Letrozole cuts breast cancer recurrence risk

Questions unanswered after trial is stopped early

Breast cancer patients who have undergone five years of tamoxifen treatment can further limit their risk of recurrence by taking the aromatase inhibitor letrozole (Femara), according to the results of an international clinical trial.

The results were so positive that an independent data and safety monitoring committee recommended early termination of the trial and that all participants be notified of the results. By stopping it early, however, researchers left many important questions unanswered, critics say.

Results show 43% reduced risk

The international, double-blind, placebo-controlled trial was designed to test the effectiveness of five years of letrozole therapy in more than 5,000 postmenopausal women with breast cancer who had completed five years of tamoxifen therapy. The primary endpoint was disease-free survival.

At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast, 75 in the letrozole group and 132 in the placebo group — a reduction of risk of 43%. The estimated four-year disease-free survival rates were 93% and 87%, respectively. Seventeen women in the placebo group and nine women in the letrozole group died of breast cancer. Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There also were new diagnoses of osteoporosis in 5.8% of the women in the letrozole group and 4.5% of the women in the placebo group; the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee made its recommendation to stop the trial.

Based on the findings, the researchers say that postmenopausal women with hormone-receptor-positive tumors who have completed about five years of adjuvant tamoxifen therapy should be considered for letrozole treatment. Physicians have previously lacked a treatment to follow the tamoxifen therapy.

The results of the study were published in the Nov. 6 issue of the New England Journal of Medicine (NEJM). Because of their importance, however, the journal published the results early on its web site.

Stopping trial early creates problems

Proponents of stopping the trial early — median follow-up of the women was 2.4 years — say it would have been unethical to withhold the positive early evidence of letrozole’s benefit from women currently not taking the treatment.

Even the researchers, however, say that the discontinuing the study leaves the optimal duration of treatment undefined and the question of long-term toxicity unanswered. Since letrozole blocks estrogen production, there is concern about its long-term effects in terms of osteoporosis or cognition.

One pharmacist who specializes in oncology services was disappointed that the trial was canceled before the question of overall survival was determined. "There was a difference in disease-free survival, so they stopped the trial. But they have no proof that that is going to carry on to be overall survival benefit," says Dominic A. Solimando Jr., MA, BCOP, president of Oncology Pharmacy Services in Arlington, VA.

He expects physicians to use the drug, but they won’t be sure of any long-term benefit. "They will not have any confidence or any real way of knowing if that translates to longer, overall survival. That’s the big reservation of the trial," he says.

An editorial accompanying the study in the NEJM echoes that sentiment. "Although the current report does show a relative reduction of 24% in the hazard of death from any cause in the letrozole group as compared with the placebo group, this reduction was not statistically significant, and it is possible that a survival advantage will never be documented, since ongoing follow-up will be confounded by crossover," say John Bryant, PhD, and Norman Wolmark, MD. They are involved in the National Surgical Adjuvant Breast and Bowel Project, which is evaluating the aromatase inhibitor exemestane. Bryant is an associate professor at the department of biostatistics, Graduate School of Public Health at the University of Pittsburgh, and Wolmark is chairman of the department of human oncology at Allegheny General Hospital in Pittsburgh.

"Nor can the findings be used to support a recommendation of five years of letrozole treatment, since none of the participants have been followed that long," they continue. "Indeed, only about one quarter of the patients have been followed for the analysis of efficacy for 30 months or more, and follow-up for adverse events has been even shorter. Thus, although the results demonstrate a meaningful biologic effect of letrozole therapy after tamoxifen therapy, they do not demonstrate a significant survival benefit, nor do they convey information about the optimal duration of treatment beyond two to three years. It is not even possible to quantify the magnitude of a potential benefit with respect to disease-free survival, not only because of the small number of events that have been reported to date, but also because of uncertainty about the interval for which the treatment benefit may persist."

Solimando equates the letrozole trial to past trials evaluating tamoxifen. The trials showed that there was a survival benefit if women received five years of tamoxifen. If the trials had continued to show a benefit for the next year and a half, researchers could have stopped them and advised that patients be given tamoxifen for 10-15 years. However, the trials continued for several more years and showed a decrease in survival for women taking the drug for 10 years.

Stopping that trial earlier than 10 years would have done many patients a disservice, he says. "It would probably have taken a number of years and a number of unnecessary patients being placed at risk."

That’s why he thinks patients should only take letrozole for about 2½ years, for which the benefit is known. "We don’t know that at three or four years the benefit holds up. It would have been preferable to continue the trial until its end and actually answer the questions."