Sequential versus concurrent adjuvant chemo-endocrine therapy for HR+ early breast cancer: a systematic review and Bayesian network meta-analysis

Abstract

Background: Chemo-endocrine therapy is the standard adjuvant treatment strategy for hormone receptor-positive (HR+) early breast cancer. Our research aimed to compare the efficacy of adjuvant chemo-endocrine therapies, regarding different endocrinal regimens and integration sequences (sequential or concomitant), for HR+ early breast cancer.

Methods: PubMed, Embase, the Cochrane Library and web of science were searched for articles published before October 2018 with Clinicaltrials.gov (https://clinicaltrials.gov) for registered clinical trials and ASCO, AACR, ESCO, SABCS meeting abstracts for addition. Randomized clinical trials (RCTs) comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of primary breast cancer patients were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status.

Results: Thirty-three trials with 28,515 patients and 19 treatments were enrolled. Comparisons between regimens has seen better efficacy of ovarian function suppressor (OFS) + aromatase inhibitors (AI) than OFS + tamoxifen, either used concurrently [HR =0.69, 95% credible intervals (CrI): 0.47-1.02] or sequentially with chemotherapy (HR =0.72, 95% CrI: 0.49-1.06) in premenopausal patients. Adding OFS to tamoxifen was marginally better than tamoxifen used alone (DFS: HR =0.85, 95% CrI: 0.65-1.09; OS: HR =0.77, 95% CrI: 0.52-1.08). Comparisons between different sequences of chemo-endocrine therapy proved equal efficacy in premenopausal and postmenopausal patients. Recommendation was given based on ranking of treatments. Sequential and concurrent use of chemotherapy and OFS + AI ranked equally in premenopausal patients and were recommended as the best option. However, tamoxifen ranked higher when used concurrently with chemotherapy in both premenopausal and postmenopausal HR+ early breast cancer.

Conclusions: In the adjuvant chemo-endocrine therapy for premenopausal HR+ early breast cancer, concurrent and sequential adjuvant chemo-endocrine therapy was demonstrated of equal efficacy in both postmenopausal and premenopausal HR+ early breast cancer.

Trial registration: PROSPERO CRD42018104889.

Keywords: Bayesian analysis; Estrogen receptor-positive breast cancer; chemotherapy; endocrine therapy; randomized clinical trial (RCTs).

Figure 1

Workflow of literature selection and geometry of studies and treatment arms included. (A) Flow chart of literature search and selection process according to the PRISMA guidelines: (B) Network plots of studies and treatment arms enrolled. Nodes represent the competing treatments and edges represent the available direct comparisons between pairs of treatments. Both nodes and edges were weighted according to the number of patients and studies enrolled, respectively. Nodes were colored into three categories: chemotherapy or hormonal therapy alone (light blue); chemotherapy and endocrine therapy used concurrently (cranberry); chemotherapy followed by endocrine therapy (dark green). Che, chemotherapy; Tam, tamoxifen; OFS, ovarian function suppression; Tri, triptorelin; Gos, goserelin; Let, letrozole; Exe, exemestane; Ana, anastrozole. Sequence of regimens was illustrated as: sequential use, “−”; concurrent use, “+”.

Figure 2

Comparisons of chemo-endocrine therapies for premenopausal HR+ early breast cancer regarding DFS, OS. (A) Comparisons of chemo-endocrine therapy for premenopausal HR+ early breast cancer by Bayesian network analysis regarding DFS and OS. Treatment arms were aligned on the diagonal line. Hazard ratios and 95% CrIs were generated by comparing the upper-left arm to the lower-right. Bricks were colored by clinical outcomes: DFS: light green, OS: light blue. 95% CrI not cross 1 was considered statistically significant and represented as bold deep green (DFS) or deep blue (OS) bricks with underline. HR <1, upper 95% CrI ≤1.05 and HR >1, lower 95% CrI ≥0.95 were considered marginal significance and represented as deep green (DFS) or deep blue (OS) bricks only. (B) Rankogram of treatment arms in DFS and OS analysis for premenopausal HR+ early breast cancer. Based on the therapeutic efficacy, the probability of each treatment on each position was calculated and presented as bar plot. Treatments were ranked by the position of the highest possibility. For two treatments with the highest possibility on the same position, the two treatments were considered a tied with equal preference. DFS, diseases-free survival; OS, overall survival; CrIs, credible intervals; Che, chemotherapy; Tam, tamoxifen; OFS, ovarian function suppression; AI, aromatase inhibitor.

Figure 3

Comparisons of chemo-endocrine therapies for postmenopausal HR+ early breast cancer regarding DFS, OS. (A) Comparisons of chemo-endocrine therapy for postmenopausal HR+ early breast cancer by Bayesian network analysis regarding DFS and OS. (B) Rankogram of treatment arms in DFS and OS analysis for postmenopausal HR+ early breast cancer. DFS, diseases-free survival; OS, overall survival.