December 20, 2008 - Overall survival in breast cancer patients is superior with five years of adjuvant letrozole compared to tamoxifen, according to results from the Breast International Group 1-98 trial.
The 13 percent reduction in mortality risk in the letrozole (Femara) group at a mean followup of 76 months in a prespecified intent-to-treat analysis fell short of statistical significance (P = .08), but that's clearly because the letrozole arm included 25 percent of all patients initially randomized to tamoxifen. These patients crossed over and spent a median of 18 months on the aromatase inhibitor after the study's unblinding in 2005. The study was unblinded for ethical reasons because of the demonstration of superior disease-free survival with letrozole, Dr. Henning Mouridsen said at the San Antonio Breast Cancer Symposium.
The new BIG 1-98 update also showed that sequential adjuvant hormonal therapy - that is, 2 years of either letrozole or tamoxifen followed by 3 years of the other drug - is not more effective than 5 years of letrozole, added Dr. Mouridsen, study investigator and professor and head of oncology at Copenhagen University Hospital.
The BIG 1-98 trial involved 8,010 women with endocrine-responsive early breast cancer in 27 countries. A landmark previous finding was that 5 years of adjuvant letrozole monotherapy was superior to 5 years of tamoxifen in terms of disease-free survival and time to distant recurrence (N. Engl. J. Med. 2005; 353:2747-57).
The update addressed two key outstanding questions. The first, whether aromatase inhibitor monotherapy is superior to tamoxifen monotherapy in terms of overall survival, was something that had yet to be shown to a level of statistical significance in any of the major randomized trials. The second was whether sequential therapy - the so-called switching strategy - offers advantages over aromatase inhibitor monotherapy, as some had theorized.
The overall survival analysis involved 4,922 BIG 1-98 participants. There were 303 deaths in the letrozole arm and 343 in the tamoxifen arm.
"Since we're almost at the conventional level of significance in the compromised intention-to-treat analysis, I take that as fairly strong evidence that in fact letrozole improves on overall survival," said Alan Coates, M.D., cochair of the scientific committee of the International Breast Cancer Study Group, which coordinated BIG 1-98.
The sequential therapy analysis involved 6,182 patients at a median follow-up of 71 months. Neither 2 years of tamoxifen followed by three years of letrozole nor 2 years of letrozole followed by 3 years of tamoxifen proved superior to five years of letrozole.
Among the 42 percent of participants at increased risk of recurrence as reflected in their node-positive status, there was a strong trend for worse outcomes in the group randomized to sequential tamoxifen followed by letrozole. Their rate of breast cancer recurrence was 7.9 percent at two years and 14.7 percent at five years, compared with 4.7 percent and 12.4 percent, respectively, in node-positive patients assigned to five years of letrozole.
"Cancer recurrence is more common while patients are on early tamoxifen and that leeway is never made up after the switch. The curves remain parallel. Many people will take the message that it's better to start with letrozole, particularly for patients at high risk," added Dr. Coates of the University of Sydney.
Among patients assigned to the reverse sequence - letrozole followed by tamoxifen - the rates of disease-free and overall survival and time to distant recurrence were closely similar to those seen in the letrozole monotherapy arm.
"I think that's a very important message for patient care. Some women find these aromatase inhibitors really hard to take, not only because of menopausal symptoms but also arthralgia and myalgia. If they were worried about doing themselves a disservice by switching after a couple of years of putting up with this or they can't afford the greater dollar cost, I think the data are reassuring that such a switch back to tamoxifen for the remainder of their 5 years would not compromise their outcome in any way," the oncologist explained.
Doctors still want to know if adjuvant hormonal therapy extend it beyond the now-standard five years to reduce late recurrences.
Source: B Jancin, Elsevier Global Medical News
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