This study tested the potential benefits of using a GnRH agonist to prevent chemotherapy-induced amenorrhea. In addition, we sought to define incidence of amenorrhea when patients were stratified for age, chemotherapy regimen, and tamoxifen use. Previous reports have suggested a considerable reduction in amenorrhea rates with temporary ovarian suppression using GnRH analogs during chemotherapy.11–16
Our results show that amenorrhea rates between the control and triptorelin groups did not differ when treating women age 44 years or younger with contemporary chemotherapeutic agents for early-stage breast cancer. All patients received four to six cycles of chemotherapy with an anthracycline-based regimen alone or followed by a taxane.
Interim analysis after enrollment of 49 patients showed a 90% resumption of menses in the control group and 88% in the triptorelin group when observed for a median of 18 months after completion of chemotherapy. Therefore, this study did not meet its primary end point of a benefit of GnRH agonists over no intervention. The study had originally planned to enroll a total of 124 patients with an expected amenorrhea rate of 10% in the triptorelin arm, based on historical data, and 30% in the control arm. However, the observed amenorrhea rate in this randomized, age- and regimen-stratified study was comparable in both arms (10% and 12%). All but one of the patients without resumption of menses were observed for at least 36 months from the onset of chemotherapy.
Defining chemotherapy-induced amenorrhea is complicated by the fact that natural menopause also occurs in this patient population over the time of follow-up, and treatment-induced amenorrhea is not distinguishable from natural menopause unless menses are observed to resume after treatment completion. Szwarc et al21
discuss a parametric model for time to amenorrhea and time to recovery of menses, which accounts for the presence of censoring and possibility that treatment may induce natural menopause. To limit bias of our observation, we performed a proportional hazards model to test if the treatment (triptorelin) had any impact on time to menses. In comparing the triptorelin with the control group, a hazard ratio of 0.76 (95% CI, 0.40 to 1.46) demonstrates that no impact was observed.
Four nonrandomized studies have shown 67% to 90% of premenopausal patients resumed menstruation if given a GnRH analog during chemotherapy.11–13,16
Median age was 37 years; in our study, it was 39 years. In those studies, the chemotherapy regimens included were primarily FEC; cyclophosphamide, methotrexate, and fluorouracil (CMF); cyclophosphamide, epirubicin, and fluorouracil (CEF); and AC. Using similar anthracycline-based treatments, our data are consistent with these findings; 88% of women receiving triptorelin resumed menstruation. However, in contrast to our study, these early trials were nonrandomized phase II studies and did not assess incidence of amenorrhea stratified by contemporary chemotherapy, age, or tamoxifen use in a control arm. Two studies with a randomized control arm have recently been presented but have not yet been published. In addition, a large, multi-institutional study SWOG (Southwest Oncology Group) 0230 (POEMS [Prevention of Early Menopause]) in women with hormone receptor–negative breast cancer is ongoing. Results of the multicenter Italian trial by GIM (Gruppo Italiano Mammella) were presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2010; 281 patients younger than age 45 years undergoing chemotherapy were randomly assigned to receive triptorelin or not. Patients were treated with CEF or EC, AC, FEC or EC followed by taxane, an anthracycline followed by CMF, or CMF alone. The primary end point was early menopause, defined as postmenopausal levels of both FSH and estradiol and no menstrual activity 1 year after end of chemotherapy. With a median age of 39 years and median number of chemotherapy cycles of six, menses resumption and/or premenopausal estradiol levels were observed in 77 (58%) of 133 patients in the control arm versus 114 (77%) of 148 patients in the triptorelin arm (P
This study had a shorter follow-up time (ie, 12 months) than our study, with 18 months.
In contrast, results of the multicenter German study ZORO (Zoladex Rescue of Ovarian Function) were recently published in Journal of Clinical Oncology
. Sixty evaluable patients younger than age 46 years with hormone receptor–negative breast cancer treated with AC with or without a taxane were randomly assigned to receive goserelin or not. The primary objective was reappearance of ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. Return of menses occurred after a median of 6.1 months in the control arm versus 6.8 months in the goserelin arm (P
= .3). By 6 months, 21 women (70%) in the goserelin arm and 17 (56.7%) in the control arm had resumed their menses (P
= .42). Two women, one in each arm, became pregnant.23,24
Preliminary data from the OPTION (Ovarian Protection Trial In Estrogen Negative) trial were presented at the 46th Annual Meeting of ASCO. This trial tested the effects of goserelin during chemotherapy in 227 premenopausal patients with breast cancer. At the time of presentation, 140 had adequate data on menstruation and 1 year of follow-up. The primary end point was cessation or no resumption of menses within 12 months of chemotherapy initiation. Women were stratified into two age groups: younger than 40 years (n = 87) and older than 40 years (n = 53) at diagnosis. In the group age younger than 40 years at 12-month follow-up, 34.7% of women treated with goserelin continued to have no resumption of menses compared with 15.8% in the chemotherapy-only group (P
Results of ZORO and OPTION were similar to those of our study and support our findings that GnRH agonists do not preserve ovarian function as measured by resumption of menses. These data are also comparable to those reported by Fornier et al5
and Sukumvanich et al.9
Fornier et al reported that 141 (85%) of 166 patients treated with contemporary chemotherapy (AC plus paclitaxel) maintained or resumed menstruation. Sukumvanich et al pointed to the importance of age and chemotherapy regimen in assessing chemotherapy-induced amenorrhea. In that study, less than 5% of women age 20 to 34 years had prolonged chemotherapy-induced amenorrhea compared with 11% of women age 35 to 39 and 40% of women age older than 39 years. Women receiving AC or AC plus paclitaxel were more likely to resume menses than those treated with AC plus docetaxel or CMF.
Our data show that in patients with a median age of 39 years, triptorelin does not prevent chemotherapy-induced amenorrhea. In this study, amenorrhea was an indirect measure of fertility. Although preservation of ovarian function is important to retain fecundity, emerging data suggest that chemotherapy-induced amenorrhea in premenopausal women may actually convey a survival advantage and that prolonged amenorrhea improves overall survival from breast cancer.
A large adjuvant study (NSABP [National Surgical Adjuvant Breast and Bowel Project] B-30) designed to compare differences in adjuvant chemotherapy (AC→T, AT, ATC) in node-positive breast cancer showed that in 2,343 premenopausal women, those with prolonged amenorrhea had better disease-free survival (relative risk, 0.70; P
< .001) and overall survival (relative risk, 0.76; P
= .04). Adjustment for treatment, ER status, age, lymph nodes, tumor size, and hormonal therapy showed consistent results among all subgroups.26
In other studies, ovarian ablation or suppression has also been correlated with better overall outcome in premenopausal women with breast cancer.3,27
On the basis of these data, it seems that ovarian preservation may adversely affect survival.
In summary, the observed incidence of chemotherapy-induced amenorrhea in our study was 10% in the control arm and 12% in the arm treated with triptorelin, with no statistical difference. These results suggest that use of GnRH agonists in premenopausal patients treated with contemporary (neo)adjuvant chemotherapy does not offer a benefit in preserving ovarian function compared with patients not treated with GnRH agonists, and it should not be recommended. The rate of amenorrhea in these patients was lower than expected based on historical, nonrandomized, non–age- or –regimen-stratified studies, with often shorter follow-up. With recent data suggesting a survival benefit in patients who become amenorrheic for at least 6 months or longer, means to preserve ovarian function in the early period after breast cancer diagnosis should be reevaluated. Instead, a number of alternative techniques for fertility preservation could be considered in these patients before administration of chemotherapy, such as in vitro fertilization with embryo cryopreservation or oocyte or ovarian cryopreservation.10,28–32