Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women With Breast Cancer

A Randomized Phase 3 Trial

Ke-Da Yu, MD, PhD; Jing-Yu Ge, MD; Xi-Yu Liu, MD; Miao Mo, MD; Min He, MD; Zhi-Ming Shao, MD


J Natl Cancer Inst. 2021;113(10):1352-1359. 

In This Article

Abstract and Introduction


Background: Chemotherapy-induced premature menopause leads to some consequences, including infertility. We initiated this randomized phase III trial to determine whether a cyclophosphamide-free adjuvant chemotherapy regimen would increase the likelihood of menses resumption and improve survival outcomes.

Methods: Young women with operable estrogen receptor-positive HER2-negative breast cancer after definitive surgery were randomly assigned to receive adjuvant epirubicin and cyclophosphamidefollowed by weekly paclitaxel (EC-wP) or epirubicin and paclitaxel followed by weekly paclitaxel (EP-wP). All patients received at least 5-year adjuvant endocrine therapy after chemotherapy. Two coprimary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year disease-free survival in the intention-to-treat population. This study is registered at (NCT01026116). All statistical tests were 2-sided.

Results: Between January 2011 and December 2016, 521 patients (median age = 34 years; interquartile range = 31–38 years) were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. The rate of menstrual resumption at 12 months after chemotherapy was 48.3% in EC-wP (95% confidence interval [CI] = 42.2% to 54.3%) and 63.1% in EP-wP (95% CI = 57.2% to 68.9%), with an absolute difference of 14.8% (95% CI = 6.37% to 23.2%, P < .001). The posthoc exploratory analysis by patient-reported outcome questionnaires indicated that pregnancy might occur in fewer women in the EC-wP group than in the EP-wP group. At a median follow-up of 62 months, the 5-year disease-free survival was 78.3% (95% CI = 72.2% to 83.3%) in EC-wP and 84.7% (95% CI = 79.3% to 88.8%) in EP-wP (stratified log-rank P = .07). The safety data were consistent with the known safety profiles of relevant drugs.

Conclusions: The cyclophosphamide-free chemotherapy regimen might be associated with a higher probability of menses resumption.


Young age is an independent predictor of adverse outcomes in patients with estrogen receptor (ER)-positive breast cancer.[1] Adjuvant chemotherapy has been firmly established as an effective treatment for breast cancer in previous meta-analyses, especially in patients with young age and higher cancer burden.[2] Cyclophosphamide, which is widely used in combination with anthracycline and/or taxane as adjuvant chemotherapy for breast cancer, may directly damage oocytes in primordial follicles, and premature menopause induced by cyclophosphamide-containing chemotherapy leads to sexual dysfunction, vasomotor symptoms, and infertility.[3]

According to the updated European Society of Human Reproduction and Embryology guidelines and European Society for Medical Oncology Clinical Practice guidelines, luteinizing hormone–releasing hormone agonists (LHRHa) during chemotherapy is recommended to reduce the risk of chemotherapy-induced ovarian failure,[4,5] and other approaches are needed. Cyclophosphamide is strongly associated with chemotherapy-induced premature ovarian failure, whereasthe addition of a taxane might exert less of an effect on amenorrhea.[6] The substitution of cyclophosphamide with paclitaxel might result in a reduced incidence of ovarian failure and an increased likelihood of early menses resumption. It has been reported that the substitution of paclitaxel for cyclophosphamide results in comparable efficacy in a general population but might produce greater benefits in high-risk patients.[7]

Therefore, we designed the present clinical trial to investigate 2 coprimary endpoints in young women with ER-positive and HER2-negative breast cancer. The first endpoint compares the menstrual resumption rate of the standard regimen (epirubicin/cyclophosphamide followed by weekly paclitaxel [EC-wP]) with the cyclophosphamide-free chemotherapeutic regimen (epirubicin/paclitaxel followed by weekly paclitaxel [EP-wP]), and the second investigates the disease-free survival (DFS) between the patients treated with the 2 regimens.