January 12, 2012 — Infertility as a result of chemotherapy for breast cancer is not improved with the use of a gonadotropin-releasing hormone (GnRH) agonist, according to a new study.
In the Suppression of Ovarian Function With Triptorelin (SOFT) trial, the rate of premature menopause among women treated with a GnRH agonist was similar to that in the control group. The trial was stopped early because of futility, and the researchers conclude that this approach "should not be recommended."
The SOFT results were published online January 9 in the Journal of Clinical Oncology.
This negative trial joins 2 others that also failed to show a benefit with GnRH agonists, although these 3 negative trials are in contrast to 2 others that were positive, according to an accompanying editorial. In view of these conflicting data, the role of ovarian suppression through chemotherapy "remains uncertain," writes the editorialist, Ann Partridge, MD, from the Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, Massachusetts.
Results From the SOFT Trial
The SOFT trial, conducted by Pamela Munster, MD, from the University of California, San Francisco, and colleagues, originally aimed to enroll 124 patients, but it was stopped after 49 patients were enrolled.
The participants were premenopausal women younger than 45 years who had been newly diagnosed with early-stage breast cancer (stage I to III). All the women received 1 of 4 adjuvant chemotherapy regimens: AC (4 cycles of doxorubicin plus cyclophosphamide), AC-T (4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of a taxane), FEC (6 cycles of fluorouracil plus epirubicin plus cyclophosphamide), or FAC (6 cycles of fluorouracil plus doxorubicin plus cyclophosphamide).
In addition, women with estrogen-receptor-positive tumors were offered tamoxifen.
Study patients in the treatment group received an intramuscular injection of the GnRH agonist triptorelin (Trelstar Depot) 3.75 mg every 28 to 30 days, starting before and continuing throughout the chemotherapy.
When the trial was halted, there was an imbalance in the number of patients available for analysis between the triptorelin group and the control group (26 vs 21).
The median follow-up was 18 months (range, 5 to 43 months) after completion of chemotherapy.
There was no difference in the rate of amenorrhea between the triptorelin and control groups (10% vs 12%). Three women in the triptorelin group and 2 in the control group stopped menstruating and their menses did not return; all 5 were taking tamoxifen.
For many of the remaining patients, menstruation stopped and then restarted. The median time to return of menses was 5.8 months in the triptorelin group and 5.0 months in the control group; the difference was not statistically significant (P = .58). One woman in the triptorelin group and 5 in the control group continued to menstruate throughout the trial.
Two of the patients in the control group subsequently became pregnant, which resulted in unassisted and normal-term deliveries. No pregnancies or miscarriages were reported in the triptorelin group.
"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," Dr. Munster and colleagues conclude.
Mixed Results From Other Trials
The approach of using GnRH agonists to suppress ovulation during chemotherapy was based on several nonrandomized phase 2 studies, which had reported high rates (67% to 90%) of preserved menstruation in treated patients, the researchers note.
"Our data are consistent with these findings," they note: 88% of women receiving triptorelin resumed menstruation. However, this study was randomized and found no difference between patients in the triptorelin group and those in the control group (90% of women resumed menses).
Results from other randomized trials have been mixed. "This study is 1 of 6 recently completed or ongoing trials that have been designed to address this important question," notes the editorialist, adding that 2 other randomized trials have also shown no clear benefit.
The recently published results from the Zoladex Rescue of Ovarian Function (ZORO) trial (J Clin Oncol. 2011;29:2334-2341), which involved 60 women with hormone-negative breast cancer, found a nonsignificant difference in the rate of menses resumption between women in the goserelin (Zoladex) group and those in the control group (70.0% vs 56.7%; P = .42). Two women in each group became pregnant.
In addition, preliminary data from the Ovarian Protection Trial in Estrogen Negative (OPTION) study, which involved 140 women and also used goserelin, showed no clear benefit (J Clin Oncol. 2010;28[suppl]:15s [abstr 590]). In fact, in the subgroup of women who were younger than 40 years, the treatment group fared worse; at 12-month follow-up, 34.7% of women in the goserelin group had not resumed menses, compared with 15.8% in the control group (P ≤ .05).
Dr. Munster and colleagues note that the negative results from the SOFT trial were similar to those from the ZORO and OPTION trials, which "support our findings that GnRH agonists do not preserve ovarian function as measured by resumption of menses."
However, there have also been 2 positive studies reported.
One of these positive trials, conducted in Italy by the Gruppo Italiono Mammella, involved 281 patients and used triptorelin (JAMA. 2011;306:269-276). The researchers report a significant (17%) difference with treatment — 25.9% of women in the goserelin group had early menopause, compared with only 8.9% in the triptorelin group (P < .001).
The other positive trial was reported a few years ago (Fertil Steril. 2009;91:694-697). It involved 78 women and used goserelin. The researchers reported that within 3 to 8 months of treatment termination, 89.6% of women resumed menses and 69.2% resumed spontaneous ovulation in the goserelin group, compared with 33.3% and 25.6%, respectively, in the control group,.
One randomized trial is still ongoing — the Prevention of Early Menopause (POEMS), in women with hormone-receptor-negative breast cancer.
In view of the conflicting data, and while mature results from ongoing studies are awaited, the role of this treatment approach remains "uncertain," Dr. Partridge notes in her editorial.
"Given the current level of evidence, women who are interested in future fertility, and the providers who are assisting them in these often difficult decisions, should not rely on GnRH agonist treatment during chemotherapy for preservation of menstrual and ovarian function or fertility," she concludes.
The SOFT trial was supported by a grant from the National Cancer Institute. Dr. Munster reports receiving research funding from Pfizer. Dr. Partridge has disclosed no relevant financial relationships.
J Clin Oncol. Published online January 9, 2012. Abstract, Editorial
In the Suppression of Ovarian Function With Triptorelin (SOFT) trial, the rate of premature menopause among women treated with a GnRH agonist was similar to that in the control group. The trial was stopped early because of futility, and the researchers conclude that this approach "should not be recommended."
The SOFT results were published online January 9 in the Journal of Clinical Oncology.
This negative trial joins 2 others that also failed to show a benefit with GnRH agonists, although these 3 negative trials are in contrast to 2 others that were positive, according to an accompanying editorial. In view of these conflicting data, the role of ovarian suppression through chemotherapy "remains uncertain," writes the editorialist, Ann Partridge, MD, from the Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, Massachusetts.
Results From the SOFT Trial
The SOFT trial, conducted by Pamela Munster, MD, from the University of California, San Francisco, and colleagues, originally aimed to enroll 124 patients, but it was stopped after 49 patients were enrolled.
The participants were premenopausal women younger than 45 years who had been newly diagnosed with early-stage breast cancer (stage I to III). All the women received 1 of 4 adjuvant chemotherapy regimens: AC (4 cycles of doxorubicin plus cyclophosphamide), AC-T (4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of a taxane), FEC (6 cycles of fluorouracil plus epirubicin plus cyclophosphamide), or FAC (6 cycles of fluorouracil plus doxorubicin plus cyclophosphamide).
In addition, women with estrogen-receptor-positive tumors were offered tamoxifen.
Study patients in the treatment group received an intramuscular injection of the GnRH agonist triptorelin (Trelstar Depot) 3.75 mg every 28 to 30 days, starting before and continuing throughout the chemotherapy.
When the trial was halted, there was an imbalance in the number of patients available for analysis between the triptorelin group and the control group (26 vs 21).
The median follow-up was 18 months (range, 5 to 43 months) after completion of chemotherapy.
There was no difference in the rate of amenorrhea between the triptorelin and control groups (10% vs 12%). Three women in the triptorelin group and 2 in the control group stopped menstruating and their menses did not return; all 5 were taking tamoxifen.
For many of the remaining patients, menstruation stopped and then restarted. The median time to return of menses was 5.8 months in the triptorelin group and 5.0 months in the control group; the difference was not statistically significant (P = .58). One woman in the triptorelin group and 5 in the control group continued to menstruate throughout the trial.
Two of the patients in the control group subsequently became pregnant, which resulted in unassisted and normal-term deliveries. No pregnancies or miscarriages were reported in the triptorelin group.
"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," Dr. Munster and colleagues conclude.
Mixed Results From Other Trials
The approach of using GnRH agonists to suppress ovulation during chemotherapy was based on several nonrandomized phase 2 studies, which had reported high rates (67% to 90%) of preserved menstruation in treated patients, the researchers note.
"Our data are consistent with these findings," they note: 88% of women receiving triptorelin resumed menstruation. However, this study was randomized and found no difference between patients in the triptorelin group and those in the control group (90% of women resumed menses).
Results from other randomized trials have been mixed. "This study is 1 of 6 recently completed or ongoing trials that have been designed to address this important question," notes the editorialist, adding that 2 other randomized trials have also shown no clear benefit.
The recently published results from the Zoladex Rescue of Ovarian Function (ZORO) trial (J Clin Oncol. 2011;29:2334-2341), which involved 60 women with hormone-negative breast cancer, found a nonsignificant difference in the rate of menses resumption between women in the goserelin (Zoladex) group and those in the control group (70.0% vs 56.7%; P = .42). Two women in each group became pregnant.
In addition, preliminary data from the Ovarian Protection Trial in Estrogen Negative (OPTION) study, which involved 140 women and also used goserelin, showed no clear benefit (J Clin Oncol. 2010;28[suppl]:15s [abstr 590]). In fact, in the subgroup of women who were younger than 40 years, the treatment group fared worse; at 12-month follow-up, 34.7% of women in the goserelin group had not resumed menses, compared with 15.8% in the control group (P ≤ .05).
Dr. Munster and colleagues note that the negative results from the SOFT trial were similar to those from the ZORO and OPTION trials, which "support our findings that GnRH agonists do not preserve ovarian function as measured by resumption of menses."
However, there have also been 2 positive studies reported.
One of these positive trials, conducted in Italy by the Gruppo Italiono Mammella, involved 281 patients and used triptorelin (JAMA. 2011;306:269-276). The researchers report a significant (17%) difference with treatment — 25.9% of women in the goserelin group had early menopause, compared with only 8.9% in the triptorelin group (P < .001).
The other positive trial was reported a few years ago (Fertil Steril. 2009;91:694-697). It involved 78 women and used goserelin. The researchers reported that within 3 to 8 months of treatment termination, 89.6% of women resumed menses and 69.2% resumed spontaneous ovulation in the goserelin group, compared with 33.3% and 25.6%, respectively, in the control group,.
One randomized trial is still ongoing — the Prevention of Early Menopause (POEMS), in women with hormone-receptor-negative breast cancer.
In view of the conflicting data, and while mature results from ongoing studies are awaited, the role of this treatment approach remains "uncertain," Dr. Partridge notes in her editorial.
"Given the current level of evidence, women who are interested in future fertility, and the providers who are assisting them in these often difficult decisions, should not rely on GnRH agonist treatment during chemotherapy for preservation of menstrual and ovarian function or fertility," she concludes.
The SOFT trial was supported by a grant from the National Cancer Institute. Dr. Munster reports receiving research funding from Pfizer. Dr. Partridge has disclosed no relevant financial relationships.
J Clin Oncol. Published online January 9, 2012. Abstract, Editorial
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The SOFT trial, conducted by Pamela Munster, MD, from the University of California, San Francisco, and colleagues, originally aimed to enroll 124 patients, but it was stopped after 49 patients were enrolled.
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