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10/10/2003

Study: Letrozole Reduces Breast Cancer Recurrence

Donna Young

An international study of the aromatase inhibitor letrozole was stopped early because the results for older women with breast cancer were so favorable, researchers reported yesterday.

Results from the clinical trial, published early in the online edition of the New England Journal of Medicine (NEJM), found that the recurrence of breast cancer was cut by nearly half—43 percent—in postmenopausal women with the disease who took letrozole after completing approximately five years of tamoxifen therapy.

Novartis Pharma AG markets letrozole under the brand name Femara.

The study was led by the National Cancer Institute of Canada Clinical Trials Group at Queens University in Kingston, Ontario.

Researchers compared therapy with letrozole 2.5 mg orally daily with a placebo in healthy postmenopausal women with previously treated early-stage breast cancer.

The results from the Canadian-led study do not apply to premenopausal women, researchers noted.

About 5,200 women were enrolled in the five-year randomized trial, with half assigned to the letrozole group and half to the placebo group.

At the first interim analysis, when no more than half of the women had taken the study drug for 2.4 or more years, about 2.4 percent (61) of women in the letrozole group and 4.1 percent (106) of women in the placebo group had local or metastatic recurrences of breast cancer, the study noted. About 0.5 percent (14) of the women in the letrozole group and 1 percent (26) of the women in the placebo group had new primary tumors in the contralateral breast.

Reseachers reported that 9 women taking letrozole and 17 women taking the placebo died of breast cancer. Four women in each group died of another type of cancer.

Aromatase inhibitors, researchers noted, suppress estrogen levels, which may reduce bone mineral density and increase the blood cholesterol level.

Women taking letrozole experienced higher rates of new diagnoses of osteoporosis than women taking the placebo, the study's authors said. Slightly more women in the letrozole group had at least one cardiovascular event or new bone fracture, but neither difference between the groups was significant, they added.

Most adverse effects of the drug included hot flashes, arthritis, arthralgia, and myalgia.

Few women discontinued the study treatment because of the adverse effects, researchers said.

The authors of the study admitted that because they ended the study early, the results leave the "optimal duration of treatment undefined and the question of the long-term toxicity unanswered."

"Data from other, ongoing aromatase-inhibitor trials will contribute information regarding toxic effects, but the question of the optimal duration of treatment will not be answered by the current trials," the authors said.

Researchers noted that, preliminary results from the Arimidex (anastrozole), Tamoxifen, Alone or in Combination trial—published in the Lancet in 2002—found that, disease-free survival is longer with anastrozole, a aromatase inhibitor, than with tamoxifen, adding that "tamoxifen therapy is still considered an acceptable standard of care."

AstraZeneca Pharmaceuticals markets anastrozole under the brand name Arimidex. 

In an editorial appearing in the same online NEJM issue, John Bryant and Norman Wolmark from the University of Pittsburgh said that, while the study's results were remarkable, the decision to end the trial early "undeniably diminishes the clinical usefulness of the data."

Moreover, they added, the primary aim of the study—to determine the disease-free survival and overall survival for women who have received about 5 years of adjuvant tamoxifen and then letrozole or placebo for five years—was not fully accomplished.

"The decision to unblind the trial," they said, "was dictated by the protocol and by the ethical need to inform patients about the evolving data that clearly indicated a benefit for letrozole therapy. In consequence critical information will be lost to the degree that the primary aim of the study will not be fully achieved. It is likely that in the coming months there will be much debate over whether the data and the safety monitoring committee made the best decision."

Harold J. Burstein of Dana-Farber Cancer Institute in Boston, in a second NEJM editorial, cautioned that because of the study's early termination, and results from several ongoing international studies examining optimal duration and sequencing of tamoxifen and aromatase inhibitors are expected within two to three years, women considering letrozole therapy should be "carefully educated" about the drug's benefits and adverse effects.

Since 1995, the U.S. National Cancer Institute has recommended that women with breast cancer not receive tamoxifen therapy for more than five years.