Bedoschi, G

Oktay, Kutluk

Turan, V

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Touro Scholar NYMC Faculty Publications Faculty 3-1-2017 Reply to M. Lambertini et al Kutluk Oktay New York Medical College V Turan G Bedoschi Follow this and additional works at: https://touroscholar.touro.edu/nymc_fac_pubs  Part of the Obstetrics and Gynecology Commons, and the Oncology Commons Recommended Citation Oktay, K., Turan, V., & Bedoschi, G. (2017). Reply to M. Lambertini et al. Journal of Clinical Oncology, 35 (7), 807-809. https://doi.org/10.1200/JCO.2016.70.6101 This Response or Comment is brought to you for free and open access by the Faculty at Touro Scholar. It has been accepted for inclusion in NYMC Faculty Publications by an authorized administrator of Touro Scholar. For more information, please contact daloia@nymc.edu. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C EReply to M. Lambertini et alLambertini et al1 challenge the conclusion of the randomizedcontrolled study by Demeestere et al,2 which showed lack of go-nadal protective effect from gonadotropin-releasing hormoneagonist (GnRHa) suppression in women with lymphoma based onquantiﬁable serum ovarian reserve markers. Lambertini et al1suggest that their studies3,4 have provided consistent results andsupport conclusions opposite of those of Demeestere et al.2However, the studies differ signiﬁcantly in their design, primaryoutcome measures, patient populations, and pregnancy outcomes(Table 1).5-7Lambertini et al1 cite their own meta-analysis as proof ofGnRHa’s effectiveness for fertility preservation. As previouslydiscussed,5 meta-analyses do not correct for original studyweaknesses, and there is no biologic rationale in limiting meta-analyses to breast cancer. When all studies that also include he-matologic cancers are meta-analyzed, there remains no beneﬁtfrom GnRHa.8In addition to using a speciﬁc deﬁnition of premature ovarianfailure (POF) and primary ovarian insufﬁciency (POI) involvingamenorrhea and follicle-stimulating hormone greater than40 mIU/mL as the primary outcome measure, Demeestere et al2measured serum anti-mu¨llerian hormone (AMH) levels to cor-roborate their ﬁndings. Serum AMH is the most reliable quanti-tative marker in measuring ovarian reserve, diagnosing occult POI(a state that is induced in most women by breast cancer che-motherapy), and predicting age at menopause. None of the studiesthat used AMH as a marker showed beneﬁt from the addition ofGnRHa treatment (Table 1).Lambertini et al1 surmise that pregnancies nullify the des-ignation of the study patients as having POI/POF. This is nota correct assessment. First, there is 5% to 15% spontaneous livebirth rate among those who are designated to be in POI. Second,spontaneous pregnancies do occur, even among those who areinduced to become menopausal by highly gonadotoxic pre-conditioning chemotherapy for hematopoietic stem-cell trans-plantation. Because in these young patients the egg quality is notreduced after chemotherapy, the conceptions may be a result of theability of few remaining follicles to ovulate sporadically or possiblythe ability of some oocytes to self-repair chemotherapy-inducedDNA damage.5,9 Hence, pregnancy and POF/POI are not exclusive;what is important is that the probability of pregnancy is signiﬁ-cantly reduced after gonadotoxic chemotherapy.Because breast cancer chemotherapy regimens often do notinduce complete POF/POI but rather result in occult POI, manywomen still retain some reserve and have the ability to sponta-neously conceive, albeit at reduced probability. Hence, it is notsurprising that, in an unblinded and non–placebo-controlleddesign where the data are not corrected for pregnancy intentand attempt and the women who are aware of their GnRHatreatment could be moremotivated to attempt pregnancy, one mayinaccurately interpret those incidental conceptions as beingGnRHa-treatment enabled.Lambertini et al1 also suggest that the use of norethisteroneby Demeestere et al2 blunted GnRHa’s beneﬁt on ovarianfunction by suppressing the pituitary gonadotropin secretion inthe control group. This claim has numerous weaknesses. First,primordial follicles that make up the ovarian reserve are qui-escent, do not express gonadotropin or GnRHa receptors,5 andhence have no pathway for responding to changes in serumgonadotropin on gonadotropin-releasing hormone levels. Sec-ond, if the authors’ claim were to be true, we would then expectany form of ovarian suppression including oral contraceptivesto preserve ovarian function against chemotherapy, which is notthe case. Third, unlike combined contraceptive pills, progestin-only treatments have a weak suppressive effect on serum go-nadotropin levels. They induce amenorrhea primarily by theireffects on endometrium, not the pituitary. Fourth, to further castdoubt that GnRHas preserve ovarian function by suppressingserum follicle-stimulating hormone levels, a time-honored ran-domized study by Waxman et al10 showed that serum gonado-tropin levels are not suppressed below minimum physiologic levelsseen during a menstrual cycle (excluding the time of ovulation)even after months of administration. Finally, Lambertini et al1suggest that GnRHas may preserve ovarian endocrine functioneven if they do not improve the chance of pregnancy. This hy-pothesis does not par with ovarian biology. Hormone productionand fertility are coupled functions of the ovary. Hence, in studiesthat show continued vaginal bleeding but not preservation offertility,3,4 one will have to look at explanations other than theeffectiveness of GnRHa treatment. These include observationalbiases as a result of lack of blinding and placebo and use ofnonquantitative and subjective markers such as the return of anykind of menstrual bleeding.5-7,11On the basis of reliable data and basic ovarian biologic facts,GnRHa suppression cannot be considered as an effectivemethod ofovarian or fertility preservation. Just-in-case administration ofGnRHas over prolonged periods of time cannot be justiﬁedgiven the cost, potential adverse effects including irreversiblebone loss, and the risk of counseling away from proven methodsof fertility preservation via embryo, oocyte, and ovarian tissuecryopreservation.11Kutluk Oktay, Volkan Turan, and Giuliano BedoschiNew York Medical College and Innovation Institute for Fertility Preservation, NewYork, NYACKNOWLEDGMENTSupported by Grant No. RO1HD053112 from the National Institutes ofHealth (National Institute of Child Health and Human Development andNational Cancer Institute).AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTDisclosures provided by the authors are available with this article atjco.org.Journal of Clinical Oncology, Vol 35, No 7 (March 1), 2017: pp 807-809 © 2016 by American Society of Clinical Oncology 807VOLUME 35 • NUMBER 7 • MARCH 1, 2017Downloaded from ascopubs.org by NEW YORK MEDICAL COLLEGE on July 5, 2018 from 064.118.223.196Copyright © 2018 American Society of Clinical Oncology. All rights reserved.REFERENCES1. Lambertini M, Falcone T, Unger JM, et al: Debated role of ovarian protectionwith gonadotropin-releasing hormone agonists during chemotherapy for preser-vation of ovarian function and fertility in women with cancer. J Clin Oncol 35:804-805, 20172. Demeestere I, Brice P, Peccatori FA, et al: No evidence for the beneﬁt ofgonadotropin-releasing hormone agonist in preserving ovarian function and fertilityin lymphoma survivors treated with chemotherapy: Final long-term report ofa prospective randomized trial. J Clin Oncol 34:2568-2574, 20163. Lambertini M, Boni L, Michelotti A, et al: Ovarian suppression with triptorelinduring adjuvant breast cancer chemotherapy and long-term ovarian function, pregnan-cies, and disease-free survival: A randomized clinical trial. JAMA 314:2632-2640, 20154. Moore HC, Unger JM, Phillips KA, et al: Goserelin for ovarian protectionduring breast-cancer adjuvant chemotherapy. N Engl J Med 372:923-932, 2015Table 1. Comparison of Randomized Studies That Used Serum AMH to Studies by Lambertini et al3 and Moore et al4Study Cancer TypePatient Age(years) Sample Size Primary Outcome Secondary Outcome Conclusion LimitationsDemeestreet al,8a 2013Hodgkin andnon-Hodgkinlymphoma18-38 GnRHa plus Chemoplus norethisteroneacetate, n 5 65;Chemo plusnorethisterone,n 5 64POF (FSH level. 40 mIU/mL) at12 months offollow-upAMH; early menstrualFSH and E2Triptorelin was notassociated witha signiﬁcantlydecreased risk ofPOFRelatively shortfollow-up periodDemeestreet al,2 2016Hodgkin andnon-Hodgkinlymphoma18-38 GnRHa plus Chemo,n 5 32; Chemoalone, n 5 35POF (FSH level. 40 mIU/mL) atapproximately66 months offollow-upAMH; early menstrualFSH and E2;pregnancy rateTriptorelin was notassociated witha signiﬁcantlydecreased risk ofPOF and did notinﬂuence futurepregnancy rateOne of the best-designed studiesElgindy et al,82013Breast cancer(ER negative)18-40 Early Chemo alone,n 5 25; earlyChemo andantagonist andagonist, n 5 25;delayed Chemoalone, n 5 25;delayed Chemoplus GnRHa, n5 25Resumption ofmenses 12 monthsafter ChemoResumption ofregular menses;random FSH, LH,and E2, as well asAFC and AMH,12 months afterthe end of ChemoTriptorelincotreatment doesnotoffer a signiﬁcantprotective effect onovarian functionOne of the best-designed studiesGerber B(ZOROstudy),8b2011Breast cancer(ER negative)18-45 Chemo plusgoserelin, n 5 30;Chemo alone,n 5 31Resumption ofmenses(2 consecutivemenstrual periodswithin 21-35 daysin a time frame of6 months afterChemo) after24-month follow-upTime until recovery ofregular menses;randomAFC, AMH,FSH, LH, and E2 at6, 12, 18, and 24months after end ofChemo; pregnancyratePatients usinggoserelin alongwith Chemo did notexperiencea statisticallysigniﬁcantly lowerrisk of amenorrhea6 months afterChemo comparedwith patientsreceiving ChemoaloneSerum FSH and E2were not drawn oncycle day 2 or 3, buta less cycleday–dependentmarker, AMH, wasusedMoore et al,42015Breast cancer(ER negative)18-49 Chemo alone, n5 69;Chemo plusgoserelin, n 5 66Rate of POF (ovarianfailure was deﬁnedas amenorrheafor the preceding6 months and FSHlevels in thepostmenopausalrange at 2 years)Pregnancy within thepast 5 years,assessed annually;ovarian dysfunction(amenorrhea inthe preceding3months) and FSH,E2, or inhibin Blevels in thepostmenopausalrangeAdministration ofgoserelin withChemo appearedto protect againstovarian failureTrial was terminatedprematurely asa result of lack offunding; anybleeding withoutregularity wasconsidered asmenstruation;random hormoneproﬁlemeasurementswithout usingAMH; pregnancyrates are notdifferent whenintent is consideredLambertiniet al,3 2015)Breast cancer(ER negativeand positive)24-45 Chemo alone,n 5 133; GnRHaplus Chemo,n 5 148Early menopause,resumption ofmenses (evaluatedby yearlyassessment ofmenstrual activity)Long-term ovarianfunction(considered aspreserved by theoccurrence of atleast 1 menstrualcycle), pregnancies,and disease-freesurvivalTriptorelin wasassociated withhigher long-termprobability ofovarian functionrecovery, withouta statisticallysigniﬁcantdifference inpregnancy ratesAny bleeding withoutregularity wasconsidered asmenstruation; noinformation regardingthe deﬁnition ofpostmenopausalstatus; no differencewas found in termsof pregnancyoutcomes amonggroupsAbbreviations: AFC, antral follicle count; AMH, anti-mu¨llerian hormone; Chemo, chemotherapy; E2, estradiol; ER, estrogen receptor; FSH, follicle-stimulating hormone;GnRHa, gonadotropin-releasing hormone agonist; LH, luteinizing hormone; POF, premature ovarian failure; ZORO, Zoladex Rescue of Ovarian Function.808 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGYCorrespondenceDownloaded from ascopubs.org by NEW YORK MEDICAL COLLEGE on July 5, 2018 from 064.118.223.196Copyright © 2018 American Society of Clinical Oncology. All rights reserved.5. Oktay K, Bedoschi G: Appraising the biological evidence for and against theutility of GnRHa for preservation of fertility in patients with cancer. J Clin Oncol 34:2563-2565, 20166. Oktay K, Rodriguez-Wallberg K, Munster P: Ovarian protection during ad-juvant chemotherapy. N Engl J Med 372:2268-2269, 20157. Oktay K, Turan V: Failure of ovarian suppression with gonadotropin-releasing hormone analogs to preserve fertility: An assessment based on thequality of evidence. JAMA Oncol 2:74-75, 20168. Elgindy E, Sibai H, Abdelghani A, et al: Protecting ovaries during chemo-therapy through gonad suppression: A systematic review and meta-analysis.Obstet Gynecol 126:187-195, 20158a. Demeestere I, Brice P, Peccatori FA, et al: Gonadotropin-releasing hor-mone agonist for the prevention of chemotherapy-induced ovarian failure in pa-tients with lymphoma: 1-year follow-up of a prospective randomized trial. J ClinOncol 31:903-909, 20138b. Gerber B, von Minckwitz G, Stehle H, et al: Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breastcancer chemotherapy: The GBG 37 ZORO study. J Clin Oncol 29:2334-2341, 20119. Titus S, Li F, Stobezki R, et al: Impairment of BRCA1-related DNA double-strandbreak repair leads to ovarian aging inmice andhumans. Sci TranslMed5:172ra21, 201310. Waxman JH, Ahmed R, Smith D, et al: Failure to preserve fertility in patientswith Hodgkin’s disease. Cancer Chemother Pharmacol 19:159-162, 198711. Oktay K, Bedoschi G, Pacheco F, et al: First pregnancies, live birth, andin vitro fertilization outcomes after transplantation of frozen-banked ovarian tissuewith a human extracellular matrix scaffold using robot-assisted minimally invasivesurgery. Am J Obstet Gynecol 214:94.e1-9, 2016DOI: 10.1200/JCO.2016.70.6101; published at jco.org on November 28,2016.n n njco.org © 2016 by American Society of Clinical Oncology 809CorrespondenceDownloaded from ascopubs.org by NEW YORK MEDICAL COLLEGE on July 5, 2018 from 064.118.223.196Copyright © 2018 American Society of Clinical Oncology. All rights reserved.AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTReply to M. Lambertini et alThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conﬂict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.Kutluk OktayNo relationship to discloseVolkan TuranNo relationship to discloseGiuliano BedoschiNo relationship to disclose© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGYCorrespondenceDownloaded from ascopubs.org by NEW YORK MEDICAL COLLEGE on July 5, 2018 from 064.118.223.196Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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