Evidence-based medicine or just a theory?

LETTER TO THE EDITOR Evidence-based medicine or just a theory? To the Editor: Recent correspondence in this journal (1, 2) renewed the interest in GnRH agonist (GnRH-a) therapy as an ‘‘ovarian protectant’’ in female patients undergoing chemotherapy. Do we have evidence-based data to recommend this treatment? Twenty-eight years ago the concept was first introduced. One would expect an evidence-based answer to the question by now. After all, this is a classic question that can be answered only by a multicenter, randomized prospective study. Do we have the answer? Blumenfeld et al. (3) have summarized their 25 years of clinical experience in a ‘‘prospective nonrandomized study with concurrent and historical controls.’’ This publication suffers from major drawbacks (4, 5). However, it did not stop the flow of theories that suppose to explain the ‘‘findings’’ (Discussion, Blumenfeld et al. [3]). We would like to emphasize the major, but not only, faulty design of the study: How can a prospective study have historical control? What are the historical controls? Well, 20 patients who presented to the clinic from 1980 to 1990. Why only 20? We can only guess. Is it possible that this is a selected group of patients referring to the clinic because of postchemotherapy signs and symptoms of premature ovarian failure? How can one explain only 20 patients during 10 years (1980–1990) and 95 patients during the 15 years (1990–2005) of the ‘‘study?’’ Has the frequency of Hodgkin’s lymphoma increased that much? A clinical experience of only 115 patients during 25 years in a major oncology referral center in Israel is definitely not a reasonable number. In short, the ‘‘control’’ group cannot be accepted as a true scientific control; therefore, the seemingly impressive statistics of this three-decade study, which includes more variables than in a juggling act, are, in our opinion, absolutely invalid. A recent abstract (6) detailing a randomized trial in 49 patients with breast cancer concluded that ‘‘The use of GnRHa does not appear to benefit patients in preserving menstrual status.’’ However, Badawy et al., (7) who performed a similar study, concluded the opposite: ‘‘GnRH-a administration before and during combination chemotherapy for breast cancer

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may preserve post treatment ovarian function in women <40 years.’’ In short, this study (3) is entirely irrelevant to the question at hand, and the latter must await a well-powered, randomized controlled study before we can offer GnRHa treatment to patients with cancer. Until then, we join Oktay et al. (1), Oktay and So¨nmezer (4), and Beck-Fruchter et al. (5) to voice the deep concern that such ‘‘scientific’’ publications (3) may derail actual patient care. Shahar Kol, M.D. Avraham Lightman, M.D., M.Sc. Joseph Itskovitz-Eldor, M.D., D.Sc. Department of Obstetrics and Gynecology, In Vitro Fertilization Unit Rambam Medical Center Haifa, Israel March 2, 2009

REFERENCES 1. Oktay K, Sonmezer M, Barad D, Gleicher N. Trying to reduce ovarian damage in patients with Hodgkin lymphoma using GnRH agonists? [letter]. Fertil Steril 2009;91:298–9. 2. Blumenfeld Z. Trying to reduce ovarian damage in patients with Hodgkin lymphoma using GnRH agonists? [letter reply]. Fertil Steril 2009;91:299. 3. Blumenfeld Z, Avivi I, Eckman A, Epelbaum R, Rowe JM, Dann EJ. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008;89:166–73. 4. Oktay K, So¨nmezer M. Gonadotropin-releasing hormone analogs in fertility preservation—lack of biological basis? Nat Clin Pract Endocrinol Metab 2008;4:488–9. 5. Beck-Fruchter R, Weiss A, Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update 2008;14:553–61. 6. Ismail-Khan R, Minton S, Cox C, Sims I, Lacevic M, Gross-King M, et al. Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: a randomized trial using GnRH agonist (triptorelin) during chemotherapy [abstract]. J Clin Oncol 2008;26 (May 20 Suppl):524. 7. 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.

doi:10.1016/j.fertnstert.2009.03.070

Fertility and Sterility Vol. 92, No. 1, July 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.

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