ASCO--Anthracycline-based chemotherapy should join tamoxifen (Nolvadex)
as standard therapy for postmenopausal breast cancer patients who have
positive lymph nodes and are estrogen-receptor positive.
The assessment came from the lead author of a study that showed significant
improvement in disease-free survival in patients treated with tamoxifen
plus an anthracycline-containing chemotherapy regimen, as opposed to tamoxifen
"CAF plus tamoxifen significantly delays the time to failure, compared
to tamoxifen alone in postmenopausal women with node-positive, receptor-positive
disease," said Kathy Albain, MD, of the Cardinal Bernadin Cancer Center
of Loyola University Medical Center.
No major subset could be identified that was not impacted favorably
by the addition of CAF to tamoxifen, and the benefit remained significant
after adjustment for important prognostic factors.
The findings came from a multicenter randomized trial that involved
almost 1,500 postmenopausal breast cancer patients. In each patient, the
cancer had spread to one or more lymph nodes. All the patients were positive
for estrogen receptors, and about 80% were proges-terone-receptor positive.
"In 1988, when this trial was designed, standard treatment for
this subset of patients was tamoxifen for 2 to 5 years," Dr. Albain
said. "CMF-like regimens added to tamoxifen did no better than tamoxifen
alone in most individual trials."
Three different trials had suggested a benefit of adding anthracycline-based
chemotherapy for receptor-negative postmenopausal women or for subsets
with four or more positive nodes, she said. However, in 1988, no data were
available on the potential survival benefit of adding anthracyclines to
treatment of a pure hormone-responsive, node-positive subset. Furthermore,
some investigators have been reluctant to use anthracyclines in postmenopausal
women who might be more susceptible to their cardiac effects.
The study included patients who had undergone mastectomy for T1-3 cancer
or breast conservation for T1-2. None had distant metastases. Patients
with cardiac disease were excluded.
The Three Treatment Arms
The trial comprised three treatment arms: 361 patients were randomized
to receive tamoxifen at a dose of 20 mg daily for five years, and 1,109
were randomized to chemotherapy with either concurrent or sequential tamoxifen.
Chemotherapy consisted of cyclophosphamide (100 mg/m² PO ×
14 days), doxorubicin (30 mg/m² IV on days 1 and 8), and fluorouracil
(500 mg/m² IV on days 1 and 8) for six cycles. Radiation therapy was
initiated either before or at the completion of chemotherapy or before
the start of tamoxifen in patients who did not receive chemotherapy.
The primary objectives of the trial were to determine whether the addition
of anthracycline-based chemotherapy improves survival; whether CAF followed
by tamoxifen is superior to CAF and concurrent tamoxifen; and whether toxicity
differed among the treatment groups.
At a second interim analysis, the trial was approved for early reporting
because one of the major objectives (tamoxifen alone vs tamoxifen plus
chemo) had reached a significant difference. The chemotherapy arms were
combined for analysis, since the data to answer the sequential tamoxifen
question were not mature.
Four-Year Disease-Free Survival
Patients randomized to chemotherapy plus tamoxifen had an estimated
four-year disease-free survival of 79% vs 72% for tamoxifen alone (P =
.001). The superiority of combined treatment persisted in the major stratification
subsets: number of positive nodes, age, and PR status. Overall survival
did not differ (about 85% in both groups). "It's too early to tell
whether there will be an overall survival benefit because there have been
too few events to date," she said.
As expected, the addition of chemotherapy was associated with increased
toxicity. However, the incidences of cardiotoxicity and thromboembolic
events were low, and no increased risk of endometrial cancer was observed.
Asked if she would now recommend anthracycline-based chemotherapy for
this subset, Dr. Albain responded, "I would as long as they meet the
same eligibility criteria as in this study."