ALEXANDRIA, VaPreliminary findings from four of five
randomized studies show no survival advantage for high-dose
chemotherapy/autologous bone marrow transplantation (HDC/ABMT) in
breast cancer patients with metastatic or high-risk disease (10 or
more positive axillary lymph nodes), researchers said at an ASCO
The negative findings in the largest of the studies in metastatic
breast cancer are unlikely to change over time, said lead author
Edward Stadtmauer, MD, of the University of Pennsylvania. However,
William Peters, MD, of the Karmanos Cancer Institute, who led the
largest of the high-risk breast cancer trials, said that, at least in
high-risk patients, its not that these are inconclusive
studies, its that its too early to draw conclusions.
In his study, the statistics call for at least 3 more years of
follow-up. We believe that it will be about 2001 before
well have a sufficient number of events to draw
conclusions, Dr. Peters said.
Allen Lichter, MD, professor of radiation oncology, University of
Michigan, and president of ASCO, said that the five abstracts
released at the teleconference and on ASCOs website, will be
presented in detail for the scientific community at ASCOs
annual meeting. He briefly summarized the findings of all five
studies, starting with the three studies of women with high-risk
The first study by CALGB (Cancer and Leukemia Group B), with Dr.
Peters as the senior author, involved 783 high-risk women randomized,
after receiving standard chemotherapy, to either high-dose or
intermediate-dose continuation chemotherapy. With follow-up of 37
months, disease-free survival is 68% for women who had high-dose chemotherapy/transplant
vs 64% for patients on intermediate-dose therapy without transplant.
Obviously, there is no statistical difference between those two
numbers, Dr. Lichter said, but it should be pointed out
that the results in both arms are about 20% better than weve
seen in historical groups of patients, so maybe one of the good news
features of this is the fact that standard therapy is doing much
better than in the past. Whether these two curves will separate as
additional time goes on remains to be seen.
A Positive Study
A South African study, led by Dr. W.R. Bezwoda, included 154
high-risk women. Those on high-dose therapy had fewer relapses (25%
vs 66%) and reduced mortality (17% vs 35%), compared with women in
the standard-dose arm. This study, which is more mature, with
follow-up extending out beyond 5 years, shows that in this setting,
high-dose therapy was beneficial, Dr. Lichter said.
However, this finding may have been due to inadequacies of the
so-called standard-dose regimen. This study was the only true
comparison between high-dose chemotherapy with transplant and
standard-dose therapy in these patients, Dr. Peters said. He
explained that in the CALGB study, all patients initially received
standard-dose therapy and then were randomized between high-dose
chemotherapy/transplant and an intermediate-dose regimen requiring
substantial additional clinical support but not transplant. He noted
that in his study, patients on both arms are doing very well,
20% better than anticipated.
The Scandinavian Study
The third study of high-risk women was done in Scandinavia by Dr.
Jonas Berg and colleagues. The researchers enrolled 525 women. With a
median of 20 months follow-up, the number of deaths in both arms is
the same, Dr. Lichter said, 40 with standard therapy and 40 in
the high-dose arm.
Dr. Lichter next reviewed the two studies performed in patients with
metastatic breast cancer. These women received their primary
treatment, then had a recurrence, he said. The question
here is, in a disease that is essentially incurable today, could
high-dose therapy extend survival and potentially even cure some of
Dr. Stadtmauers ECOG study involved 553 women treated initially
with chemotherapy; 199 responded and agreed to continue, with 184
finally eligible for analysis. Three-year survival was
virtually identical in high-dose and standard- dose patients, 32% for
high dose and 38% for standard dose, Dr. Lichter said.
The other metastatic disease study, from Dr. Jean-Pierre Lotz and
colleagues in Paris, was a much smaller trial of 61 women. At the
ASCO meeting, this study will be presented at a poster session, while
the other four will be discussed at the plenary session, Dr. Lichter said.
Dr. Lotz said that it was difficult to accrue patients because
so many patients wanted to be transplanted. He pointed
out that although overall survival was not significantly different at
5 years, there was a significant difference at 3 years (P = .02),
because of a difference in time to relapse (P = .013).
In this small study, he said, we were able to delay
the time of relapse with high-dose therapy, and when the relapse
occurred, we were able to induce a new complete response. Dr.
Lotz and his colleagues find these results encouraging.
Its not the end of high-dose therapy in breast cancer; it
is the beginning for us, he said, adding that another French
study is ongoing with 180 patients randomized after four cycles of
conventional chemotherapy to receive high-dose therapy with
transplant or observation.
In terms of the ability of high-dose therapy to delay relapse, Dr.
Lichter said that for some patients, being alive without
disease involves a much improved quality of life. He said that
although delay in relapse is not as powerful an endpoint as
overall survival, it is an endpoint that, in oncology, we think is
very much worth looking for, and our patients tell us its important.
Dr. Peters noted that in the CALGB study, the primary endpoint is
disease-free survival, so time to failure of the treatment is
actually very important. He explained that in this study,
patients who were randomzied to the intermediate-dose arm were
eligible to receive a transplant later, which complicates the
determination of overall survival. Improved overall survival
generally follows improved disease-free survival, he said,
but usually requires far larger numbers of patients to determine.
In the question-and-answer session, Dr. Lichter was asked if the
issue of high-dose therapy/transplant in metastatic breast cancer was
now closed. Its uncommon for a very important issue like
this to be decided on the results of a single study, Dr.
Lichter said, pointing out that the ECOG study with 184 analyzed
patients is not an incredibly large trial. Rather, he
said, the findings should stimulate additional research.
Dr. Peters pointed to the history of adjuvant therapy of breast
cancer using standard doses. It took 144 trials involving
77,000 women before we finally were able to conclude that adjuvant
chemotherapy offered an advantage to patients.
Dr. Lichter said that he hoped the results would encourage more women
to participate in trials of high-dose therapy. Of some 12,000
transplants performed in breast cancer patients in this country to
date, only about 1,000 have been done in the context of a clinical
I hope that ratio will shift, he said. I hope these
studies will begin to dispel the concerns of women who have been
reluctant to go on study because of a tacit assumption that high-dose
chemotherapy has to be better.