Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis | Breast Cancer | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.129.82. Please contact the publisher to request reinstatement.
1.
Jemal  A, Bray  F, Center  MM, Ferlay  J, Ward  E, Forman  D.  Global cancer statistics.  CA Cancer J Clin. 2011;61(2):69-90.PubMedGoogle ScholarCrossref
2.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.  Lancet. 2005;365(9472):1687-1717.PubMedGoogle ScholarCrossref
3.
Trivers  KF, Fink  AK, Partridge  AH,  et al.  Estimates of young breast cancer survivors at risk for infertility in the U.S.  Oncologist. 2014;19(8):814-822.PubMedGoogle ScholarCrossref
4.
Howard-Anderson  J, Ganz  PA, Bower  JE, Stanton  AL.  Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review.  J Natl Cancer Inst. 2012;104(5):386-405.PubMedGoogle ScholarCrossref
5.
Schover  LR.  Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility.  J Clin Oncol. 2008;26(5):753-758.PubMedGoogle ScholarCrossref
6.
Goldhirsch  A, Gelber  RD, Castiglione  M; The International Breast Cancer Study Group.  The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients.  Ann Oncol. 1990;1(3):183-188.PubMedGoogle Scholar
7.
Valagussa  P, Moliterni  A, Zambetti  M, Bonadonna  G.  Long-term sequelae from adjuvant chemotherapy.  Recent Results Cancer Res. 1993;127:247-255.PubMedGoogle Scholar
8.
Bines  J, Oleske  DM, Cobleigh  MA.  Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer.  J Clin Oncol. 1996;14(5):1718-1729.PubMedGoogle Scholar
9.
Goodwin  PJ, Ennis  M, Pritchard  KI, Trudeau  M, Hood  N.  Risk of menopause during the first year after breast cancer diagnosis.  J Clin Oncol. 1999;17(8):2365-2370.PubMedGoogle Scholar
10.
Stearns  V, Schneider  B, Henry  NL, Hayes  DF, Flockhart  DA.  Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants.  Nat Rev Cancer. 2006;6(11):886-893.PubMedGoogle ScholarCrossref
11.
Jeruss  JS, Woodruff  TK.  Preservation of fertility in patients with cancer.  N Engl J Med. 2009;360(9):902-911.PubMedGoogle ScholarCrossref
12.
Del Mastro  L, Venturini  M, Sertoli  MR, Rosso  R.  Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications.  Breast Cancer Res Treat. 1997;43(2):183-190.PubMedGoogle ScholarCrossref
13.
Burstein  HJ, Winer  EP.  Primary care for survivors of breast cancer.  N Engl J Med. 2000;343(15):1086-1094.PubMedGoogle ScholarCrossref
14.
Gadducci  A, Cosio  S, Genazzani  AR.  Ovarian function and childbearing issues in breast cancer survivors.  Gynecol Endocrinol. 2007;23(11):625-631.PubMedGoogle ScholarCrossref
15.
Kil  WJ, Ahn  SD, Shin  SS,  et al.  Treatment-induced menstrual changes in very young (<35 years old) breast cancer patients.  Breast Cancer Res Treat. 2006;96(3):245-250.PubMedGoogle ScholarCrossref
16.
Petrek  JA, Naughton  MJ, Case  LD,  et al.  Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study.  J Clin Oncol. 2006;24(7):1045-1051.PubMedGoogle ScholarCrossref
17.
Venturini  M, Del Mastro  L, Aitini  E,  et al.  Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.  J Natl Cancer Inst. 2005;97(23):1724-1733.PubMedGoogle ScholarCrossref
18.
Ganz  PA, Land  SR, Geyer  CE  Jr,  et al.  Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial.  J Clin Oncol. 2011;29(9):1110-1116.PubMedGoogle ScholarCrossref
19.
Fornier  MN, Modi  S, Panageas  KS, Norton  L, Hudis  C.  Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane.  Cancer. 2005;104(8):1575-1579.PubMedGoogle ScholarCrossref
20.
Blumenfeld  Z.  How to preserve fertility in young women exposed to chemotherapy? the role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries.  Oncologist. 2007;12(9):1044-1054.PubMedGoogle ScholarCrossref
21.
Ataya  KM, McKanna  JA, Weintraub  AM, Clark  MR, LeMaire  WJ.  A luteinizing hormone-releasing hormone agonist for the prevention of chemotherapy-induced ovarian follicular loss in rats.  Cancer Res. 1985;45(8):3651-3656.PubMedGoogle Scholar
22.
Bokser  L, Szende  B, Schally  AV.  Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.  Br J Cancer. 1990;61(6):861-865.PubMedGoogle ScholarCrossref
23.
Ataya  K, Rao  LV, Lawrence  E, Kimmel  R.  Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys.  Biol Reprod. 1995;52(2):365-372.PubMedGoogle ScholarCrossref
24.
Recchia  F, Saggio  G, Amiconi  G,  et al.  Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma.  Cancer. 2006;106(3):514-523.PubMedGoogle ScholarCrossref
25.
Urruticoechea  A, Arnedos  M, Walsh  G, Dowsett  M, Smith  IE.  Ovarian protection with goserelin during adjuvant chemotherapy for pre-menopausal women with early breast cancer (EBC).  Breast Cancer Res Treat. 2008;110(3):411-416.PubMedGoogle ScholarCrossref
26.
Del Mastro  L, Catzeddu  T, Boni  L,  et al.  Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients.  Ann Oncol. 2006;17(1):74-78.PubMedGoogle ScholarCrossref
27.
Kim  SS, Lee  JR, Jee  BC,  et al.  Use of hormonal protection for chemotherapy-induced gonadotoxicity.  Clin Obstet Gynecol. 2010;53(4):740-752.PubMedGoogle ScholarCrossref
28.
Munster  PN, Moore  AP, Ismail-Khan  R,  et al.  Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer.  J Clin Oncol. 2012;30(5):533-538.PubMedGoogle ScholarCrossref
29.
Gerber  B, von Minckwitz  G, Stehle  H,  et al; German Breast Group Investigators.  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.PubMedGoogle ScholarCrossref
30.
Del Mastro  L, Boni  L, Michelotti  A,  et al.  Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.  JAMA. 2011;306(3):269-276.PubMedGoogle ScholarCrossref
31.
Sverrisdottir  A, Nystedt  M, Johansson  H, Fornander  T.  Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial.  Breast Cancer Res Treat. 2009;117(3):561-567.PubMedGoogle ScholarCrossref
32.
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.PubMedGoogle ScholarCrossref
33.
Han  HS, Ro  J, Lee  KS,  et al.  Analysis of chemotherapy-induced amenorrhea rates by three different anthracycline and taxane containing regimens for early breast cancer.  Breast Cancer Res Treat. 2009;115(2):335-342.PubMedGoogle ScholarCrossref
34.
Leonard  RC, Adamson  D, Anderson  R, Ballinger  R, Bertelli  G, Coleman  RE,  et al The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer.  J Clin Oncol. 2010;28(15s):(suppl; abstr 590).Google Scholar
35.
Elgindy  EA, El-Haieg  DO, Khorshid  OM,  et al.  Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.  Obstet Gynecol. 2013;121(1):78-86.PubMedGoogle ScholarCrossref
36.
Moore  HCF, Unger  JM, Phillips  K-A,  et al; POEMS/S0230 Investigators.  Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.  N Engl J Med. 2015;372(10):923-932.PubMedGoogle ScholarCrossref
37.
Song  G, Gao  H, Yuan  Z.  Effect of leuprolide acetate on ovarian function after cyclophosphamide-doxorubicin-based chemotherapy in premenopausal patients with breast cancer: results from a phase II randomized trial.  Med Oncol. 2013;30(3):667.PubMedGoogle ScholarCrossref
38.
Chen  H, Li  J, Cui  T, Hu  L.  Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women.  Cochrane Database Syst Rev. 2011;(11):CD008018.PubMedGoogle Scholar
39.
Bedaiwy  MA, Abou-Setta  AM, Desai  N,  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):906-14.e1, 4.PubMedGoogle ScholarCrossref
40.
Ben-Aharon  I, Gafter-Gvili  A, Leibovici  L, Stemmer  SM.  Pharmacological interventions for fertility preservation during chemotherapy: a systematic review and meta-analysis.  Breast Cancer Res Treat. 2010;122(3):803-811.PubMedGoogle ScholarCrossref
41.
Del Mastro  L, Ceppi  M, Poggio  F,  et al.  Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials.  Cancer Treat Rev. 2014;40(5):675-683.PubMedGoogle ScholarCrossref
42.
Vitek  WS, Shayne  M, Hoeger  K, Han  Y, Messing  S, Fung  C.  Gonadotropin-releasing hormone agonists for the preservation of ovarian function among women with breast cancer who did not use tamoxifen after chemotherapy: a systematic review and meta-analysis.  Fertil Steril. 2014;102(3):808-815.e1.PubMedGoogle ScholarCrossref
43.
Wang  C, Chen  M, Fu  F, Huang  M.  Gonadotropin-releasing hormone analog cotreatment for the preservation of ovarian function during gonadotoxic chemotherapy for breast cancer: a meta-analysis.  PLoS One. 2013;8(6):e66360.PubMedGoogle ScholarCrossref
44.
Yang  B, Shi  W, Yang  J,  et al.  Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials.  Breast. 2013;22(2):150-157.PubMedGoogle ScholarCrossref
45.
Loren  AW, Mangu  PB, Beck  LN,  et al; American Society of Clinical Oncology.  Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update.  J Clin Oncol. 2013;31(19):2500-2510.PubMedGoogle ScholarCrossref
46.
Partridge  AH, Gelber  S, Peppercorn  J,  et al.  Fertility and menopausal outcomes in young breast cancer survivors.  Clin Breast Cancer. 2008;8(1):65-69.PubMedGoogle ScholarCrossref
47.
Falcone  T, Attaran  M, Bedaiwy  MA, Goldberg  JM.  Ovarian function preservation in the cancer patient.  Fertil Steril. 2004;81(2):243-257.PubMedGoogle ScholarCrossref
48.
Jadad  AR, Moore  RA, Carroll  D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12.PubMedGoogle ScholarCrossref
49.
Rossi  E, Morabito  A, Di Rella  F,  et al.  Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial.  J Clin Oncol. 2009;27(19):3192-3197.PubMedGoogle ScholarCrossref
50.
Karimi-Zarchi  M, Forat-Yazdi  M, Vafaeenasab  MR,  et al.  Evaluation of the effect of GnRH agonist on menstrual reverse in breast cancer cases treated with cyclophosphamide.  Eur J Gynaecol Oncol. 2014;35(1):59-61.PubMedGoogle Scholar
51.
Lambertini  M, Boni  L, Michelotti  A,  et al.  Long-term outcome results of the phase III PROMISE-GIM6 study evaluating the role of LHRH analog (LHRHa) during chemotherapy (CT) as a strategy to reduce ovarian failure in early breast cancer (BC) patients.  J Clin Oncol. 2014;32(26)(suppl):105.Google Scholar
52.
Tham  YL, Sexton  K, Weiss  H, Elledge  R, Friedman  LC, Kramer  R.  The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane.  Am J Clin Oncol. 2007;30(2):126-132.PubMedGoogle ScholarCrossref
53.
Davis  AL, Klitus  M, Mintzer  DM.  Chemotherapy-induced amenorrhea from adjuvant breast cancer treatment: the effect of the addition of taxanes.  Clin Breast Cancer. 2005;6(5):421-424.PubMedGoogle ScholarCrossref
54.
Lee  S, Kil  WJ, Chun  M,  et al.  Chemotherapy-related amenorrhea in premenopausal women with breast cancer.  Menopause. 2009;16(1):98-103.PubMedGoogle ScholarCrossref
55.
Swain  SM, Jeong  JH, Geyer  CE  Jr,  et al.  Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer.  N Engl J Med. 2010;362(22):2053-2065.PubMedGoogle ScholarCrossref
56.
Pagani  O, O’Neill  A, Castiglione  M,  et al.  Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI.  Eur J Cancer. 1998;34(5):632-640.PubMedGoogle ScholarCrossref
57.
Parulekar  WR, Day  AG, Ottaway  JA,  et al; National Cancer Institute of Canada Clinical Trials Group.  Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5.  J Clin Oncol. 2005;23(25):6002-6008.PubMedGoogle ScholarCrossref
58.
Anders  CK, Hsu  DS, Broadwater  G,  et al.  Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.  J Clin Oncol. 2008;26(20):3324-3330.PubMedGoogle ScholarCrossref
Original Investigation
January 2016

Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Hospital Sírio Libanês, São Paulo, Brazil
  • 2Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil
  • 3Universidade Estadual de Campinas, Campinas, Brazil
  • 4Breast Cancer Service, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Hospital HCor/Oncoclínicas, São Paulo, Brazil
JAMA Oncol. 2016;2(1):65-73. doi:10.1001/jamaoncol.2015.3251
Abstract

Importance  Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved.

Objective  To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation.

Data Sources  PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well.

Study Selection  Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected.

Data Extraction and Synthesis  Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process.

Main Outcomes and Measures  Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model.

Results  Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials.

Conclusions and Relevance  Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation.

×