BENEFITS OF OVARIAN SUPPRESION DURING BREAST CANCER CHEMOTHERAPY-BAD TRIAL DESIGN

Temporary ovarian suppression during chemotherapy in young women with early-stage breast cancer reduced the occurrence of treatment-induced early menopause, according to Italian researchers.
In a phase 3 study, triptorelin, a gonadotropin-releasing hormone agonist (GnRH), was administered to suppress ovarian function during chemotherapy in the hope of protecting women 18 to 45 years of age from ovarian failure, say the authors, led by Lucia Del Mastro, MD, from the Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy. They report their results in the July 20 issue of the Journal of the American Medical Association.
The exact mechanism through which this protection takes place is not known, admit the authors.
Nonetheless, patients randomized to the group that received chemotherapy plus triptorelin had a lower rate of early menopause than those randomized to the group that received chemotherapy alone, for an absolute difference of −17% (8.9% vs 25.9%; P <.001).
Early menopause was defined as either the failure to resume menses or to recover premenopausal levels of estradiol 12 months after the end of chemotherapy.
Triptorelin "can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," conclude the authors.
However, a pair of American breast cancer experts suggest that this conclusion is overreaching.
"Recovery of a single menstrual cycle or premenopausal levels of estradiol are not definitive measures of recovery of ovarian function," write Hope Rugo, MD, and Mitchell Rosen, MD, from the University of California San Francisco, in an editorial accompanying the study.
Furthermore, the editorialists note that a large portion (82%) of the study participants had hormone-receptor-positive disease. If these women recovered their menses after treatment with triptorelin, the study protocol called for the immediate use of 2 more years of ovarian suppression with triptorelin, in addition to 5 years of tamoxifen, to avoid the adverse effects of ovarian-produced estrogen on disease outcome. As a result, "it is impossible to evaluate the effects of ovarian suppression on true recovery of ovarian function or on ovarian reserve," they write. True recovery means long-term recovery, they suggest.
Another problem with the study and its approach is that other research suggests that loss of menses is helpful in the treatment of hormone-receptor-positive breast cancer, the editorialists note.
They point out that "recent data have confirmed that amenorrhea 12 months after the start of therapy had an important effect on outcome, with an almost 50% relative improvement in risk of recurrence or death in women with hormone-receptor-positive disease and amenorrhea, compared with those with persistent menstrual function" (N Engl J Med. 2010;362:2053-2065).
Because the current study has no information about disease outcome and because women with hormone-receptor-positive disease who had evidence of recovery were immediately resuppressed, per the study protocol (and thus cannot be counted as having long-term recovery of ovarian function), the editorialists believe too much is unknown about ovarian suppression with triptorelin.
Thus, the use of triptorelin is not wholly advisable in women with hormone-sensitive disease, they argue.
The current study — and mixed results from other, smaller studies on this subject — indicate that, for women with hormone-sensitive disease, "the use of GnRH agonists concomitant with chemotherapy cannot be recommended as a standard treatment and should be approached with caution," they write.
The Matter of Fertility
The study, known as PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6), was conducted at 16 Italian centers. Between October 2003 and January 2008, the investigators enrolled 281 patients who were premenopausal with stage I to III breast cancer.
Patients received adjuvant or neoadjuvant treatment with anthracycline-based chemotherapy, anthracycline plus taxane-based chemotherapy, or CMF-based chemotherapy (100 mg/m² of oral cyclophosphamide on days 1 to 14 or 600 mg/m² of intravenous cyclophosphamide on days 1 and 8; 40 mg/m² of methotrexate on days 1 and 8; and 600 mg/m² of fluorouracil on days 1 and 8).
The patients randomized to receive triptorelin (n = 148) were given an intramuscular dose of 3.75 mg at least 1 week before starting chemotherapy, and then every 4 weeks for the duration of the treatment, according to the authors.
Women with hormone-receptor-positive disease received 20 mg/day of tamoxifen for 5 years starting after chemotherapy ended.
Predictably, recovery of menses was less common in women receiving tamoxifen, and the protection with triptorelin from early menopause was greater in women with hormone-receptor-negative disease than in those with hormone-receptor-positive disease.
Multivariate analysis showed that only treatment with triptorelin was associated with a significant reduction in the risk of developing early menopause (odds ratio, 0.28; 95% confidence interval, 0.14 to 0.59; P <.001). Patient age and the type of chemotherapy (taxane- or CMF-containing) did not significantly affect the risk, report the authors.
Although the incidence of early menopause was the primary outcome measure, the investigators say that infertility is another major concern for these young women.
"Young survivors of breast cancer consider premature menopause, sexual dysfunction, and infertility the most distressing aspects of their cancer experience," write the authors, referring to chemotherapy-induced adverse events.
As a strategy to preserve fertility, ovarian suppression has a number of advantages over cryopreservation. It "does not require a male partner, is simple to administer, does not require delaying chemotherapy, and is less invasive and less expensive," the authors say. These 2 approaches to preserving fertility are "not mutually exclusive," they write, adding that "they can be used together to increase the probability of preserving fertility."
The editorialists agree that GnRH agonist therapy during chemotherapy can "potentially expand fertility possibilities." However, they point out that "recovering menses is not the same as fertility preservation." Instead, what matters most is "ovarian reserve," which is an end point that "clearly affects reproductive potential but is more difficult to measure." In short, the resumption of menses is a surrogate marker for fertility.
The editorialists champion reproductive technology for women in the "difficult situation" of being treated with chemotherapy for breast cancer. They write: "The most effective option for fertility preservation is assisted reproductive technology with embryo or oocyte cryopreservation, and this option should be discussed with young women facing chemotherapy for breast cancer and other curable malignancies."
This study was sponsored by the Istituto Nazionale per la Ricerca sul Cancro, and partly supported by a grant from the Associazione Italiana per la Ricerca sul Cancro, Italy. The triptorelin used in the study was provided by Ipsen (Milan, Italy). Dr. Del Mastro reports receiving honoraria for speaking activity from Ipsen. Another author reports receiving payment for lectures from AstraZeneca. Dr. Rugo reports that her institution has received research funding from Pfizer, Novartis, Roche/Genentech, Abbott, Celgene, Merck, and Bristol-Meyers Squibb, and she reports receiving honoraria from Genomic Health. Dr. Rosen has disclosed no relevant financial relationships.