Evidence-based medicine or just a theory?

17 03 2009

To the Editor:

Recent correspondence in this journal (1,2) renewed interest in GnRH agonist 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 only be answered by a multi-center, 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”, 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 due to post chemotherapy 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 115 patients only during twenty five 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 of 49 breast cancer patients concluded that “The use of GnRH-a 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 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 GnRH-a treatment to cancer patients. Until then, we join Oktay et al (1,4) and Beck-Fruchter et al (5) to voice the deep concern that such “scientific” publication (3) may derail actual patient care.

S. Kol
A. Lightman
Joseph Itskovitz-Eldor, MD, DSc
Department of Obstetrics and Gynecology
IVF Unit
Rambam Medical Center
Haifa, Israel

References
1. Oktay K et al 2009 Trying to reduce ovarian damage in patients with Hodgkin lymphoma using GnRH agonists? Fertil Steril. 91: 298-9.

2. Blumenfeld Z 2009 Trying to reduce ovarian damage in patients with Hodgkin lymphoma using GnRH agonists? Reply of the Author Feril Steril. 91:299.

3. Blumenfeld Z, Avivi I, Eckman A et al 2008 Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril. 89:166-73.

4. Oktay K, Sönmezer M. 2008 Gonadotropin-releasing hormone analogs in fertility preservation-lack of biological basis? Nat Clin Pract Endocrinol Metab. 4:488-9.

5. Beck-Fruchter R, Weiss A, Shalev E. 2008 GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update. 14:553-61.

6. Ismail-Khan R, Minton S, Cox C, et al 2008 Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: a randomized trial using GnRH agonist (triptorelin) during chemotherapy. American Society of Clinical Oncology, 2008 Annual Meeting, Abstract No 524.

7. Badawy A, Elnashar A, El-Ashry et al 2008 Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril (in press, doi:10.1016).

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.03.070

The Authors Respond

I appreciate the editorial invitation to the letter by Kol et al regarding our paper (1). Specifically, to the question: “Has the frequency of Hodgkin lymphoma (HL) increased…?” The answer has been provided by Bleyer et al (2) who found that cancer and HL in adolescents and young adults, has increased in the last 25 years: “The incidence of cancer…increased steadily during the past quarter century”, and “the incidence…increases exponentially” (2). The survival has also significantly increased in the last three decades, affecting the number of patients who were available for follow up along the study years (1,2). The historical controls included all the HL female patients in the recordings of the hematology department, and were not preselected (1). In addition, the referral of young lymphoma patients to our hematology and bone marrow transplantation institute has indeed significantly increased in the last 15 years.

As to the argument that there is no prospective randomized study, let me refer the authors to the following peer reviewed study by Badawy et al (3), in Fertility and Sterility entitled: “…prospective randomized study.” This study (3) has found a significant effect of the agonist in decreasing the gonadotoxic effect of chemotherapy. Similarly, the only prospective randomized study, in monkeys, with histological count of follicles (4), has also found that GnRH-a significantly decreased the total and daily follicular demise. It is surprising that Kol et al did not accept these level-A evidence studies, and elected to adopt a non-peer-reviewed abstract, which has not undergone the accepted peer review evaluation (5).

Furthermore, two recent human reproductive update reviews have summarized all the published studies on this debate (6,7). Both have summarized a 9-11% rate of premature ovarian failure (POF) in the young women who received GnRH-a vs. 55-59% in controls (6,7). The accompanying editorial comment (8), claimed, referring to the prospective randomized study (3): “Complete and transparent publication of this study may help resolve many outstanding questions”. Indeed, this study (3) has been published, showing almost identical results of 11.4% POF in the GnRH-a group vs. 66% POF in controls (P<0.001). In the last decade there were 16 publications with similar positive results regarding the use of GnRH-a for fertility preservation (6-8) for hematologic diseases (lymphoma, leukemia), SLE, or breast cancer. These publications concluded that using GnRH-a concurrently with chemotherapy is associated with a higher rate of ovarian function preservation (6-8). A recent ASCO educational publication (9) similarly found the rates of POF to be 0-6% with GnRH-a vs. 32-47%, without it. Most recently, another randomized study (10) has concluded that: “Among women treated with goserelin, there was a statistically significant increase in the proportion of menstruating women” and “…protective effect of goserelin on ovarian function in CMF treated women.” Thus, there are three prospective studies with positive results.

Last but not least, GnRH-a administration effectively prevents severe menorrhagia and anemia in hemato-oncology patients with thrombocytopenia, a beneficial by-product (11).

Zeev Blumenfeld, MD
Reproductive Endocrinology, Obstetrics and Gynecology
Rambam Health Care Campus
Rappaport Faculty of Medicine & Research Institute
Technion – Israel Institute of Technology
Haifa, Israel

References
1. Blumenfeld Z, Avivi I, Eckman A et al 2008 Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril. 89:166-73.

2. Bleyer A, Viny A, Barr R. 2006. Cancer in 15- to 29-year-olds by primary site. Oncologist. 11:590-601.

3. Badawy A, Elnashar A, El-Ashry et al. 2008. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril (in press, doi:10.1016).

4. Ataya K, Rao LV, Laurence E, Kimmel R. 1995. Luteinizing hormone–releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys. Biol Reprod; 52:365–72.

5. Ismail-Khan R, Minton S, Cox c, et al 2008. Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: a randomized trial using GnRH agonist (triptorelin) during chemotherapy. American Society of Clinical Oncology, 2008 Annual Meeting, Abstract No 524.

6. Blumenfeld Z, von Wolff M.2008 GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update; 14: 543-52. Review.

7. Beck-Fruchter R, Weiss A, Shalev E.2008.GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update. 14:553-61.

8. Hughes EG, Neal MS. 2008. Ovulation suppression to protect against chemotherapy-induced ovarian toxicity: helpful or just hopeful? Hum Reprod Update.14:541-2.

9. Moore HC. 2008. Ovarian Failure after Chemotherapy for Breast Cancer and the Role of Gonadotropin-releasing Hormone Analogs in Protection of Ovarian Function. Am Soc Clin Oncol educational book: 39–42.

10. Sverrisdottir A, Nystedt M, Johansson H, Fornander T (2009) Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. doi:10.1007/s10549-009-0313-5.

11. Meirow D, Rabinovici J, Katz D, et al. (2006) Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer 107, 1634-1641.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.03.072 

We agree with Kol et al. that despite three decades have elapsed since the introduction of the hypothesis that GnRH analogs (GnRHa) may preserve fertility, not a single randomized study has proved that hypothesis. In contrast two randomized studies proved the opposite (1,2). In the most recent randomized study, which was performed on 44 women with breast cancer, patients were randomized to a GnRHa vs. no treatment during breast cancer chemotherapy (2). After 18 months of follow-up, the percentage of patients who resumed menstruation was similar (88% vs 84%). Only 2 pregnancies occurred and those were in the control group. Furthermore, serum FSH and estradiol levels were also similar between the groups. Authors then concluded that GnRHa treatment does not protect ovarian function or fertility and stopped the study at that point. Despite the evidence from experimental data, Dr. Blumenfeld continues to cite observational data and uncontrolled studies to defend a biologically implausible treatment. For example, he cites a pregnancy after bone marrow transplant (BMT) claiming this as a proof of GnRHa effectiveness. As Dr. Blumenfeld pointed out, spontaneous pregnancies may occur following BMT.

Further Dr. Blumenfeld cites another non-randomized study in which baseline ovarian assessment before enrollment was made upon FSH and LH measurements on day 1-5, and normal ovarian function postchemotherapy was determined as the presence of regular menstrual bleeding and on the basis serum FSH and LH <15 IU/l (3). Ovarian reserve assessment should include not only FSH, but also serum estradiol and antral follicle counts as well as anti-Mullerian hormone levels. It is well established that in women with severely diminished ovarian reserve, estradiol levels rise prematurely and suppress FSH levels and thus measurement of FSH levels only will yield false impression of normal ovarian reserve. Moreover in the study by Huser et al, GnRH-a co-treatment was demonstrated ineffective when higher doses of combination chemotherapy were given, as was clearly demonstrated in childhood cancers. While Dr. Blumenfeld cited a rodent study by Ataya et al. which found GnRH-a effective, another primate study by the same group proved the opposite in rhesus monkeys treated by radiation, and was not mentioned (4). Due to space limitation we could not reference the study by Letterie et al. in our previous letter in which ovarian suppression was clearly demonstrated ineffective against chemotherapy in rodents (5).

While Dr. Blumenfeld continues to argue that GnRHa protects ovarian function, even on his account there has not been a single study demonstrating that GnRHa preserves fertility. He also suggests that because there is no randomized comparison comparing oocyte or embryo cryopreservation to no interventions, the success of these techniques are unproven. Given tens of thousands of children born from embryo and oocyte freezing, this would be an unethical study. As Kol et al. suggested, it is time that Dr. Blumenfeld acknowledges the flaws in thinking leading to the misconception of GnRHa as a fertility preservation drug and turn to prospective randomized studies as a source of proof where women are offered GnRHa vs. placebo in addition to effective proven strategies such us embryo and oocyte freezing, with the primary outcome being fertility.

Murat Sonmezer, MD1
Kenny Rodriguez Wallberg, MD, PhD2
Kutluk Oktay, MD3
1Ankara University School of Medicine
Department of Obstetrics and Gynecology
Ankara University Center for Research on Human Reproduction
Ankara, Turkey
2Fertility Preservation Program Fertility Unit
Karolinska University Hospital
Stockholm, Sweden
3Institute for Fertility Preservation at Center for Human Reproduction and Department of Obstetrics and Gynecology
New York Medical College
New York, NY

References
1. Waxman JH, Ahmed R, Smith D et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159-62.

2. Ismail-Khan R, Minton S, Cox c, et al 2008 Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: a randomized trial using GnRH agonist (triptorelin) during chemotherapy. J Clin Oncol 2008; (suppl) 26.

3. Huser M, Crha I, Ventruba P et al. Prevention of ovarian function damage by a GnRH analogue during chemotherapy in Hodgkin lymphoma patients. Hum Reprod 2008;23:863-8.

4. Ataya K, Pydyn E, Ramahi-Ataya A, Orton CG. Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: Preliminary observations. J Clin Endocrinol Metab 1995;80:790-5.

5. Letterie GS. Anovulation in the prevention of cytotoxic-induced follicular attrition and ovarian failure. Hum Reprod 2004;19:831– 7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.03.071

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3 responses

17 03 2009
Zeev Blumenfeld, MD

It is surprisng that Sonmeser and Oktay disregard the two recently published prospective randomized studies (1,2), proving the opposite to their argument….
1.Badawy A, Elnashar A, El-Ashry et al. (2009) Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril . Mar;91(3):694-7.
2.Sverrisdottir A, Nystedt M, Johansson H, Fornander T (2009) Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. doi:10.1007/s10549-009-0313-5.

27 03 2009
Zeev Blumenfeld, MD

A recent meta-analysis (1) has found that, “The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR=1.68, 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR=1.65, CI 1.03–2.6).” These investigators have concluded, “…premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.”

1.Clowse ME, Behera MA, Anders CK, et al. (2009)Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt) 18:311-9.

2 04 2009
Lucia Del Mastro

Correspondence in this journal between supporters of GnRH agonist therapy and supporters of cryopreservation strategies for fertility preservation in women with cancer who are candidates for chemotherapy, do underline the lack of data robust enough to consider one or other as the standard stratregy.

For evidence-based medicine, the quality of evidence is considered good if it is based on good randomized controlled trials (RCTs) or meta-analyses (1). No randomized trial assessed the role of embryo or oocyte cryopreservation strategies. The quality of evidence for recommending such strategies should be considered low, because it is based on nonrandomized, case-control or observational studies.

The role of Gn-RH agonist therapy in preserving ovarian function has been assessed both in randomized trials (2,3) and in nonrandomized, case-control studies. Available randomized trials evaluating the role of Gn-RH therapy may be criticized because of both the small sample size (78 patients in the study of Badawy et al and 44 patients in that of Ismail-Khan et al.) and the unclear definition of study end-points. As a consequence, the quality of evidence for GnRH agonist strategy should be considered as fair.

The strength of a recommendation should be based on both the quality of the evidence and the net benefit of the therapeutic procedure. If we consider the net benefit as intermediate and small for GnRH analog and cryopreservation strategies, respectively, the strength of recommendation is C (weak recommendation) for both strategies.

A large (282 patients enrolled) multicenter randomized trial (PROMISE-GIM6 study) has been carried out in Italy (4) and final results are expected in June 2009. Waiting for these results, the Gn-RH analog strategy for preserving ovarian function should neither be considered as standard therapy nor as a “biologically implausible treatment”(5).

Lucia Del Mastro, MD
Paola Taveggia, MD
Department Medical Oncology
Istituto Nazionale per la Ricerca sul Cancro
Genova, Italy

Marco Venturini
Department Medical Oncology
Ospedale Sacro Cuore Negrar (VR) – Italy

References
1. Fleisher LA, Bass EB, McKeown 2005 Methodological approach. American College of Chest physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest 128: 17S-23S

2. Badawy A, Elnashar A, El-Ashry et al. 2008 Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril (in press, doi: 10.1016)

3. Ismail-Khan R, Minton S, Cox C, et al. 2008 Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer : a randomized trial using GnRH agonist (Triptorelin) during chemotherapy. American Society of Clinical Oncology, 2008 Annual Meeting, Abstract no. 524

4. National Cancer Institute: Clinical Trials http://www.clinicaltrials.gov/ct/show/NCT00311636

5. Sonmezer M, Oktay K Fertil Steril 2009 , correspondence

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