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

Disclosures

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

In This Article

Results

From January 2011 to December 2016, 521 patients (median age = 34 years, interquartile range = 31–38 years) with ER-positive and HER2-negative breast cancer were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. Figure 1 shows the trial profile. Chemotherapy was completed by 93.9% of patients in the EC-wP group and 94.2% of those in the EP-wP group. Baseline patient and tumor characteristics were well balanced between treatment groups (Table 1).

Figure 1.

Trial profile. *Adverse events indicate grade 3 and 4 events; †Other reasons except for adverse events. EC-wP = epirubicin/cyclophosphamide followed by weekly paclitaxel; EP-wP = epirubicin/paclitaxel followed by weekly paclitaxel; ITT, intention to treat.

For the primary endpoint of menstrual resumption at 12 months after chemotherapy, the rates were 48.3% (95% CI = 42.2% to 54.3%) for the EC-wP group and 63.1% (95% CI = 57.2% to 68.9%) for the EP-wP group, and the absolute difference was 14.8% (95% CI = 6.37% to 23.2%, P < .001; Table 2) with an estimated odds ratio of 1.83 (95% CI = 1.29 to 2.60). When accounting for DFS events by competing risk, the adjusted odds ratio was 1.55 (95% CI = 1.23 to 1.95, P < .001). We further conducted a sensitivity analysis by excluding case patients with unknown information on menses resumption at 12 months after chemotherapy (Table 2). Among the 470 patients (233 in the EC-wP group and 237 in the EP-wP group), menses had resumed in 126 patients (54.1%) in EC-wP group and 164 patients (69.2%) in the EP-wP group, with an odds ratio of 1.94 (95% CI = 1.33 to 2.84, P < .001).

Regarding the other primary endpoint of DFS, at a median follow-up of 62 months (interquartile range = 45–82 months), 92 DFS events were observed in the intention-to-treat population, including 53 (20.3%) in the EC-wP group and 39 (15.0%) in the EP-wP group (Table 3). The 5-year DFS rate was 78.3% (95% CI = 72.2% to 83.3%) in the EC-wP group and 84.7% (95% CI = 79.3% to 88.8%) in the EP-wP group (stratified log-rank P = .07) (Figure 2, A), with a stratified hazard ratio of 0.68 (95% CI = 0.45 to 1.04). No statistically significant differences in distant DFS (HR = 0.62, 95% CI = 0.37 to 1.06, P = .11) or overall survival (HR = 0.81, 95% CI = 0.38 to 1.69, P = .54) were observed (Figure 2, B and C).

Figure 2.

Survival outcomes. Kaplan-Meier plots for disease-free survival (A), distant disease-free survival (B), and overall survival (C) are shown. P values were based on the stratified log-rank test and were 2-sided. CI = confidence interval; EC-wP = epirubicin/cyclophosphamide followed by weekly paclitaxel; EP-wP = epirubicin/paclitaxel followed by weekly paclitaxel; HR = hazard ratio.

In posthoc exploratory analysis of pregnancy outcomes (within 48 months) in the 228 patients who completed the questionnaire survey, 11 of 113 (9.7%, 95% CI = 4.3% to 15.2%) patients in the EC-wP group and 19 of 115 (17.4%, 95% CI = 10.5% to 24.3%) patients in the EP-wP group reported an attempt to become pregnant (P = .09). Successful pregnancy occurred in fewer women in the EC-wP group than in the EP-wP group (2.7% vs 9.6%, P = .03; Table 2). The median time interval between random assignment and pregnancy was 42 months. In exploratory subgroup analyses of DFS, patients with the node-positive disease appeared to benefit more from EP-wP treatment (Figure 3).

Figure 3.

Forest plots of subgroup analysis of disease-free survival. All statistical tests were 2-sided. CI = confidence interval; EC-wP = epirubicin/cyclophosphamide followed by weekly paclitaxel; EP-wP = epirubicin/paclitaxel followed by weekly paclitaxel; HR = hazard ratio.

Patients who received at least 1 cycle of chemotherapy were included in the safety analysis (259 in EC-wP and 257 in EP-wP). Treatment-related grade 3 to 4 adverse events are listed in Table 4. Both treatments were generally well tolerated, and all serious adverse events were resolved and were nonfatal.

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