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Is There a Role for Dose-Intensive Chemotherapy With Stem Cell Rescue in Breast Cancer?

Is There a Role for Dose-Intensive Chemotherapy With Stem Cell Rescue in Breast Cancer?

During the 1990s, perhaps no
other therapy for women with
breast cancer was more controversial than high-dose chemotherapy with autologous
bone marrow and/or peripheral stem cell support. With encouraging results from
late phase I and early phase II trials in the early to mid-1990s, high-dose
chemotherapy was promoted by its many enthusiastic proponents as a potentially
great leap forward for women with high-risk, node-positive or metastatic
disease.

In the absence of controlled randomized phase III clinical trial data, as
noted by Williams in this excellent review, breast cancer became the leading
indication for autologous stem cell transplant in North America in the 1990s.
Most of these stem cell transplants occurred outside of a clinical trial, which
led to many heated and publicized battles between insurers and women for access
to these therapies. Indeed, the battle became so heated, and positions so
ingrained, that one investigator resorted to outright research fraud to make the
case for high-dose therapy.[1]

At the plenary session of the American Society of Clinical Oncology in 1999,
investigators presented several abstracts detailing preliminary results from
phase III randomized studies of high-dose therapy vs the more
"standard" chemotherapy regimens for both high-risk node-positive
breast cancer and metastatic breast cancer. After these studies demonstrated
little or no apparent benefit for high-dose chemotherapy over the standard
regimens, interest in high-dose therapy, both inside and outside the context of
clinical trials, waned. After 3 years of reflection, is there currently a role
for high-dose chemotherapy in the management of breast cancer?

Rational Basis,
Disappointing Results

Williams correctly notes that high-dose therapy has a reasonable experimental
and perhaps reasonable clinical rationale. Alkylating agents demonstrated a
steep dose-response curve in experimental systems,[2] and an early phase II
clinical trial demonstrated high overall and complete response rates in
metastatic breast cancer.[3]

The data from randomized clinical trials presented to date, however, have
been mixed. As noted, one randomized trial in metastatic disease was
fraudulent.[1] One trial enrolled women with metastatic disease and a complete
response to initial standard-dose induction therapy to immediate or delayed
high-dose therapy at progression.[4] Immediate consolidation with high-dose
therapy produced a better disease-free survival than delayed consolidation but a
poorer over- all survival. Another study randomized women with metastatic breast
cancer and a response to induction therapy to high-dose or standard
chemotherapy.[5] This trial demonstrated no difference in disease-free or
overall survival between the arms.

Randomized trials of high-dose chemotherapy as adjuvant therapy for high-risk
node-positive breast cancer have fared no better. To date, although there have
been encouraging signs of a trend toward improved disease-free survival in one
study,[6] no trial randomizing women to high-dose vs standard-dose regimens has
demonstrated a significant disease-free or overall survival benefit.

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