Aromatase Inhibitors Prolong Survival Over Tamoxifen

IOANNINA, Greece, Sept. 21 -- The aromatase inhibitors should be promoted over tamoxifen to first-line therapy for advanced breast cancer, according to findings from a meta-analysis.

In the meta-analysis of 23 randomized controlled trials, the use of the aromatase inhibitors led to an 11% increase in survival over tamoxifen, found John P.A. Ioannidis, M.D., of the University of Ioannina School of Medicine here and Tufts in Boston. He and colleagues reported the results of the analysis of n the Sept. 20 issue of the Journal of the National Cancer Institute.

They concluded that the aromatase inhibitors should be the standard of care for first-line treatment. "It is common practice for patients with hormone receptor-positive advanced breast cancer to receive both tamoxifen and an aromatase inhibitor, typically in sequence," they wrote. "Our results indicate that aromatase inhibitors and inactivators should be the first-line therapy for such patients."

They referred specifically to four third-generation aromatase inhibitors -- Femara (letrozole), Aromasin (exemestane), Arimidex (anastrazole), and the invstigational vorozole, which were included in the various studies.

First- and second-generation drugs -- Cytadren (aminoglutethimide), formestane, and fadrozole -- had no significant benefit compared to other agents, the researchers found.

The benefit for the third-generation agents was roughly equivalent regardless of whether they were used as first-line therapy, compared with tamoxifen, or as second- and third-line therapy, compared to progestagens, Dr. Ioannidis and colleagues found.

Specifically:

• Compared to tamoxifen, the third-generation drugs had an 11% relative hazard reduction, which was significant at P=0.03.
• The third-generation aromatase inhibitors were significantly associated with increased survival compared with standard hormone therapy. The relative hazard was 0.87, with a 95% confidence interval from 0.82 to 0.93, which was significant at P <.001.
• In contrast, the relative hazard for the first- and second-generation drugs was 0.98, with a 95% confidence interval from 0.90 to 1.07, which was not significant.
• Compared to progestagens, the third-generation drugs had a relative hazard reduction of 14%, which was significant at P<0.001.

The study has some of the common limitations of a meta-analysis, Dr. Ioannidis and colleagues said, including the possibility of publication bias. Also, the researchers noted they did not have individual patient data, which might have allowed a more refined analysis.

Despite the limitations, "we believe that this study was well executed and that the results are acceptable," said Catherine Van Poznak, M.D., and Daniel Hayes, M.D., of the University of Michigan Health and Hospital System in Ann Arbor, Mich., in an accompanying editorial.

In fact, they said, some of the limitations may actually have caused an under-estimate of the benefit of the aromatase inhibitors. For instance, they argued, using prolongation of survival as an endpoint precluded evaluation of quality of life and cost-effectiveness issues.

The study is not likely to change clinical practice, they said, because in the U.S., it is already shifting. The conclusions "are welcome confirmation of common clinical practice in the United States," they wrote.

At the same time, however, it is too soon to throw tamoxifen on the scrap heap, they said, if only because the optimal adjuvant therapy for hormone-receptor-positive breast cancer is yet to be established.

"There is much to be done and much to be learned," they concluded.