Gonad Suppression During Chemotherapy: Is the Evidence Real?

Alexander M. Castellino, PhD

June 11, 2015

A new meta-analysis questions the use of gonadotropin-releasing hormone (GnRH) analogues during chemotherapy to preserve fertility, but a researcher involved in a recent large trial with one of these agents questions the conclusions of the meta-analysis and remains convinced about this approach.

The American Society of Clinical Oncology recommends that physicians treating women of childbearing age with chemotherapy for cancer should integrate fertility preservation measures into their treatment plans. One option for doing this is through gonad suppression using GnRH during chemotherapy. Several trials have shown the merit of this procedure, including the recent POEMS trial with goserelin, which was hailed as practice-changing when presented and was subsequently published in the New England Journal of Medicine.

However, a meta-analysis published online June 5 in Obstetrics and Gynecology indicates that GnRH analogues may not protect ovaries from chemotherapy toxicity. Indeed, the authors conclude: "It [use of GnRH analogues] is not a reliable method of fertility preservation."

The meta-analysis, which included 10 randomized trials, was conducted by Eman Elgindy, MD, PhD, and colleagues at the Departments of Obstetrics and Gynecology, Zagazig University School of Medicine and the Cairo University Faculty of Medicine, in Egypt, and the Department of Obstetrics and Gynecology, Maastricht University, the Netherlands.

Medscape Medical News asked Halle Moore, MD, from the Department of Hematology-Oncology, Cleveland Clinic, in Ohio, for her reaction. Dr Moore was not associated with the meta-analysis, but she was the first author of the POEMS study, which was one of the 10 studies included in the meta-analysis.

"These findings do not dissuade me in my belief that GnRH analogues offer an option for ovarian function preservation," she said.

"This meta-analysis does not supercede the findings from POEMS," Dr Moore told Medscape Medical News.

"POEMS was carefully designed to overcome limitations of previous studies, which were inconclusive regarding the role of GnRH analogues for ovarian protection. This meta-analysis included studies with varying endpoints, and in some of the trials, patients took tamoxifen, which confounds assessment of ovarian function," she said.

Meta-analysis Details

The authors of the meta-analysis conducted a search across several databases through March 2015. Two of the authors independently screened titles and abstracts of search results to identify trials that met their criteria of randomized clinical trials with key phrases.

Of 1300 screened records, 32 articles were assessed for eligibility. The meta-analysis included 10 randomized trials that included women of reproductive age who were receiving chemotherapy for breast cancer, lymphomas, or ovarian cancer. Studies with as few as 18 women and as many as 281 women were included in the analysis and were appropriately weighted.

The meta-analysis showed that compared with women receiving chemotherapy alone, resumption of ovarian function was not significant for women who received GnRH analogues with chemotherapy (68.4% vs 59.9% for women receiving only chemotherapy; risk ratio, 1.12; 95% confidence interval, 0.99-1.27; P = .07).

Similar trends were shown when data were separately analyzed for the six breast cancer studies and the three lymphoma studies. No significant benefit of GnRH analogues was reported for women younger than 40 years as well as for women aged 40 years and older.

"Our meta-analysis showed that GnRH analogs during chemotherapy do not significantly increase resumption of ovarian function after the end of chemotherapy," the researchers write in their discussion.

"There is no convincing evidence that the analog offers protection of ovarian reserve," they add. Ovarian reserve was analyzed for studies that reported quantitative values for early follicular FSH, antral follicle count, and antimüllerian hormone, and by reports on pregnancy.

Questions Raised

Dr Moore told Medscape Medical News: "The trend reported in the meta-analysis favors the importance of GnRH analogues in ovarian function and prospects for spontaneous pregnancy," but the results from the meta-anlysis did not reach statistical significance.

"The meta-analysis had limitations that made the findings more difficult to interpret," Dr Moore said.

Two critical studies were omitted in this meta-analysis, Dr Moore indicated, and both of these had statistically significant results. Most of the studies included in the analysis showed more modest improvement in ovarian function preservation, she added.

One of the two studies that were omitted from the meta-analysis was by Ahmed Badawy, MD, and colleagues and showed a dramatic improvement for women receiving GnRH analogue treatment: 33% for chemotherapy alone and 90% for GnRH plus chemotherapy. The other study was by Dr Guiping Song and colleagues, who showed that leuprolide acetate was associated with a significant reduction in the occurrence of early menopause (17% vs 29% for women receiving chemotherapy alone; P < .01).

The authors of the meta-analysis explained that they excluded the study by Dr Badawy and colleagues "because of major flaws, whether in study methods or results, with strong doubts about the randomized nature of the study."

Dr Moore said that the studies that were included in the meta-analysis were of varying quality and with varying endpoints, and she pointed out that prior meta-analyses using most of the same studies but choosing different endpoints led to the opposite conclusion.

Dr Moore told Medscape Medical News: "There is convincing evidence that GnRH analogues improve prospects for fertility preservation. It may not be a perfect treatment, but no treatment is."

In addition to improving fertility prospects, the use of GnRH analogues also reduces the risk for early menopause and its associated unwanted effects, she said.

Other approaches to preserving ovarian function or fertility include cryopreservation of ovarian tissues, oocytes, and embryos, she noted.

"Not everyone is a perfect candidate for these procedures," she said. If possible, women should not rely on a GnRH agonist alone for ovarian function, she noted. Although referral to a reproductive endocrinologist should be routinely offered, the assisted reproduction approaches are costly, time consuming, and not for all, she suggested.

The different approaches for protecting fertility are not all mutually exclusive, Dr Moore said.

The meta-analysis authors claim that "according to our results, a RCT including at least 819 participants in each arm is needed to proof [sic] a beneficial effect of GnRH analogs in preventing ovarian toxicity."

Dr Moore thinks this is unlikely. However, she told Medscape Medical News that an individual patient-level meta-analysis is planned and should hopefully provide more conclusive information than the current analysis.

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