Chemotherapy combined with gonadotropin-releasing hormone agonist in early breast cancer patients： a single-centre, double-blind, randomized controlled trial

doi:10.3969/j.issn.1009-976X.2022.01.002

Abstract

Abstract: Objective To analyze the effect of chemotherapy combined with gonadotropin-releasing hormone （GnRHa） on the menstrual recovery of breast cancer patients after chemotherapy and explore the potential side effects of GnRHa on patients. Methods This is a single-centre, double-blind, randomized clinical trial. A total of 141 early- or middle-stage breast cancer patients aged 14 ~ 45 years were included. The patients were randomly assigned to the intervention group （n=69） and control group （n=72） using random digits generated by SPSS. The follow-up was conducted in Sun Yat-sen Memorial Hospital, Sun Yat-sen University from August 2008 to December 2021. Logistic regression was used to study the effect of GnRHa on menstrual recovery after chemotherapy, linear regression was used to study the relationship between GnRHa and liver function indicator and antral follicle count （AFC）, and Cox regression was used to analyze the impact of menstrual recovery on the prognosis of patients. Results At six months after chemotherapy, 69.2% of the patients in the intervention group recovered menstruation compared with 75.9% in the control group, with no statistically significant difference （P>0.05）. Multivariate logistic regression showed that the use of GnRHa had no significant effect on menstrual recovery （OR=0.19, 95% CI： 0.03~1.14）; no significant side effects on alanine aminotransferase and AFC （P> 0.05）. There were no significant associations between menstrual recovery with death, metastasis, and relapse （P>0.05）. The average volume of the right ovarian was significantly negatively associated with metastasis （HR=0.76; P=0.046）. The Log-rank test indicated no significant difference in metastasis-free survival （MFS） and relapse-free survival （RFS） between the intervention group and the control group （P>0.05）. Conclusion The use of GnRHa in chemotherapy among breast cancer patients had no significant effect on the menstrual recovery after chemotherapy. The safety of using GnRHa was high and there was no significant hepatotoxicity.

Key words: breast cancer, chemotherapy, gonadotropin-releasing hormone agonists, menstrual recovery

摘要： 目的分析化疗联合促性腺激素释放激素激动剂（GnRHa）对于乳腺癌患者化疗后月经恢复的情况,并探讨GnRHa的应用对患者的潜在副作用。方法本研究是一项单中心,双盲,随机对照临床试验。共纳入了141名年龄从14 ~ 45岁的女性乳腺癌早、中期患者并采用SPSS软件生成随机码把患者随机分为干预组（n = 69）和对照组（n = 72）。随访在中山大学孙逸仙纪念医院进行,从2008年8月到2021年12月结束。使用Logistic回归来研究GnRHa对化疗结束后患者月经恢复的疗效,线性回归研究GnRHa与肝功能指标和卵泡计数的关系,Cox回归分析月经恢复与否对于患者预后的影响。结果化疗结束六个月后,干预组患者有69.2%恢复月经,同比对照组为75.9%,差异无统计学意义（P > 0.05）。多因素logistic回归显示使用GnRHa与否对月经恢复无显著影响（OR=0.19,95% CI：0.03 ~ 1.14）;对丙氨酸转氨酶、窦卵泡计数均无显著副作用（P > 0.05）。Cox回归显示月经恢复与否死亡,转移和复发无显著联系（P > 0.05）,右侧卵巢容积与转移呈显著负相关（HR=0.76;P = 0.046）。Log-rank test结果显示干预组与对照组的无转移生存期（MFS）和无复发生存期（RFS）无显著差异（P > 0.05）。结论在乳腺癌患者化疗中配合使用GnRHa对化疗后月经恢复率无显著影响,使用GnRHa安全性较高,无显著肝脏毒性。

关键词: 乳腺癌, 化疗, 促性腺激素释放激素激动剂, 月经恢复

CLC Number:

R735.7

LIN Wei-wei, LIN Que-ran, HE Zuan-yu, SU Feng-xi, PAN Ping, CHEN Kai, YANG Dong-zi. Chemotherapy combined with gonadotropin-releasing hormone agonist in early breast cancer patients： a single-centre, double-blind, randomized controlled trial[J]. Lingnan Modern Clinics In Surgery, 2022, 22(01): 7-13.

林威威, 林确然, 何钻玉, 苏逢锡, 潘萍, 陈凯, 杨冬梓. 早期乳腺癌患者化疗联合促性腺激素释放激素激动剂：一项单中心、双盲、随机对照临床试验[J]. 岭南现代临床外科, 2022, 22(01): 7-13.

References

[1] Global Cancer Observatory. Latest global cancer data: Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in2020 [EB/OL]. (2020-12-15) [2021-2-10]. https://www.iarc.who.int/wp-content/uploads/2020/12/pr292_E.pdf
[2] Kocarnik JM, Compton K, Dean FE, et al.Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019[J]. JAMA Oncol, 2021, 30:e216987.
[3] 国家癌症中心,中国医学科学院肿瘤医院.2020中国肿瘤登记年报[EB/OL]. [2021-2-10]. http://www.cicams.ac.cn/Hospitals/Departments/Index?id=45
[4] Siegel RL, Miller KD, Fuchs HE, et al.Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33.
[5] Anders CK, Johnson R, Litton J, et al.Breast cancer before age 40 years[J]. Semin Oncol, 2009, 36(3): 237-249.
[6] 国家卫生健康委员会. 中国卫生健康统计年鉴2020 [EB/OL]. (2020-10-1) [2021-2-10]. http://www.nhc.gov.cn/zwgk/tjnj1/ejlist_2.shtml
[7] Ma F, Wu J, Li F, et al.Interpretation of specification for breast cancer screening, early diagnosis, and treatment management in Chinese women[J]. J Natl Cancer Center, 2021, 1(3):97-100.
[8] Howard-Anderson J, Ganz PA, Bower JE, et.al. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review[J]. J Natl Cancer Inst, 2012, 104(5): 386-405.
[9] Poggio F, Lambertini M, Bighin C, et al.Potential mechanisms of ovarian protection with gonadotropin-releasing hormone agonist in breast cancer patients: areview[J]. Clin Med Insights Reprod Health, 2019, 13: 1-5.
[10] Ruddy KJ, Gelber SI, Tamimi RM, et al.Prospective study of fertility concerns and preservation strategies in young women with breast cancer[J]. Clin Oncol, 2014,32(11): 1151-1156.
[11] Senkus E, Gomez H, Dirix L, et al.Attitudes of young patients with breast cancer toward fertility loss related to adjuvant systemic therapies. EORTC study 10002 BIG 3-98[J]. Psychooncology, 2014, 23(2): 173-182.
[12] National Comprehensive Cancer Network. Breast Cancer.2021 [EB/OL]. [2021-2-10] https://www.nccn.org/guidelines/category_1
[13] Badawy A, Elnashar A, El-Ashry M, et al.Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study[J]. Fertil Steril,2009, 91(3): 694-697.
[14] Zong X, Yu Y, Yang H, et al.Effects of gonadotropin-releasing hormone analogs on ovarian function against chemotherapy-induced gonadotoxic effects in premenopausal women with breast cancer in china: arandomized clinical trial[J]. JAMA Oncol,2022, 8(2):252-258.
[15] Ruddy KJ, DeSantis SD, Barry W, et al. Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen[J]. J Assist Reprod Genet, 2014, 14(6): 413-416.
[16] Zhang Y, Ji Y, Li J, et al.Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival[J]. Breast Cancer Res Treat, 2018, 168(3): 679-686.
[17] 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]. J Clin Oncol, 2012, 30(5): 533-538.
[18] Gerber B, von Minckwitz G, Stehle H, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study[J]. J Clin Oncol, 2011, 29(17): 2334-2341.
[19] Oktay K, Harvey BE, Partridge AH, et al.Fertility preservation in patients with cancer: ASCO clinical practice guideline update[J]. J Clin Oncol, 2018, 36(19): 1994-2001.