Taking the GnRH analogue triptorelin during chemotherapy led to a 17% absolute reduction in the occurrence of early menopause in young women with early-stage breast cancer, investigators have reported.
“Our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause. This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy,” wrote Dr. Lucia Del Mastro of Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and her associates.
In what they described as the largest phase III study to examine this issue, the investigators assessed 281 women aged 18-45 years who were treated for stage I, II, or III breast cancer at 16 Italian medical centers. The patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone or chemotherapy plus intramuscular triptorelin, and were followed for 1 year to compare the incidence of early menopause. For this open-label trial, early menopause was defined as no resumption of menstrual activity and postmenopausal levels of FSH.
Women with hormone-sensitive tumors were also given tamoxifen for 5 years following the end of chemotherapy. Those whose ovarian function returned during the follow-up year also received triptorelin every 4 weeks until ovarian function had been suppressed for at least 2 years, to optimize their chance of eradicating the breast cancer.
The rate of early menopause was 26% for chemotherapy alone, compared with 9% for the addition of triptorelin, an absolute decrease of 17%. The number of patients who needed to take triptorelin to prevent one case of early menopause was just six, Dr. Del Mastro and her colleagues wrote (JAMA 2011;306:269-76).
Moreover, in a multivariate analysis the only factor found to significantly reduce the development of premature menopause was the use of triptorelin.
In a secondary analysis of a subgroup of 260 patients, menses resumed in 50% of the chemotherapy-only group, compared with 63% of the chemotherapy-plus-triptorelin group. The median time to resumption of menses was 6.7 months with the addition of triptorelin, but was not reached in the women who received chemotherapy alone.
“There was no difference in the incidence of selected toxicities that may have been partly related to the use of triptorelin,” they added.
Longer follow-up is needed to assess the long-term maintenance of ovarian function and preservation of fertility in these patients. However, “at the time of the last annual follow-up, 1 full-term pregnancy in the chemotherapy-alone group and 3 pregnancies (1 full-term, 1 premature delivery, and 1 voluntary abortion) in the chemotherapy plus triptorelin group were reported,” the researchers said.
In addition, longer follow-up is necessary to assess the effectiveness of the breast cancer therapy. So far, it doesn't appear that adding triptorelin interferes with chemotherapy's effects. There have been 27 breast cancer recurrences (13 with chemotherapy alone and 14 with the addition of triptorelin) and 11 deaths (3 in the chemotherapy-alone group, 8 in the chemotherapy plus triptorelin group), the researchers said.
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Approach With Caution
The findings of Del Mastro and associates are “intriguing, and represent an important and encouraging addition to the study of ovarian preservation for women in this difficult situation,” wrote Dr. Hope S. Rugo and Dr. Mitchell P. Rosen.
However, it would be premature to advocate the routine use of GnRH analogues for these patients of childbearing age who are facing early menopause.
“Given that patients with hormone receptor–positive disease in the current study who had evidence of ovarian recovery were immediately suppressed without data on long-term recovery and that breast cancer outcome data are not available, and given as well the potential adverse effects on disease outcome, the use of GnRH agonists concomitant with chemotherapy cannot be recommended as a standard treatment and should be approached with caution in women with hormone-sensitive disease,” they said.
HOPE S. RUGO, M.D., and MITCHELL P. ROSEN, M.D., are at the University of California, San Francisco. The university has received research funding from Pfizer, Novartis, Roche/Genentech, Abbott, Celgene, Merck, and Bristol-Meyers Squibb. Dr. Rugo reported receiving honoraria from Genomic Health. Dr. Rosen reported having no disclosures. These remarks were taken from their editorial accompanying Dr. Del Mastro's report (JAMA 2011;306:312-4).
