Englert, Y

Falcone, T

Lambertini, M

Oktay, Kutluk

Phillips, K

Turan, V

Unger, J

English

The Touro College and University System

Touro Scholar NYMC Faculty Publications Faculty 3-1-2017 Debated Role of Ovarian Protection with Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women with Cancer M Lambertini T Falcone J Unger K Phillips Y Englert See next page for additional authors Follow this and additional works at: https://touroscholar.touro.edu/nymc_fac_pubs  Part of the Medicine and Health Sciences Commons Recommended Citation Lambertini, M., Falcone, T., Unger, J., Phillips, K., Englert, Y., Oktay, K., & Turan, V. (2017). Debated Role of Ovarian Protection with Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women with Cancer. Journal of Clinical Oncology, 35 (7), 804-809. https://doi.org/10.1200/JCO.2016.69.2582 This Letter to the Editor 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. Authors M Lambertini, T Falcone, J Unger, K Phillips, Y Englert, Kutluk Oktay, and V Turan This letter to the editor is available at Touro Scholar: https://touroscholar.touro.edu/nymc_fac_pubs/669 JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C EDebated Role of Ovarian ProtectionWith Gonadotropin-ReleasingHormone Agonists DuringChemotherapy for Preservation ofOvarian Function and Fertility inWomen With CancerTO THE EDITOR: In 2015, two large randomized controlledtrials (RCTs) in patients with breast cancer (ie, Prevention of EarlyMenopause Study–Southwest Oncology Group [POEMS-SWOG]S0230 and Prevention of Menopause Induced by Chemotherapy: AStudy in Early Breast Cancer Patients–Gruppo Italiano Mammella6 [PROMISE-GIM6]) demonstrated improvement in both ovarianfunction and fertility with gonadotropin-releasing hormone ag-onist (GnRHa) administration during chemotherapy.1,2 The con-sistent absolute and relative results support the reliability of theseﬁndings (Table 1).1-3 The largest meta-analysis including all RCTsin patients with breast cancer conﬁrmed a reduced risk of pre-mature ovarian failure (POF; odds ratio [OR], 0.36; P, .001) andan increased chance of achieving pregnancy (OR, 1.83; P5 .04) withGnRHa during chemotherapy.4 On the basis of these ﬁndings,current guidelines recommend use of GnRHa as a strategy to offerpatients with breast cancer who are interested in fertility and/orovarian function preservation.5Demeestere et al3 have recently reported follow-up data fromtheir RCT investigating use of GnRHa during chemotherapy forpreservation of ovarian function and fertility in patients withlymphoma. The authors concluded that after more than 5 years offollow-up, GnRHa administration did not signiﬁcantly reducePOF or increase pregnancy rate.3 However, several issues shouldbe considered in interpreting the results.Although there is no standard deﬁnition of chemotherapy-induced POF, a composite end point using both clinical andlaboratory measures (eg, irregular periods or amenorrhea withfollicle-stimulating hormone [FSH] levels . 40 mIU/mL)6 lendsgreater speciﬁcity. The role of anti-mu¨llerian hormone (AMH),a marker of ovarian reserve commonly used in fertility clinics, iscontroversial in predicting chemotherapy-induced gonadal dam-age and subsequent fertility loss.7 Demeestere et al3 relied only onFSH or AMH levels, which might have increased false-positiveresults that incorrectly identiﬁed patients as having POF who didnot in fact develop the event, as conﬁrmed by the observation ofﬁve pregnancies in women with protocol-deﬁned POF.Although pregnancy represents the best marker of fertility,prevention of POF has other advantages in preserving quality oflife. None of the RCTs of ovarian protection with GnRHa requiredinterest in future pregnancy for eligibility, and only a minorityreported pregnancies. The POEMS-SWOG S0230 trial, the onlystudy to include pregnancy as a predeﬁned secondary end point,showed a signiﬁcantly higher pregnancy rate with use of GnRHa.1,8In the study by Demeestere et al,3 the use of the hormonenorethisterone acetate in both study arms during chemotherapymay have diminished the observed protective effect of GnRHa.Norethisterone acetate directly affects the hypothalamic-pituitaryaxis, slowing gonadotropin-releasing hormone pulse frequencyand lowering gonadotropins9; this effect would only be seen in thecontrol arm, because the pituitary gonadotropin-releasing hor-mone receptors would be downregulated by the GnRHa in theexperimental arm.Furthermore, 46% of patients had no information on the use ofhormonal contraceptives at the time of ovarian function assessment.3Hormonal contraceptives can suppress FSH, which may have furtherconfounded the results, especially if use was unbalanced between thetwo treatment arms.According to the original analysis plan, 157 patients wererequired; however, only 129 women were randomly assigned, with84 patients (65%) completing 1 year of follow-up and included inthe primary analysis.10 Long-term analyses were not preplanned;hence, the time points for ovarian function evaluation were notprespeciﬁed or mandatory. Only 63 patients (49%) and 37 patients(29%) had information on FSH and AMH, respectively.3 Althoughreported as a negative study, the ORs for POF and pregnancy seenin the trial by Demeestere et al3 are consistent with the protectiveeffect of GnRHa seen in other studies (Table 1) and may not haveachieved statistical signiﬁcance only because of lack of power.Table 1. Main Results of the Largest Randomized Controlled Trials Investigating the Role of GnRHa During Chemotherapy in Preservation of Ovarian Function andFertility in Women With CancerOutcome Demeestere et al3 POEMS-SWOG S02301 PROMISE-GIM62Treatment-induced POF (CT 1 GnRHa vCT alone), %19 v 25 (OR, 0.72; P 5 .76) 8 v 22 (OR, 0.30; P 5 .04) 8.9 v 25.9 (OR, 0.28; P , .001)Patients with pregnancies (CT 1 GnRHa vCT alone), %53 v 43 (OR, 1.51; P 5 .47) 21 v 11 (OR, 2.45; P 5 .03) 5 v 2 (HR, 2.40; P 5 .20)Disease-free survival (CT 1 GnRHa vCT alone), %82 v 87.5 (NR) 89 v 78 (HR, 0.49; P 5 .04) 80.5 v 83.7 (HR, 1.17; P 5 .52)Abbreviations: CT, chemotherapy; GnRHa, gonadotropin-releasing hormone agonist; HR, hazard ratio; NR, not reported; OR, odds ratio; POEMS-SWOG, Prevention ofEarly Menopause Study–Southwest Oncology Group; POF, premature ovarian failure; PROMISE-GIM6, Prevention of Menopause Induced by Chemotherapy: A Study inEarly Breast Cancer Patients–Gruppo Italiano Mammella 6.804 © 2016 by American Society of Clinical Oncology Journal of Clinical Oncology, Vol 35, No 7 (March 1), 2017: pp 804-805VOLUME 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.Regarding the assessment of missing data, although charac-teristics between patients who did versus did not drop out weresimilar,3 this is not relevant to the assessment of whether missingdata bias the treatment effect. It is more important to know whetherthere was differential dropout between patients who did versus didnot drop out by arm using interaction tests. Finally, because theirstudy was not designed to test the equivalency of the two regimens,the absence of a beneﬁcial effect with GnRHa cannot be claimed toconﬁrm that GnRHa is not efﬁcient in preventing POF3; at best, thestudy showed no evidence that GnRHa reduced the incidence of POF.Although the study by Demeestere et al3 was unable to dem-onstrate ovarian protection with GnRHa during chemotherapy inpatients with lymphoma, this was an underpowered and exploratoryanalysis of a study in which both control and experimental armpatients received hormonal treatment and in which the end pointwas ﬂawed. Hence, these results should be considered as exploratoryand do not refute ﬁndings from well-designed large RCTs on thistopic.Although embryo or oocyte cryopreservation is the ﬁrst choicefor fertility preservation, GnRHa during chemotherapy remainsan option for women interested in preserving ovarian function andfertility.Matteo LambertiniBreast Adjuvant Study Team Data Centre, Institut Jules Bordet, and Universite´Libre de Bruxelles, Brussels, BelgiumTommaso FalconeCleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OHJoseph M. UngerSouthwest Oncology Group Statistical Center, Fred Hutchinson Cancer ResearchCenter, Seattle, WAKelly-Anne PhillipsPeterMacCallumCancer Centre andUniversity ofMelbourne,Melbourne, Victoria,AustraliaLucia Del MastroIstituto di Ricovero e Cura a Carattere Scientiﬁco–Azienda OspedalieraUniversitaria San Martino–Istituto Nazionale per la Ricerca sul Cancro, Genova,ItalyHalle C.F. MooreCleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OHL.D.M. and H.C.F.M. contributed equally to this work.AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTDisclosures provided by the authors are available with this article atjco.org.REFERENCES1. Moore HCF, Unger JM, Phillips K-A, et al: Goserelin for ovarian protectionduring breast-cancer adjuvant chemotherapy. N Engl J Med 372:923-932, 20152. Lambertini M, Boni L, Michelotti A, et al: Ovarian suppression with trip-torelin during adjuvant breast cancer chemotherapy and long-term ovarian func-tion, pregnancies, and disease-free survival: A randomized clinical trial. JAMA 314:2632-2640, 20153. 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, 20164. Lambertini M, Ceppi M, Poggio F, et al: Ovarian suppression using lutein-izing hormone-releasing hormone agonists during chemotherapy to preserve ovarianfunction and fertility of breast cancer patients: A meta-analysis of randomizedstudies. Ann Oncol 26:2408-2419, 20155. Paluch-Shimon S, Pagani O, Partridge AH, et al: Second internationalconsensus guidelines for breast cancer in young women (BCY2). Breast 26:87-99,20166. 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, 20167. Hamy A-S, Porcher R, Eskenazi S, et al: Anti-Mu¨llerian hormone in breastcancer patients treated with chemotherapy: A retrospective evaluation of sub-sequent pregnancies. Reprod Biomed Online 32:299-307, 20168. Moore HC, Unger JM, Albain KS: Ovarian protection during adjuvant che-motherapy. N Engl J Med 372:2269-2270, 20159. Gordon A, Garrido-Gracia JC, Aguilar R, et al: Understanding the regulationof pituitary progesterone receptor expression and phosphorylation. Reproduction149:615-623, 201510. Demeestere I, Brice P, Peccatori FA, et al: Gonadotropin-releasing hormoneagonist for the prevention of chemotherapy-induced ovarian failure in patients withlymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol 31:903-909, 2013DOI: 10.1200/JCO.2016.69.2582; published at jco.org on November 28,2016.n n njco.org © 2016 by American Society of Clinical Oncology 805CorrespondenceDownloaded 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 INTERESTDebated Role of Ovarian Protection With Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Functionand Fertility in Women With CancerThe 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.Matteo LambertiniOther Relationship: European Society for Medical OncologyTranslational Research FellowshipTommaso FalconeNo relationship to discloseJoseph M. UngerNo relationship to discloseKelly-Anne PhillipsNo relationship to discloseLucia Del MastroHonoraria: Takeda, Roche, AstraZeneca, NovartisConsulting or Advisory Role: Eli LillySpeakers’ Bureau: Takeda, IpsenTravel, Accommodations, Expenses: RocheHalle C.F. MooreResearch Funding: Puma Biotechnology (Inst), Abbvie (Inst),Parexel International (Inst)© 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.

Debated Role of Ovarian Protection with Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women with Cancer

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Debated Role of Ovarian Protection with Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women with Cancer

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