Ovarian Suppression Has Role in Premenopausal Breast Cancer Therapy

LONDON, May 18 -- Ovarian suppression can help reduce the risk of recurrence of hormone-sensitive premenopausal breast cancer, found international researchers.

A meta-analysis of data from 16 studies involving nearly 12,000 women found that ovarian suppression with a lutenizing-hormone-releasing hormone (LHRH) agonist, added to tamoxifen, chemotherapy, or both, reduced the risk of recurrence by 12.7%, the investigators reported in the May 19 issue of The Lancet.

The risk of death after recurrence was reduced by 15.1%, added Jack Kuzick, Ph.D., of the Wolfson Institute of Preventive Medicine here, and colleagues. They included co-authors at Johns Hopkins and at the Dana-Farber Cancer Institute in Boston.

Although ovarian suppression with an LHRH agonist as the sole form of adjuvant therapy was not associated with a significant reduction in the risk of cancer recurrence or death, this may have been because of the relatively small number of patients treated that way, commented Nicholas Wilcken, M.D., and Martin Stockler, M.D., both of the University of Sydney in Australia, in an accompanying editorial.

"When an LHRH analogue was the only systemic therapy used, the risk of recurrence was reduced by about a quarter (28%, P=0.08)," they wrote. "This reduction is almost identical to that from oophorectomy, so the borderline P value reflects the small numbers of individuals involved rather than genuine uncertainty about the treatment effect. The addition of LHRH analogues to either tamoxifen or chemotherapy led to smaller, but more clearly proven, reductions in the risk of recurrence."

Previous studies have looked at the effects of LHRH agonists such as goserelin (Zoladex) or leuprorelin (Lupron) alone or in combination with tamoxifen and other adjuvant therapies, or pitted against a chemotherapy regimen. But results from these trials had been inconclusive about the effects of LHRH agonists on time to recurrence, death after recurrence, or overall survival, the meta-analysis authors noted.

For their meta-analysis to resolve the inconclusive findings, the authors, known collectively as the LHRH-agonists in Early Breast Cancer Overview group, collected data on individual patients from published trials and conducted analyses focused on women with tumors that were estrogen-receptor or progesterone receptor positive, or both. The main study endpoints were cancer recurrence and death after recurrence.

They identified 11,906 premensopausal women with early breast cancer who were enrolled in 16 randomized clinical trials.

They found that when an LHRH agonist was used as the only systemic adjuvant therapy, there was a 28.4% relative reduction in risk of recurrence, but this was not statistically significant (95% confidence interval, 50.5% reduction to a 3.5% increase, P=0.08).

Similarly, solo use of an LHRH agonist was associated, but not significantly, with a 17.8% relative reduction in risk of death after recurrence (95% CI. 52.8% reduction to 42.9% increase, P=0.49).

When they looked at the addition of LHRH agonists to tamoxifen, chemotherapy, or both, however, they found that the agents reduced recurrence by 12.7% (95% CI, 2.4-21.9, P=0.02), and death after recurrence by 15.1% (95% CI, 1.8-26.7, P=0.03).

In trials where LHRH agonists were tested head-to-head against chemotherapy, they were roughly comparable in effectiveness, the authors noted.

"LHRH agonists also showed a small additional benefit when used after chemotherapy, either alone or with tamoxifen, in women aged 40 years or younger, in whom chemotherapy is less likely to induce permanent amenorrhea than in older women," they wrote. "The occurrence of this outcome might now be more common with the use of modern, non-CMF [cyclophosphamide, methotrexate, and 5-fluorouracil] -based chemotherapy, for which permanent amenorrhea after treatment seems to be less common."

The results of the meta-analysis suggest that ovarian suppression is a "reasonable alternative" to chemotherapy in younger women with low-risk, hormone-sensitive breast cancer, Drs. Wilcken and Stockler wrote in their editorial.

"In women with higher-risk disease, chemotherapy followed by tamoxifen should still be the standard approach, with the addition of an LHRH analogue a reasonable consideration for those who remain premenopausal," they wrote.

Dr. Kuzick and colleagues noted that one possible limitation of their study was the potential for bias, since all of the trial included in the analysis were open-label studies.