The treatment with Letrozole ( Femara ) of postmenopausal women with early breast cancer prolonged disease-free survival by reducing the risk of recurrence an additional 19% over that offered by Tamoxifen ( Nolvadex ) when used as initial treatment after surgery, according to data from the Breast International Group ( BIG ) 1-98 study.
Use of Letrozole resulted in greater disease free survival in two subgroups of women who are at particularly increased risk of recurrence -- those whose cancer had already spread to the lymph nodes at the time of diagnosis ( node positive ) and those who had received chemotherapy.
The risk reductions in these subgroups were 29% and 30%, respectively.
The results also showed that for all women in the study, Letrozole reduced, by 27%, the risk that cancer would spread to other parts of the body ( distant metastases ), compared with the reduction offered by Tamoxifen ( p=0.0012 ).
Women who develop distant metastases are at greater risk of dying from breast cancer.
" Women with early breast cancer are at highest risk of recurrence during the first five years after surgery, " said PD Beat Thurlimann, of Early Breast Cancer Senology Center of Eastern Switzerland, Kantonsspital, St. Gallen. " The BIG 1-98 study showed that Femara offered postmenopausal women with hormone-sensitive early breast cancer increased benefit, compared with Tamoxifen, by reducing the risk of recurrence and by decreasing the risk of distant metastasis, a risk factor for death. "
Further, there was a statistically significant reduction of 17% in the risk of systemic failure.
That is, a recurrence of cancer in sites other than the breast, or death without recurrence ( p=0.017 ).
There was a 14% reduction in risk of death in favor of Femara that was not statistically significant.
The Phase III, randomized, double-blind, controlled clinical trial enrolled more than 8,000 postmenopausal women with early breast cancer, in 27 countries.
The median follow-up time was 26 months.
Disease free survival ( DFS ), the primary efficacy endpoint in this study, was defined as the time from randomization to invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, a second non-breast primary tumor or death without recurrence, whichever occurred first.
These data complement those of the landmark MA-17 trial for the use of Femara in the extended adjuvant setting. The term extended adjuvant describes the period following standard adjuvant treatment with Tamoxifen.
Femara is the only aromatase inhibitor shown to be effective in both the adjuvant and extended adjuvant settings.
Initial results from the final analysis of the head-to-head comparison of Femara with Tamoxifen in study BIG 1-98 were presented at the Primary Therapy of Early Breast Cancer 9th International Conference in St. Gallen, Switzerland in January 2005.
The trial was conducted by the International Breast Cancer Study Group ( IBCSG ), with participation of the Danish Breast Cancer Group, the French FNCLCC group, the Yorkshire Group and many independent centers.
BIG 1-98 is the only clinical trial designed to incorporate both a head- to-head comparison of Femara with Tamoxifen during the first five years following breast cancer surgery and a sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence.
Patients were randomized to the following arms: Tamoxifen for five years; Femara for five years; Tamoxifen for two years followed by Femara for three years; and Femara for two years followed by Tamoxifen for three years.
Results from the ongoing arms of the study, which are expected to determine whether monotherapy or sequential therapy is more effective, and if sequential therapy, which sequence is more effective, are expected in 2008.
The spectrum of adverse events found in the study is consistent with published data.
In this trial, patients treated with Femara had significant reductions in vaginal bleeding ( 3.3% vs. 6.6% ); hot flushes ( 33.5% vs. 38% ); endometrial biopsies ( 2.3% vs. 9.1% ); invasive endometrial cancer ( 0.2% vs. 0.5% ); and, thromboembolic disorders, both overall ( 1.5% vs. 3.5% ) and severe events ( 0.8% vs. 2.1% ) when compared to Tamoxifen.
Average non-fasting blood levels of cholesterol were slightly higher in the Letrozole arm than in the Tamoxifen arm.
There were more severe ischemic cardiovascular disorders ( 1.1% vs. 0.6% ) including myocardial infarction ( 0.5% vs. 0.3% ) in patients treated with Femara than with Tamoxifen.
As expected with estrogen deprivation, the number of women reporting new bone fractures to date was 5.7% on Femara and 4.0% on Tamoxifen.
Overall, more deaths were reported on Tamoxifen (n=192) than on Letrozole (n=166).
More patients on Tamoxifen (n=154) died from breast cancer than Femara (n=111).
In patients whose breast cancer did not recur, more deaths due to cardiac causes were reported in Femara treated patients (n=13) than Tamoxifen treated patients (n=6).
Letrozole is a once-a-day oral aromatase inhibitor currently available in more than 90 countries worldwide.
Femara is approved for extended adjuvant treatment of early breast cancer in postmenopausal women who have completed standard adjuvant Tamoxifen therapy in 57 countries worldwide, now including member countries of the EU as well as the United States.
In addition, it is indicated for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer and for the treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. Not all indications are available in every country.
Femara is contraindicated in pregnancy as it may cause fetal harm.
Commonly reported side effects are generally mild to moderate.
Those seen more often with Femara versus placebo were hot flashes ( 50% vs. 43% ), joint pain ( 22% vs. 18% ) and muscle pain ( 7% vs. 5% ).
Other side effects, which were comparable to placebo, include fatigue ( 34% vs. 32% ), swelling due to fluid retention ( 18% vs. 16% ), headache ( 20% vs. 20% ), increase in sweating ( 24% vs. 22% ) and increase in cholesterol ( 6% vs. 16% ).
Longer follow up is needed to determine the risk of fracture associated with long-term use of Femara.
The percentage of patients on Femara versus placebo reporting a fracture was 5.9% vs. 5.5%.
The percentage of patients reporting osteoporosis was 6.9% vs. 5.5%.
Bisphosphonates, drugs that increase bone strength, were given to 21.1% of Femara patients and 18.7% of placebo patients.
Source: 41st Annual Meeting of the American Society of Clinical Oncology ( ASCO ), 2005