was started more than 10 years ago. Dr. Peters, director of the Karmanos Cancer Institute, Detroit, spoke at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO).
He said that the high-dose outcomes "are as good as what was seen in our pilot studies that preceded this study, but the intermediate-dose outcomes were better than what we had seen in standard-dose cooperative group studies."
Women with 10 or more involved axillary nodes were enrolled in the study between 1991 and 1998. They were given four cycles of CAF (cyclophosphamide, Adriamycin, fluorouracil(Drug information on fluorouracil)), then randomized to either high-dose cyclophosphamide(Drug information on cyclophosphamide)/cisplatin/BCNU (CPB) with autologous bone marrow/peripheral stem cell support or to an intermediate dose of CPB with G-CSF (Neupogen) support. Patients on intermediate-dose CPB who relapsed were eligible for salvage transplant.
Each patient was scheduled to receive local-regional radiation therapy; likewise, all hormone-receptor-positive patients were to receive tamoxifen(Drug information on tamoxifen) (Nolvadex) for 5 years.
In this intent-to-treat analysis, event-free survival at a median of 5.5 years was 60% for high-dose CPB and, similarly, 57% for the intermediate-dose arm (P = .28). Overall survival was 70% and 72%, respectively. High-dose therapy was associated with fewer relapses (28.9% vs 39.1% for intermediate dose). However, there were 32 treatment-related deaths in the high-dose arm vs none in the intermediate-dose arm.
Treatment-related mortality was lower at the centers that accrued more patients, but still 7% at the highest-accruing center. Likewise, treatment-related mortality was higher for older patients (14% mortality for those over age 50) and lower, but not negligible, for younger women (4%).
Treatment-related mortality "is a concern" and has "implications for the generalizability of this approach," said discussant James N. Ingle, MD, of the Mayo Clinic. He also noted that overall outcomes better than previously reported are nonetheless only observations and not rigorous scientific conclusions.
"This is why we have randomized clinical trials," Dr. Ingle said. "The problems of historical controls have been with us as long as we have been a discipline, and the relationship to standard chemotherapy for either of these arms would require a randomized clinical trial."
Nevertheless, Dr. Peters said he was encouraged by the overall survival rates, saying it looks "as though we have changed something in the natural history of patients with high-risk node-positive disease."
He emphasized that in the CALGB study, the Italian study, and the Canadian metastatic disease trial, "the patients under age 50 showed strong trends toward improved disease-free survival. All of the pilot studies were performed only in patients under 50. It may well be that in the effort to extend the value to a wider group, we overlooked the importance of age."
He said that for the high-risk patient under age 50, in a properly designed trial at a center with sufficient volume, high-dose consolidation remains a viable treatment option. "For high-risk patients over the age of 50, intermediate-dose therapy would generally be considered preferable, but should be evaluated further," he said. "The selection of a proper regimen gives us a chance to reduce the tumor burden to allow application of other treatmentsbiologics or vaccines."