Comment on GnRH analogue cotreatment with chemotherapy for preservation of ovarian function

19 07 2011

To the Editor:

With great interest we have read the systematic review and meta-analysis by Bedaiwy et al. (1). The outcomes of the meta-analysis suggest a potential benefit of GnRH analogs as a cotreatment with chemotherapy in preserving future fertility, with higher rates of spontaneous resumption of menstruation and ovulation.

Six randomized controlled trials (RCTs) met the inclusion criteria. One of the largest studies was published in 2009 (2). After publication, this study was criticized for significant methodological weaknesses invalidating any conclusion based on this study (3). Additional criticisms were that the study group consisted of very young women compared to European and American women with breast cancer, had an unlikely low resumption of menstruation (in particular, only 33% of the controls), and had a short follow-up time (maximum 8 months after the last dose of chemotherapy) (4). Based on these criticisms we doubt the wisdom of including this controversial study.

We performed a new meta-analysis excluding this controversial study (2) (fig.1). According to this new meta-analysis, the incidence of premature ovarian failure is not significantly different anymore (OR 2.25; 95% CI, 0.65-7.78) compared to the original meta- analysis in which a potential benefit of GnRH analogs was suggested (OR 3.46; 95% CI 1.13-10.57). The I2 test in the original meta analysis was 66%, in our new meta analysis the I2 test was 51%, showing a high amount of heterogeneity in the original meta-analysis. An I2 value of 50% and higher is defined as moderate, above 75% as high (5).

Figure 1

The published review did furthermore only include a follow-up of six months from the ZORO Trial (6) and refrained from reporting the 24 months follow-up which was also reported in this trial. This way, the original meta-analysis turned out to be more in favor of intervention with GnRH analogs: the results after a follow up of 24 months in this study did not show a difference in resumption of menses between the GnRH agonists and the control group. With only a follow-up of six months the odds ratio in the new meta-analysis would be 2.33 [0.80-6.77]. Including the follow-up of 24 months in the new meta-analysis (Fig. 1) results in an odds ratio of 2.25 [0.65-7.78].

Although the authors acknowledge the high risk of bias because of missing data of non-compliant patients in four out of six studies included, in three of the six studies included there were also other forms of bias: significantly different baseline FSH levels and significantly different periods of follow-up between GnRH analogue and control groups. By including studies with questionable data the authors introduced a high risk of potentially invalid conclusions. Finally, there was financial support provided by a pharmaceutical company.

Taking all these arguments together, we feel that there is not enough evidence yet to consider cotreatment with GnRH analogs in premenopausal women receiving chemotherapy. Results of large high quality trials have to be awaited before making strong conclusions.

Eva Balkenende, Medical Student
Taghride Dahhan, M.D.
Fulco van der Veen, M.D, Ph.D.
Mariëtte Goddijn, M.D, Ph.D.
Centre for Reproductive Medicine
Academical Medical Centre
University of Amsterdam
Amsterdam, The Netherlands

References
1. Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-Nashar SA et al. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Fertil Steril 2011; 95(3):906-914.

2. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009; 91(3):694-697.

3. Oktay K, Sonmezer M. Questioning GnRH analogs for gonadal protection in cancer patients. Fertil Steril 2009; 92(2):e32.

4. Peccatori F, Demeestere I. GnRH analogue for chemotherapy-induced ovarian damage: too early to say? Fertil Steril 2009; 92(2):e33.

5. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414):557-560.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.07.1112

The Authors Respond:

We would like to thank Balkenede et al. for their interest in our article. We are aware of the potential methodological weakness of the included trials, especially the trial published by Badawy et al. (1) that favored intervention. In the Badawy et al. (1) trial, at the end of the observation period almost 44% more patients were ovulating in the GnRH agonist group than controls. We mentioned clearly in our discussion that this study generated a great deal of controversy.(2, 3) We mentioned in our discussion that the reported amenorrhea rates were twice as high as other groups with even more gonadotoxic chemotherapy and older study populations (4). Even so, since this is a systematic review of the evidence, rather than a narrative review, we are obliged to include all trials that fulfilled the inclusion criteria rather than to exclude trials, as Balkenende et al. suggest, on the basis of literature criticism of their validity. The potential risk of bias of trials were assessed and reported in accordance to the guidelines set forth by the Cochrane Collaboration.

Additionally, we really did not stress at all in our conclusion the superiority of the GnRH analogues. As for the issue with the second trial, Gerber et al. (5), we decided to analyze data from the 6-month follow-up, as this was the primary outcome of the trial. Furthermore in this trial 93-96% of chemotherapy-treated patients had normal periods at the 24-month follow-up, regardless of whether they were co-treated with an agonist. Either assessment of regular periods at the 24-month follow is not an appropriate metric of ovarian injury or the concept of ovarian injury from chemotherapy can be challenged, since virtually everyone had return of regular menstruation. Had we used the 2-year data, then the results would be non-significant (O.R = 3.34, 95% CI = 0.97 to 11.52).

Clinical trial bias is an important concept. However if one domain of the risk of bias tool is considered to be high, then the whole trial is considered to be at a high risk of bias, regardless of the outcome of the other domains. In other words, there is nothing called very high risk of bias (or double risk of bias), as Balkenende et al. suggest. According to the latest version of the Cochrane Handbook (6), study sponsorship is not a source of bias; again discrediting the argument that pharmaceutical sponsorship per se is a reason to doubt the results of an included trial. Finally, another meta-analysis showed that GnRHa cotreatment during chemotherapy can protect ovarian function (7).

In conclusion, it is important for new interventions to be tested rigorously in well-designed and power controlled trials. Systematic reviews help to fill the gaps found in individual trials and increase the overall power to detect differences between competing interventions. A rigorous, meticulous and transparent strategy is needed to ensure that the conclusions can be generalized to a wider population.

Mohamed A. Bedaiwy M.D., Ph.D.1
Ahmed M. Abou-Setta M.D., Ph.D.2
Nina Desai Ph.D., H.C.L.D.3
William Hurd, M.D.1
Tommaso Falcone, M.D.3

1Department of OB/GYN
University Hospitals Case Medical Center
Case Western Reserve University
Cleveland, Ohio
2Alberta Research Centre for Health Evidence (ARCHE)
University of Alberta
Edmonton, Alberta, Canada
3Department of OB/GYN and Women’s Health Institute
Cleveland Clinic Foundation
Cleveland, Ohio

References
1. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91:694-7.

2. Oktay K, Sonmezer M. Questioning GnRH analogs for gonadal protection in cancer patients. Fertil Steril 2009;92:e32; author reply e4.

3. Peccatori F, Demeestere I. GnRH analogue for chemotherapy-induced ovarian damage: too early to say? Fertil Steril 2009;92:e33; author reply e4.

4. Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-Nashar SA, Al-Inany HG, Falcone T. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Fertil Steril. 2011 ;95(3):906-14.e1-4.

5. Gerber B, Stehle H, Ricardo F, Maass D, Fischer N, Sommer HL et al. ZORO: A prospective randomized multicenter study to prevent chemotherapy-induced ovarian failure with the GnRH-agonist goserelin in young hormone insensitive breast cancer patients receiving anthracycline containing (neo-) adjuvant chemotherapy (GBG 37). In: American Society of Clinical Oncology (ASCO) Annual Meeting: J Clin Oncol, 2009:15s.

6. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org.

7. Kim SS, Lee JR, Jee BC, Suh CS, Kim SH, Ting A, Petroff B. Use of hormonal protection for chemotherapy-induced gonadotoxicity. Clin Obstet Gynecol. 2010;53(4):740-52.

6. Gerber B, von MG, Stehle H, Reimer T, Felberbaum R, Maass N et al. Effect of Luteinizing Hormone-Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study. J Clin Oncol 2011; 29(17):2334-2341.

Published online in Fertility and Sterility


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