Chemotherapy-induced Amenorrhea in Patients with Breast Cancer
Abstract & Commentary
By Bindu Kanapuru, MD
Hematology/Oncology Division, IASIA-Falls Church, Falls Church, VA
Dr. Kanapuru reports no financial relationships relevant to this field of study.
Synopsis: The frequency of chemotherapy-induced amenorrhea was found to be greater than 90% in premenopausal breast cancer patients treated with standard adjuvant chemotherapy. Of these, nearly 60% had long-term (> 12 months) amenorrhea and risk factors included age > 40 years, treatment with a taxane in addition to adriamycin/cytoxan, and exposure to tamoxifen. Chemotherapy-induced amenorrhea was associated with significant negative impact on menopause-associated quality of life, as measured by the MENQOL self-assessment questionnaire. Future studies are warranted to better understand and manage chemotherapy-induced amenorrhea.
Source:Yoo C, et al. 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 2013;72:565-575.
Advances in adjuvant therapy for premenopausal breast cancer have resulted
in improved overall survival, but this often comes at the cost of ovarian failure,1which can be the source of both physical and emotional distress. Depending on how chemotherapy-induced amenorrhea (CIA) is defined and on what drugs are used in the adjuvant setting, its occurrence has ranged from 29-93%.1,2Although the development of CIA may suggest better tumor control, the adverse effects on quality of life are of considerable importance. This may be particularly true in Asia where there is a greater prevalence of premenopausal breast cancer.3
To examine this question further, Yoo and Korean colleagues conducted a prospective, observational study in premenopausal women with breast cancer receiving adjuvant chemotherapy. The aims of the study were to define the pattern of CIA, describe menopause-specific QOL (MENQOL) using a validated self-questionnaire,4evaluate endocrine profiles at baseline and following chemotherapy, and determine the predictors for CIA, MENQOL, and hormonal profiles.
For this study, 387 premenopausal women with breast cancer who underwent curative surgery from October 2003 through July 2007 were initially enrolled. However, 75 were later excluded because of noncompliance or disease recurrence. The inclusion criteria for the study population were as follows: age ≥ 30 years, premenopausal status with regular menstruation at diagnosis, intact ovary and uterus, and a q3 week adjuvant chemotherapy schedule. Exclusion criteria included prior treatment for ovarian suppression or ablation. Planned chemotherapy included four cycles of adriamycin (60 mg/m2) and cyclophosphamide (600 mg/m2), with or without four cycles of a taxane, depending on lymph node status. The majority of patients continued treatment with tamoxifen.
Assessment of menstrual pattern, laboratory studies including measures of follicle-stimulating hormone (FSH) and estradiol, and the MENQOL self-questionnaire were obtained prior to chemotherapy and at 1, 6, and 12 months thereafter.
Data analysis was done on 312 patients. Of these, the median age was 43 years (range 30-52) and body mass index was 22.5 kg/m2(range 18-32). All patients received the adriamycin and cyclophosphamide, 120 patients (39%) received a taxane, and 215 (69%) received tamoxifen. The median duration of follow-up was 17.5 months (range 7.5-29.2 months).
All patients experienced some degree of variation in their normal menstrual cycles and were subsequently classified into one of three categories: 1) long-term CIA (n = 180, 57.7%), 2) temporary CIA (n = 113, 36.2%), and 3) menstrual irregularity (n = 19, 6.1%). For patients who developed temporary or long-term CIA, the median time to onset of amenorrhea was 2 months (range 0-13 months). Risk factors for long-term CIA included age ≥ 40 years (P < 0.001), taxane use (P = 0.01), and tamoxifen use (P = 0.03). For patients with temporary CIA, amenorrhea was significantly longer in those who received taxane therapy (mean 9.4 vs 6.2 months,
P = 0.001).
Endocrine profiles and MENQOL scores were assessed for each group of patients. In all groups, the MENQOL scores were the worst at 1 month after completion of therapy and improved over time.
In the long-term CIA group, FSH was substantially increased after chemotherapy when compared to baseline (P < 0.001), and estrogen was significantly lower than baseline at all time points (P < 0.001). In the temporary CIA group, FSH was again significantly increased after treatment (P < 0.001). There was a significant difference in estrogen level at 1 month when compared to baseline (P < 0.001), but this difference was not sustained at additional time points. In the menstrual irregularity group, FSH was significantly increased at 1 month post-treatment (P < 0.001), but was not different from baseline at additional time points. For this group, there were no statistically significant differences in estrogen levels when compared to baseline.
In approximately 60% of premenopausal breast cancer patients treated with standard anthrcycline-based adjuvant chemotherapy, long-term amenorrhea occurred, and in all but a few of the rest, a temporary cessation of menses (median 7 months) occurred. Risks for long-term CIA included age > 40 years, the addition of a taxane to adriamycin and cyclophosphamide, and exposure to tamoxifen.
A strength of the current study is the valuable quality-of-life data using the MENQOL questionnaire. MENQOL was worst immediately after the completion of adjuvant chemotherapy, but tended to improve over time, especially in patients with temporary CIA and menstrual irregularity; however, this reduced MENQOL did not recover to baseline levels until 12 months after chemotherapy. As expected, the long-term CIA group experienced the most severe disturbances to their MENQOL compared with the other groups.
Considering that most premenopausal patients will experience at least temporary CIA, the findings highlight the prevalent disruption of quality of life, particularly in domains related to menopause (e.g., sexuality, vasomotor, and psychosocial). These are the expected rather than the unusual consequence of adjuvant chemotherapy. Patient education and counseling may be of value in preparing for these changes, but the truth is we have a lot to learn about the immediate and long-term consequences and the management of rapid-onset menopause in the context of young patients receiving cancer chemotherapy.
- Walshe JM, et al. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006;24:5769-5779.
- Parulekar WR, et al. 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;23:6002-6008.
- Jung KW, et al. Cancer statistics in Korea: Incidence, mortality and survival in 2006-2007. J Korean Med Sci 2010;25:1113-1121.
- Hilditch JR, et al. A menopause-specific quality of life questionnaire: Development and psychometric properties. Maturitas 1996;24:161-175.