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 reported in the July 20 issue of JAMA.
"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 randomly assigned to receive adjuvant or neoadjuvant chemotherapy alone or chemotherapy plus IM 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 follicle-stimulating hormone (FSH).
Women with hormone-senstive 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 25.9% for chemotherapy alone, compared with 8.9% 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 only 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 49.6% of the chemotherapy-only group, compared with 63.3% 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 three pregnancies (one full-term, one premature delivery, and one voluntary abortion) in the chemotherapy plus triptorelin group were reported," Dr. Del Mastro and fellow 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.
The mechanisms by which GnRH analogues may preserve ovarian function "are not fully understood but may include the interruption of FSH secretion, a decrease in utero-ovarian perfusion, the activation of GnRH receptors, the up-regulation of intragonadal antiapoptotic molecules such as sphingosine-1-phosphate, or the protection of undifferentiated germ-line stem cells," they noted.