Ovarian suppression with luteinizing hormone-releasing hormone agonists is an effective adjuvant treatment for premenopausal women with hormone receptor-positive early breast cancer, according to a meta-analysis of published trials.
“Our results broadly support those of the previous analyses, but also show other important details. Of particular importance is the benefit of LHRH agonists after chemotherapy in women younger than 40 years … and the equivalence of LHRH agonists with chemotherapy” in hormone receptor-positive cancers, wrote Dr. Jack Cuzick of the University of London, and colleagues.
The study of nearly 12,000 premenopausal women randomized in 16 trials showed that luteinizing hormone-releasing hormone (LHRH) agonists were beneficial when used alone, and effective in addition to tamoxifen or chemotherapy, or as an alternative to chemotherapy. Only trials in which more than half the treatments were with an LHRH agonist were included in the analysis (Lancet 2007;369:1711–23).
Hormone-containing drugs used in the studies included goserelin (10,450 patients), triptorelin (821), and leuprorelin (589). Most of the chemotherapy given was cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) based, but anthracycline-based chemotherapy was used for 38% of the patients who received randomized chemotherapy. No patients received taxanes.
The duration of LHRH treatment was 2 years in most trials, but 18-month, 3-year, and 5-year regimens also were used. Treatment duration was 3 years in the two trials using triptorelin.
From the entire cohort of women, the investigators focused on 9,000 hormone receptor-positive patients, who accounted for 76% of all randomized patients. Of these, 92% were estrogen receptor-positive, whereas the remainder were estrogen receptor-negative but progesterone receptor-positive.
The use of an LHRH agonist, compared with no systemic treatment, did not have a significant effect on recurrence, death after recurrence, or death from any cause, but the effect size was large, the authors said, noting that the number of patients included in this comparison was very small.
The use of an LHRH agonist had similar absolute results for rates of recurrence (3.9% increase), death after recurrence (6.7% decrease), and death from any cause (14.9% decrease), compared with chemotherapy.
The addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced the hazard rate for recurrence by 12.7% and for death after recurrence by 15%, the researchers said, adding that LHRH agonists showed similar efficacy to chemotherapy.
LHRH agonists were ineffective in hormone receptor-negative tumors.
“The scope, focus, and rigor of this overview lend substantial weight to its findings,” Dr. Nicholas Wilcken and Dr. Martin Stockler wrote in an accompanying editorial. They pointed out that a previous meta-analysis on the subject was reported in 2005, with data obtained in 2000, lending this newer and larger study additional weight (Lancet 2007;369:1668–70).
This meta-analysis “has established that ovarian suppression is an active treatment” in the setting of hormone receptor-positive breast cancer in premenopausal women, and “one that can be regarded as a reasonable alternative to chemotherapy in women with low-risk disease,” said Dr. Wilcken and Dr. Stockler of the University of Sydney. “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 added that it is not yet known whether ovarian suppression is as effective as chemotherapy when tamoxifen is used.
Another important question is whether adding an LHRH agonist is only useful when amenorrhea is not achieved with chemotherapy, said Dr. Cuzick and colleagues. “Some trials have shown a worse outcome after chemotherapy in women who did not experience amenorrhea after chemotherapy, and these women could be the ones who benefit most from the addition of an LHRH agonist,” they said.