HAMBURG, Germany Recent clinical trials presented at the 25th
Congress of the European Society of Medical Oncology (ESMO) suggest
that new standards for the hormonal treatment of breast cancer may be emerging.
Adjuvant Goserelin vs CMF
In the Zoladex Early Breast Cancer Research Association (ZEBRA)
study, the luteinizing hormone-releasing hormone (LHRH) agonist
goserelin (Zoladex) emerged as a serious alternative to adjuvant
chemotherapy for pre- and peri-menopausal women with node-positive,
estrogen-receptor (ER)-positive breast cancer.
The chief advantage of goserelin monotherapy is that it matches the
efficacy of the CMF chemotherapy regimen (cyclophosphamide,
methotrexate, 5-fluorouracil) without causing nausea, vomiting, and
alopecia, said Moise Namer, MD, of Antoine Lacassagne Center, Nice, France.
Between 1990 and 1996, ZEBRA trialists at 102 centers in 15 countries
randomized more than 1,600 women who had undergone surgery for breast
cancer to receive either goserelin or the CMF regimen.
Dr. Namer pointed out that study participants were stratified
according to ER status and age. Three quarters of the women in both
treatment arms were ER positive, and roughly three quarters had
between one and three positive lymph nodes.
After a median follow-up period of 6 years, Dr. Namer said,
disease-free survival among ER-positive patients was equivalent in
those treated with goserelin and in those assigned to cytotoxic
In contrast, CMF was significantly more effective than hormonal
treatment in ER-negative women. Measurement of ER status is
vital for treatment decisions, he stressed.
The overall survival results mirrored the disease-free survival
outcome, although the data lack maturity, Dr. Namer said.
In the goserelin arm, amenorrhea was achieved in almost 100% of
patients, but, most importantly, menses returned after cessation of
treatment, Dr. Namer said. With CMF, however, amenorrhea proved
to be irreversible.
Not surprisingly, CMF produced a significantly higher incidence of
nausea and vomiting (56% vs 5% with goserelin) and alopecia (43% vs
3% with goserelin).
The most prominent side effects of goserelin were those typical of
estrogen suppression, with vaginal dryness developing in 24% of women
(vs 14% with CMF) and hot flashes occurring in 72% (vs 42% with CMF).
Neoadjuvant Letrozole vs Tamoxifen
In the largest endocrine comparative trial performed to date in the
neoadjuvant setting, the aromatase inhibitor letrozole (Femara)
proved superior to tamoxifen (Nolvadex) in reducing tumor size and
facilitating breast-conserving surgery.
If there is an indication for preoperative endocrine therapy in
postmenopausal breast cancer patients, letrozole should be used
rather than tamoxifen, said Wolfgang Eiermann, MD, of the Red
Cross Womens Clinic, Munich, Ger-many.
The Letrozole Neoadjuvant Breast Cancer Study group, encompassing 55
centers in 16 countries, randomly assigned more than 300 ER-positive
and/or progestogen-receptor (PR)-positive postmenopausal women with
early breast cancer (T2-4, N0-2, M0) to 4 months of therapy with
letrozole 2.5 mg once daily or tamoxifen 20 mg once daily. All
patients were ineligible for breast-conserving therapy at the time of enrollment.
The results revealed a striking benefit with letrozole treatment,
irrespective of whether objective response was assessed clinically
(55% vs 36% with tamoxifen, P < .001); by ultrasound (35%
vs 25% with tamoxifen, P = .042); or by mammography (34% vs
17% with tamoxifen, P < .001).
Baseline tumor size, number of positive nodes, and age had no
influence on the response to letrozole, Dr. Eiermann said.
Mastectomy could be avoided in 45% of letrozole-treated patients, but
in only 35% of those assigned to tamoxifen (P = .022).
Eligibility for breast-conserving surgery increased most markedly in
women whose tumors were initially larger than 5 cm in size, Dr.
Letrozole vs Tamoxifen in Advanced Disease
Letrozole also proved superior to tamoxifen as first-line hormonal
treatment for postmenopausal women with locally advanced or
metastatic breast cancer, reported Henning Mouridsen, MD, of
Rigshospitalet, Copenhagen, on behalf of the Letrozole P025 Breast
Cancer Study Group.
In this double-blind trial, more than 900 women were randomized to
therapy with letrozole 2.5 mg once daily or tamoxifen 20 mg once
daily until progression occurred, at which point patients suitable
for another endocrine therapy were crossed over to the alternative
treatment. Approximately two thirds of participants were ER and/or PR
positive, while receptor status was unknown in the remainder.
Patients were ineligible for inclusion if they had recurrence while
receiving adjuvant tamoxifen or within 12 months of completing such
therapy; prior endocrine therapy or more than one prior course of
chemotherapy for metastatic disease; or CNS metastases or major lung
or liver involvement.
Letrozole significantly prolonged the median time to progression to
9.4 months, compared with 6.0 months with tamoxifen. These data
correspond to a hazard ratio of 0.7, which means that the chance of
progression was 30% lower for patients on letrozole than for patients
on tamoxifen, Dr. Mouridsen said. The difference was
highly significant, P = .0001, he added.
The median time to failure was likewise significantly longer with
letrozole than with tamoxifen (9.1 vs 5.7 months, P = .0001).
The benefit in favor of letrozole held for all patient subgroups,
independent of receptor status, dominant site of disease, or prior
adjuvant endocrine therapy.
An objective response was observed in 30% of patients
randomized to letro-zole, as against 20% of those on tamoxi-fen,
Dr. Mouridsen reported. This gives an odds ratio of 1.7 and a P
value of .0006, indicating that the chance of response was 70% higher
for patients randomized to letrozole, compared to tamoxifen.
Similarly, 49% of letrozole-treated patients showed clinical benefit,
compared with 38% of those treated with tamoxifen.
Here again, the superior response rate with letrozole was evident
across the board, in all patient subgroups, he said. The durations of
response and clinical benefit were similar with both endocrine
Letrozole was as well tolerated as tamoxifen. The frequencies of such
side effects as hot flushes, nausea, and hair thinning were similar
in both treatment arms, although there was a nonsignificant trend
toward a lower incidence of thromboembolic events with letrozole.
On the basis of these data, letrozole should now be considered
as first-line therapy for advanced breast cancer, Dr. Mouridsen said.
Anastrozole vs Tamoxifen in Advanced Disease
Additional support for the value of aromatase inhibitors in the
first-line treatment of advanced breast cancer came from two large
randomized trials, one North American and the other European, that
compared anastrozole (Arimidex) 1 mg/d with tamoxifen 20 mg/d in more
than 1,000 postmenopausal women.
In the North American trial, anas-trozole significantly delayed the
time to progression by 44%, compared with tamoxifen, reported Aman
Buzdar, MD, of M.D. Anderson Cancer Center. The median time to
progression was 11.1 months among patients receiving the aromatase
inhibitor vs 5.6 months in the tamoxifen group (P = .005).
After a median follow-up interval of 18 months, clinical benefit was
apparent in 59% of anastrozole-treated patients vs 46% of those
receiving tamoxifen (P = .0098).
The benefit of anastrozole was not replicated in the European study,
however. Dr. Buzdar attributed this discrepancy to the fact that 89%
of participants in the American trial were known to be ER or PR
positive, compared with 45% of their European counterparts.
Indeed, analysis of time to progression only in those European
enrollees who were receptor positive pointed to a benefit in favor of
anastrozole. Pooled data from the 700 receptor-positive participants
in both trials likewise revealed that the time to progression was
significantly longer with anastrozole than with tamoxifen (10.7 vs
6.4 months, respectively, P = .022).
These data highlight the importance of hormone-receptor
assessment prior to initiation of endocrine therapy, Dr. Buzdar commented.
Anastrozole was associated with significantly fewer episodes of
thromboembolism (4.5% vs 7.6% with tamoxifen, P = .0056) and
vaginal bleeding (1.0% vs 2.2% with tamoxifen, P = .0083).
These data clearly support the use of anastrozole as front-line
therapy in metastatic disease, Dr. Buzdar said. I think
that the ultimate test of the value of these compounds will be in the
adjuvant setting. To this end, the ongoing ATAC study is
assessing the efficacy of anastrozole vs tamoxifen vs the combination
of both drugs in 9,000 women with invasive breast cancer.