Postmenopausal breast cancer survivors who took the aromatase inhibitor letrozole following a 5-year course of tamoxifen therapy had significantly fewer new and recurrent cancers, as well as a trend toward lower overall mortality, compared with women taking a placebo, Dr. Paul E. Goss and associates reported.
The trial was planned to last 5 years. However, an interim analysis conducted after a median follow-up of 2.4 years showed that the hazard ratio for a tumor recurrence in the ipsilateral breast or a new cancer in the contralateral breast was 0.57 for the women taking letrozole, compared with women in the placebo group.
The estimated 4-year disease-free survival among the 2,575 women taking letrozole was estimated at 93%, compared with 87% among the 2,612 women in the placebo group. Overall estimated 4-year survival was 96% and 94%, respectively. The hazard ratio for death from any cause in the letrozole group as compared with the placebo group was 0.76 (N. Engl. J. Med. 349:1793-1802, 2003).
These findings prompted the study's data and safety monitoring committee to terminate the trial early, publish the results on the New England Journal of Medicine's Web site last month, and offer women in the placebo group the opportunity to switch to letrozole, Dr. Goss of Princess Margaret Hospital, Toronto, and his colleagues said.
Currently, adjuvant therapy with tamoxifen for breast cancer is limited to 5 years because there is evidence associating longer therapy with poorer outcomes. However, there is also evidence that aromatase inhibitors are effective in women with metastatic disease that progresses despite treatment with tamoxifen.
The study was led by the National Cancer Institute of Canada Clinical Trials Group and funded in part by Novartis, which markets letrozole as Femara.
A total of 5,187 postmenopausal women who had completed an average of 5 years' adjuvant treatment with tamoxifen for primary breast cancer were randomized to receive either 2.5 mg/day letrozole or placebo for 5 years.
During a median follow-up time of 2.4 years, there were 75 new or recurrent breast tumors among women in the letrozole group, compared with 132 in the placebo group, resulting in a hazard ratio of 0.57 for new or recurrent tumors associated with letrozole.
Hot flashes, arthritis, arthralgia, and myalgia were more common in the letrozole group. Women in that group also reported more new cases of osteoporosis and osteoporotic fractures, prompting the authors to recommend that women also take calcium and vitamin D supplements.
These findings are promising, but some important questions and reservations remain, write the authors of two editorials published in the same issue. None of the women have yet completed the full 5 years of the study, so the optimal duration of letrozole therapy remains unclear, according to Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, Boston (N. Engl. J. Med. 349:1857-59, 2003).
Also, he writes, these findings suggest that candidates for letrozole therapy should be chosen carefully, especially given consequences of the marked estrogen deprivation induced by letrozole.
Because the study was terminated early, "it is possible that a survival advantage will never be documented, since ongoing follow-up will he confounded by crossover," write John Bryant, Ph.D., and Dr. Norman Wolmark, investigators on the National Surgical Adjuvant Breast and Bowel Project. Early cessation of the study may also lead to an underestimate of the long-term adverse effects of letrozole treatment (N. Engl. J. Med. 349:1855-57, 2003).
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