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.
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), then randomized to either high-dose 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 (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."