Skip to main content

Advertisement

SpringerLink
Log in

What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

To evaluate the incidence of chemotherapy-induced amenorrhea (CIA) and its therapeutic impact in premenopausal breast cancer patients. A systematic search was performed to identify clinical studies that compared the incidence of CIA with different chemotherapy regimens and oncological outcomes with and without CIA. The fixed-effects and random-effects models were used to assess the pooled estimates. Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. A total of 15,916 premenopausal breast cancer patients from 46 studies were included. The cyclophosphamide-based regimens, taxane-based regimens, and anthracycline/epirubicin-based regimens all increased the incidence of CIA with pooled odds ratios of 2.25 (95 % CI 1.26–4.03, P = 0.006), 1.26 (95 % CI 1.11–1.43, P = 0.0003) and 1.39 (95 % CI 1.15–1.70, P = 0.0008), respectively. The three-drug combination regimens of cyclophosphamide,anthracycline/epirubicin, and taxanes (CAT/CET) caused the highest rate of CIA compared with the other three drug combinations (OR 1.41, 95 % CI 1.16–1.73, P = 0.0008). Tamoxifen therapy was also correlated with a higher incidence of CIA, with an OR of 1.48. Patients with CIA were found to exhibit better disease-free survival (DFS) and overall survival (OS) compared with patients without CIA. With respect to molecular subtype, this DFS advantage remained significant in hormone-sensitive patients (HR 0.61, 95 % CI 0.52–0.72, P < 0.00001). The current meta-analysis has demonstrated that anthracycline/epirubicin, taxanes, cyclophosphamide, and tamoxifen all contributed to elevated rates of CIA, and CIA was not merely a side effect of chemotherapy but was a better prognostic marker, particularly for ER-positive premenopausal early-stage breast cancer patients. However, this topic merits further randomized control studies to detect the associations between CIA and patient prognosis after adjusting for age, ER status, and other influential factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  2. Surveillance E, and End Results Program. http://seer.cancer.gov/csr/1975_2010/sections.html Accessed 3 Dec 2013

  3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717

    Article  Google Scholar 

  4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (1996) Ovarian ablation in early breast cancer: overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 348(9036):1189–1196

    Article  Google Scholar 

  5. Martin M et al (2005) Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352(22):2302–2313

    Article  CAS  PubMed  Google Scholar 

  6. Davis AL, Klitus M, Mintzer DM (2005) Chemotherapy-induced amenorrhea from adjuvant breast cancer treatment: the effect of the addition of taxanes. Clin Breast Cancer 6(5):421–424

    Article  CAS  PubMed  Google Scholar 

  7. Swain SM et al (2009) Amenorrhea in premenopausal women on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm of NSABP B-30 trial. Breast Cancer Res Treat 113(2):315–320

    Article  CAS  PubMed  Google Scholar 

  8. Fornier MN et al (2005) Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 104(8):1575–1579

    Article  CAS  PubMed  Google Scholar 

  9. Tham YL et al (2007) The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol 30(2):126–132

    Article  CAS  PubMed  Google Scholar 

  10. Swain SM et al (2010) Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 362(22):2053–2065

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Colleoni M et al (2006) Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24(9):1332–1341

    Article  CAS  PubMed  Google Scholar 

  12. Yoo C et al (2013) Chemotherapy-induced amenorrhea, menopause-specific quality of life, and endocrine profiles in premenopausal women with breast cancer who received adjuvant anthracycline-based chemotherapy: a prospective cohort study. Cancer Chemother Pharmacol 72(3):565–575

    Article  CAS  PubMed  Google Scholar 

  13. Clarke M, Horton R (2001) Bringing it all together: lancet-cochrane collaborate on systematic reviews. Lancet 357(9270):1728

    Article  CAS  PubMed  Google Scholar 

  14. Stroup DF et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283(15):2008–2012

    Article  CAS  PubMed  Google Scholar 

  15. Wells G SB, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute Website. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 3 Dec 2013

  16. Higgins J, Green S (eds) (2008) Cochrane handbook for systematic reviews of interventions: cochrane book series. John Wiley & Sons, Chichester

    Google Scholar 

  17. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834

    Article  CAS  PubMed  Google Scholar 

  18. Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. March 2011. Cochrane Collabo-ration, 2011. http://www.cochrane-handbook.org. Accessed 3 Dec 2013

  19. Tormey DC et al (1990) Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An Eastern Cooperative Oncology Group trial. Cancer 65(2):200–206

    Article  CAS  PubMed  Google Scholar 

  20. International Breast Cancer Study Group (1990) Late effects of adjuvant oophorectomy and chemotherapy upon premenopausal breast cancer patients. Ann Oncol 1(1):30–35

    Google Scholar 

  21. Boccardo F et al (1990) Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. J Clin Oncol 8(8):1310–1320

    CAS  PubMed  Google Scholar 

  22. Tormey DC et al (1992) Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. J Clin Oncol 10(12):1848–1856

    CAS  PubMed  Google Scholar 

  23. Reyno LM et al (1992) Chemotherapy induced amenorrhoea in a randomised trial of adjuvant chemotherapy duration in breast cancer. Eur J Cancer 29A(1):21–23

    CAS  PubMed  Google Scholar 

  24. Bonadonna G et al (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 332(14):901–906

    Article  CAS  PubMed  Google Scholar 

  25. Pagani O et al (1998) 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 34(5):632–640

    Article  CAS  PubMed  Google Scholar 

  26. Goodwin PJ et al (1999) Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17(8):2365–2370

    CAS  PubMed  Google Scholar 

  27. Stone ER, Slack RS, Novielli A (2000) Rate of chemotherapy related amenorrhea (CRA) associated with adjuvant adriamycin and cytoxan (AC) and adriamycin and cytoxan followed by taxol (AC + T) in early stage breast cancer. Breast Cancer Res Treat 64(1):61

    Google Scholar 

  28. Poikonen P et al (2000) Prognostic effect of amenorrhoea and elevated serum gonadotropin levels induced by adjuvant chemotherapy in premenopausal node-positive breast cancer patients. Eur J Cancer 36(1):43–48

    Article  CAS  PubMed  Google Scholar 

  29. Borde F et al (2003) Role of chemo-induced amenorrhea in premenopausal, node-positive, operable breast cancer patients: 9-year follow-up results of French Adjuvant Study Group (FASG) data base. Breast Cancer Res Treat 821:S30

  30. Alton J, Jacobs L, Fox K (2004) Chemotherapy-related amenorrhea (CRA) in breast cancer survivors: impact of taxanes on ovarian function. Breast Cancer Res Treat 881:S61–S62

    Google Scholar 

  31. Parulekar WR et al (2005) 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 23(25):6002–6008

    Article  PubMed  Google Scholar 

  32. Samuelkutty S, Gluz O, Mohrmann S (2005) Chemotherapy-induced amenorrhea (CIA) in patients treated with adjuvant CEF/CMF or EC/docetaxel: analysis from a phase III randomized EC/Doc Trial. Breast Cancer Res Treat 941:S105–S106

    Google Scholar 

  33. Li HP et al (2006) Observation and clinical significance of adjuvant chemotherapy-induced amenorrhea in premenopausal breast cancer patients. Zhonghua Zhong Liu Za Zhi 28(11):848–851

    PubMed  Google Scholar 

  34. Kil WJ et al (2006) Treatment-induced menstrual changes in very young (<35 years old) breast cancer patients. Breast Cancer Res Treat 96(3):245–250

  35. Zhou L et al (2007) The association of menstruation of breast cancer patients with chemotherapy regimen and aging period. Tumor 27:999-1002

  36. Reh A, Oktem O, Oktay K (2008) Impact of breast cancer chemotherapy on ovarian reserve: a prospective observational analysis by menstrual history and ovarian reserve markers. Fertil Steril 90(5):1635–1639

    Article  CAS  PubMed  Google Scholar 

  37. Berliere M et al (2008) Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel. BMC Cancer 8:56

    Article  PubMed Central  PubMed  Google Scholar 

  38. Han HS et al (2009) Analysis of chemotherapy-induced amenorrhea rates by three different anthracycline and taxane containing regimens for early breast cancer. Breast Cancer Res Treat 115(2):335–342

    Article  CAS  PubMed  Google Scholar 

  39. Lee S et al (2009) Chemotherapy-related amenorrhea in premenopausal women with breast cancer. Menopause 16(1):98–103

    Article  PubMed  Google Scholar 

  40. Kim HA, Shin DS, Moon NM (2009) The incidence of chemotherapy-induced amenorrhea and recovery in young (<45-year-old) breast cancer patients. J Breast Cancer 12(1):20–26

    Article  Google Scholar 

  41. Sukumvanich P et al (2010) Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study. Cancer 116(13):3102–3111

    Article  PubMed  Google Scholar 

  42. Zhou WB et al (2010) Incidence of chemotherapy-induced amenorrhea associated with epirubicin, docetaxel and navelbine in younger breast cancer patients. BMC Cancer 10:281

    Article  PubMed Central  PubMed  Google Scholar 

  43. Jung M et al (2010) The clinical outcome of chemotherapy-induced amenorrhea in premenopausal young patients with breast cancer with long-term follow-up. Ann Surg Oncol 17(12):3259–3268

    Article  PubMed  Google Scholar 

  44. Abusief ME et al (2010) The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 116(4):791–798

    Article  CAS  PubMed  Google Scholar 

  45. Perez-Fidalgo JA et al (2010) Incidence of chemotherapy-induced amenorrhea in hormone-sensitive breast cancer patients: the impact of addition of taxanes to anthracycline-based regimens. Breast Cancer Res Treat 120(1):245–251

    Article  PubMed  Google Scholar 

  46. Rokutanda N, Horiguchi J, Koibuchi Y (2010) Chemotherapy-induced amenorrhea and adjuvant endocrine therapy for premenopausal women with early breast cancer. EJC Suppl 8(3):74

    Article  Google Scholar 

  47. Okanami Y et al (2011) Incidence of chemotherapy-induced amenorrhea in premenopausal patients with breast cancer following adjuvant anthracycline and taxane. Breast Cancer 18(3):182–188

    Article  PubMed  Google Scholar 

  48. Ganz PA et al (2011) 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 29(9):1110–1116

    Article  PubMed Central  PubMed  Google Scholar 

  49. Najafi S et al (2011) Taxane-based regimens as a risk factor for chemotherapy-induced amenorrhea. Menopause 18(2):208–212

    PubMed  Google Scholar 

  50. Arslan E, Karsy M, Moy F (2011) The effect of taxanes on menstruation and ovarian reserve in women with breast cancer. Fertil Steril 96(3):S77

    Article  Google Scholar 

  51. Zhou W et al (2012) The risk of amenorrhea is related to chemotherapy-induced leucopenia in breast cancer patients receiving epirubicin and taxane based chemotherapy. PLoS One 7(5):e37249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Park IH et al (2012) Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer. Ann Oncol 23(9):2283–2289

    Article  CAS  PubMed  Google Scholar 

  53. Narmadha MP, Veena M, Rajendran NN (2012) Assessment of chemotherapy induced amenorrhea (CIA) in hormone receptor positive premenopausal women with breast cancer. Res J Pharm Biol Chem Sci 3(4):97–106

    CAS  Google Scholar 

  54. Basso E, Rossi L, Tomao F (2012) Incidence of chemotherapy (CT)-induced amenorrhea in premenopausal patients (pts) with breast cancer (BC) following adjuvant anthracycline (A), cyclophosphamide (C), and taxane (T). J Clin Oncol 30:e11039

  55. Canney P, Coleman R, Morden J (2012) TACT2 Trial in Early Breast Cancer (EBC): differential Rates of Amenorrhoea in Premenopausal Women Following Adjuvant Epirubicin (E) or Accelerated Epirubicin (aE) Followed by Capecitabine (X) or CMF. Eur J Cancer 481:S102

    Article  Google Scholar 

  56. Meng K et al (2013) Impact of chemotherapy-induced amenorrhea in breast cancer patients: the evaluation of ovarian function by menstrual history and hormonal levels. World J Surg Oncol 11:101

    Article  PubMed Central  PubMed  Google Scholar 

  57. Walshe JM, Denduluri N, Swain SM (2006) Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 24(36):5769–5779

    Article  CAS  PubMed  Google Scholar 

  58. Torino F et al (2013) Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer. Crit Rev Oncol Hematol 89(1):27–42

    Article  PubMed  Google Scholar 

  59. Maltaris T et al (2006) Reproduction beyond cancer: a message of hope for young women. Gynecol Oncol 103(3):1109–1121

    Article  PubMed  Google Scholar 

  60. Bines J, Oleske DM, Cobleigh MA (1996) Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14(5):1718–1729

    CAS  PubMed  Google Scholar 

  61. Basser RL et al (2006) Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol 24(3):370–378

    Article  PubMed  Google Scholar 

  62. Del Mastro L et al (2011) 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 306(3):269–276

    PubMed  Google Scholar 

  63. Goldhirsch A, Gelber RD, Castiglione M (1990) The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group. Ann Oncol 1(3):183–188

    CAS  PubMed  Google Scholar 

  64. Cobleigh M, Bines J, Harris D (1995) Amenor-rhea following adjuvant chemotherapy for breast cancer. Proc Am Soc Clin Oncol 14:115

    Google Scholar 

  65. Jordan VC et al (1991) Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst 83(20):1488–1491

    Article  CAS  PubMed  Google Scholar 

  66. Karlsson P et al (2011) Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer. Ann Oncol 22(10):2216–2226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Giobbie-Hurder A, Gelber RD, Regan MM (2013) Challenges of guarantee-time bias. J Clin Oncol 31(23):2963–2969

    Article  PubMed  Google Scholar 

  68. Ahn SH et al (2007) Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea–a report from the Korean Breast Cancer Society. J Clin Oncol 25(17):2360–2368

    Article  PubMed  Google Scholar 

  69. Aebi S et al (2000) Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 355(9218):1869–1874

    Article  CAS  PubMed  Google Scholar 

  70. Xue C et al (2012) Distribution, clinicopathologic features and survival of breast cancer subtypes in Southern China. Cancer Sci 103(9):1679–1687

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Anders C et al (2008) A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest 26(3):286–295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant 81172524).

Conflict of interest

The authors have reported no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Breast Surgery, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Jianli Zhao, Jieqiong Liu, Kai Chen, Shunrong Li, Ying Wang, Yaping Yang, Heran Deng, Weijuan Jia, Nanyan Rao, Qiang Liu & Fengxi Su

Authors
  1. Jianli Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jieqiong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shunrong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heran Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weijuan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nanyan Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fengxi Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fengxi Su.

Additional information

Jianli Zhao, Jieqiong Liu, and Kai Chen contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. 1

Funnel plot of the incidence of CIA with and without the cyclophosphamide-based regimen

Fig. 2

Funnel plot of the incidence of CIA with and without the taxane-based regimen

Fig. 3

Funnel plot of the incidence of CIA with and without the anthracycline or epirubicin-based regimen

Fig. 4

Funnel plot of the incidence of CIA(CAT or CET vs other three-drug combination regimens)

Fig. 5

Funnel plot of the incidence of CIA with and without tamoxifen

Fig. 6

Funnel plot of DFS with and without CIA (ER +)

Fig. 7

Funnel plot of DFS with and without CIA (HR–)

Supplementary material 8 (XLSX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, J., Liu, J., Chen, K. et al. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res Treat 145, 113–128 (2014). https://doi.org/10.1007/s10549-014-2914-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-2914-x

Keywords

Search

Navigation