SAN FRANCISCOHigh-dose chemotherapy plus stem cell rescue
did not improve overall survival vs standard chemotherapy alone in women with
chemotherapy-sensitive metastatic breast cancer, according to the results of a
National Cancer Institute of Canada (NCIC) trial reported at the 37th
Annual Meeting of the American Society of Clinical Oncology (ASCO).
"We could not find any subgroup in our analysis that
appeared to benefit from this approach," said Michael Crump, MD, medical
oncologist, Princess Mar-garet Hospital, Toronto, Canada.
The toxicity of high-dose therapy was significantly greater
than that of standard-dose chemotherapy. Furthermore, risk of treatment-related
mortality was higher in the high-dose chemotherapy arm.
The study was one of several major breast cancer trials of
high-dose chemotherapy with transplantation reported at ASCO, all of which
failed to illustrate significant differences in overall survival vs
In the Canadian study, women with no prior chemotherapy for
metastatic breast cancer received induction therapy with an anthracycline-based
regimen. If patients had previous anthracycline exposure, they received taxane-based
Accrual for this 397-patient trial opened in 1997, around
the time breast cancer had become the most common indication in North America
for high-dose therapy with stem cell support. Encouraging single-institution
phase II results, according to Dr. Crump, had suggested durable disease-free
survival for this approach. However, it was not clear how much results were
influenced by patient selection.
After four cycles, responders were randomized to additional
standard chemotherapy for up to four cycles, or to one or two cycles of
standard chemotherapy followed by high-dose chemotherapy with cyclophosphamide,
mitoxantrone (Novantrone), and carboplatin (Paraplatin). All
estrogen-receptor-positive patients received tamoxifen (Nolvadex) or other
hormone therapy after chemotherapy.
Overall response rates were assessed at 6 weeks
post-transplant in the high-dose arm, and 15 weeks after day 1 of cycle 6 in
the standard-dose arm. With a median follow-up of almost 2 years, there was no
difference in overall survival.
There was a small but statistically significant difference
in progression-free survival: a mean of 1.0 years in the high-dose arm vs 0.7
years in the standard-dose arm. But Dr. Crump advised that difference should be
interpreted with caution, since regular restaging was not performed. "Some
bias may have crept into this assessment," he said.
In an exploratory analysis, the three most important
variables with respect to overall survival were presence or absence of visceral
disease, use of an anthracycline as part of induction therapy, and response to
tamoxifen. All three variables were significant. However, treatment assignmenthigh-dose
vs standardwas not.
Investigators were concerned they would see a high rate of
congestive heart failure due to the intensive use of anthracyclines and the
addition of mitoxantrone, a potentially cardiotoxic agent, in the high-dose
arm. However, grade 2-4 heart failure was seen in only five patients in the
high-dose arm, and four in the standard-dose arm.
More grade 3-4 toxicities were seen in the high-dose arm. In addition, there
were seven treatment-related deaths in the high-dose arm, for an overall toxic
death rate of 6%. Most were related to infections arising during pancytopenia.