Adjuvant treatment with
Adriamycin/Taxotere (AT) did not improve
outcome over standard treatment
(AC) for women with early-stage
breast cancer, Lori J. Goldstein, MD,
of Fox Chase Cancer Center reported
(abstract 512). Both regimens tested
in a phase III Eastern Cooperative Oncology
Group trial (E2197) produced
better-than-expected results, but toxicity
was higher in the AT group.
Neutropenia associated with fever
and infection occurred in 28% of the
AT group and in 10% of the AC group.
There were 18 cases of congestive heart
failure in the AT group and 10 cases in
the AC group, but this was not considered
Disease-free and overall survival
curves for the two regimens overlapped.
The trial opened in July 1998 and
"closed rapidly due to great accrual"
in January 2000, Dr. Goldstein said.
Patients were balanced for age, hormone
receptor status, menopausal status,
nodes, surgery, as well as grade
and size of the tumor. The median age
was 51 years (range, 24-85 years). Sixty-
four percent of patients were estrogen
receptor positive (ER+) and 65%
of tumors were lymph node negative.
"The ER/PR subgroups were prespecified
at randomization designed
to balance the treatment arms," Dr.
Patients were randomized to receive
AT (doxorubicin 60 mg/m2 plus
docetaxel 60 mg/m2) with ciprofloxacin
(Cipro) support or AC (doxorubicin
60 mg/m2 plus cyclophosphamide
600 mg/m2) every 3 weeks for four
cycles. Tamoxifen was given for 5 years
postchemotherapy to all patients with
ER+ and/or PR+ tumors.
Subgroup analysis found no significant
effect for nodes, tumor size, age,
menopausal status, grade, type of surgery,
or race. Nor were there any significant
interactions between the treatment
and the subgroups.
Data for disease-free survival "suggest
that the PR-negative tumors may
potentially benefit from AT, but this
study was not powered to statistically
detect these differences," Dr. Goldstein
reported. The pattern was the
same for overall survival, she said, and
supports the hypothesis "that in ER+
tumors, the large benefit presented by
tamoxifen overwhelms the potential
benefit of taxane therapy... The prognosis
of these tumors is so good, it is
difficult to detect a difference between
these two chemotherapy arms. Taken
together, along with the genomic
health data, these data support the
hypothesis that the biology of a tumor
may predict the benefit to individual
The Case for Taxanes
"Given their single-agent activity,
relative non-cross-resistance, partially
nonoverlapping toxicities, and different
mechanisms of action, there was
a clear rationale for combining taxanes
with doxorubicin," Dr. Goldstein
explained. The selection of AT was
"based on the relative cardiac safety of
this combination," and several ran-
domized trials supported such investigation.
In a discussion of the trial, Gabriel
N. Hortobagyi, MD, Director of the
Breast Cancer Research Program at
M. D. Anderson Cancer Center in
Houston, referred to several trials that
have demonstrated a clear advantage
to using taxanes in the adjuvant setting
for high-risk breast cancer. "The
addition of a taxane clearly improves
event-free survival, relapse-free survival,
and probably overall survival in
patients with high-risk primary breast
cancer," he observed. "Whether this
can be readily translated to a lower risk
population awaits additional trials but
is probably likely."
Why was E2197 a negative study?
Dr. Hortobagyi offered several possibilities,
including insufficient duration
of therapy and inadequate dose of
docetaxel. He also speculated on
whether the sequential use of anthracyclines
and taxanes might be better
than simultaneous use of these agents.
"AT x 4 remains unproven, more
toxic than AC x 4, unlikely to match
TAC (Taxotere [docetaxel], Adriamycin
[doxorubicin], and cyclophosphamide)
x 6 or any of the other regimens.
Therefore, I would propose that it
should not be used outside of a clinical
trial and probably not even in a clinical
trial since there are more effective
and probably better tolerated regimens,"
"On the basis of our increased biological
knowledge and our better understanding
that there are biologic
methods to select differences in subsets
of different patients, we should
concentrate on how to identify the
optimal regimens for individual tumors
and stop getting involved in these
large trials in which one size is supposed
to fit all patients."