BETHESDA, MdHigh-risk breast cancer patients receiving
intermediate- or high-dose consolidation chemotherapy after CAF achieved
overall survival that is "better than any other experience within the
CALGB," William Peters, MD, PhD, said at the NIH Consensus Conference on
Adjuvant Therapy for Breast Cancer. He gave an update of CALGB 9082/SWOG
Dr. Peters, of the Karmanos Cancer Institute, reported 5-year
follow-up, based on the occurrence of 83% of the requisite 373 events needed
for final analysis. "This is a very recent update. Final data that will be
important for interpretation and context are not yet available; however, the
major conclusions are not likely to change," he said.
The 1999 ASCO plenary session (Atlanta) on high-dose
chemotherapy, where Dr. Peters presented preliminary results based on the
occurrence of 66% of
the requisite events, generated much attention, and follow-up analyses of these
trials have been eagerly awaited.
CALGB 9082 included 783 patients with 10 or more positive lymph
nodes who received one of two doses of combination alkylating agents as
consolidation after four cycles of CAF (cyclophosphamide, Adriamycin,
fluorouracil). Patients were randomized to receive either high-dose
cyclophosphamide, cisplatin (Plat-inol), and BCNU with bone marrow or
peripheral blood progenitor cell support or intermediate doses of the same
drugs with G-CSF (Neupogen) support.
Patients relapsing on the intermediate-dose regimen were
eligible for subsequent autologous bone marrow transplant with the same
high-dose regimen as used in the initial arm. Local-regional radiotherapy was
also planned for each patient, and hormone-receptor-positive patients received
tamoxifen (Nolvadex) for 5 years.
The high-dose regimen was cyclophosphamide 5,625 mg/m2,
cisplatin 165 mg/m2, and BCNU 600 mg/m2. The intermediate-dose regimen was cyclophosphamide
900 mg/m2, cisplatin 90 mg/m2, and BCNU 90
Based on 373 events (recurrences or transplant mortality),
which occurred equally in the high- and intermediate-dose arms, there was no
significant difference in event-free survival, which was more than 60% at 5
years for both groups, Dr. Peters reported.
At this point, the overall survival figures of CALGB 9082
appear superior to those from other trials. "The truth is, we don’t know
why this difference in survival might appear, and it serves as a reason to
consider other studies," Dr. Peters commented.
He added that salvage high-dose therapy and transplant may
confound the interpretation of overall survival in this study, but these
factors have not been sorted out yet.
While there was no significant overall survival advantage for
the high-dose treatment, it did favorably affect the recurrence rate. There
were 154 relapses in the intermediate-dose arm vs 115 for the high-dose
recipients, for an absolute reduction of 10% and a relative reduction of 34% in
number of relapses.
However, in the over-50 subgroup, high-dose therapy was
actually associated with more relapses than intermediate-dose therapy. Relapses
on the intermediate-dose arm peaked during the first year after randomization.
"There is an apparent earlier wave of relapse in the
intermediate-dose group vs the high-dose group, which is useful for hypothesis
generation. It could be consistent with a dose-response effect, and it could
also be consistent with the infusion of malignant cells in the bone marrow or
in peripheral blood progenitor cells," Dr. Peters suggested.
There were 32 treatment-related deaths and 7 secondary
malignancies. Treatment-related mortality was higher among patients on
high-dose therapy, and occurred predominantly in the first year after
randomization. Transplant centers with the highest volume had the lowest rate
of treatment-related mortality.
A clear increase in treatment-related mortality was noted with
increasing age, with deaths occurring in 14% of women over 50 and 4% of women
"The preliminary conclusion from this study is that there
is no difference in event-free survival between intermediate- and high-dose
chemotherapy," Dr. Peters said. "Note that this is not a comparison
with standard-dose therapy but a comparison between high-dose and
intermediate-dose therapy. The high-dose outcomes are as predicted from the
pilot data, but the intermediate-dose patients have done much better than
He said that high-dose consolidation remains a viable treatment
option, but it should not be considered outside of the context of a clinical
trial. "For the high-risk patient over 50, intermediate-dose therapy would
seem preferred for reasons of toxicity and efficacy," Dr. Peters
With 83% of the requisite events occurring, the overall
outcomes remain better than any results previously observed in the CALGB, he
reemphasized. More effective treatment, better patient selection, consolidation
with combined alkylating agents, local-regional radiation therapy, and hormonal
therapy may all have contributed to these outcomes, he said, "and they
clearly warrant further study."