Identification and selection of studies

The review followed methodology outlined in a pre-specified study protocol and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7, 8]. Systematic searches were conducted to identify peer-reviewed RCTs published from 1 January 2007 to 22 March 2019 in Embase, MEDLINE (via PubMed), and the Cochrane Library. Search strategies included a combination of controlled vocabulary including relevant medical subject headings and free-text terms such as ‘breast cancer’, ‘breast neoplasm’, ‘metastasis’, and ‘locally advanced’. The full search strategies describing the population, study design, and treatment search parameters are presented in Additional file 1. Conference proceedings of five key meetings from the 2 years prior to preparation of this manuscript (2018 to 2019) were searched, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the Japan Society of Clinical Oncology, the Japan Society of Medical Oncology, and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Conference proceedings from the above meetings were hand-searched using free-text terms for ‘breast cancer’. Additionally, bibliographies of identified SLRs were also searched manually to confirm that all relevant studies were included.

Screening was conducted using pre-defined eligibility criteria that were based on population, interventions, comparisons, outcomes, and study design (PICOS; Table 1). At the title/abstract level, all abstracts were screened by one investigator, and a second reviewer examined 10% of exclusions to validate screening quality of the first reviewer. Full-text screening was conducted by two independent investigators, with discrepancies resolved by a third investigator. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), rate of treatment discontinuation due to adverse events (TDAEs), and rate of serious adverse events (SAEs). Comparators of interest for inclusion in the NMA were monotherapy and combination strategies of: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), vinorelbine (VIN), and treatment by physician’s choice (TPC).

PICOS Criteria for Study Selection

Patients with LABC or MBC who had received at least one prior therapy

•. LABC or MBC defined as stage IV, any T, and N, M1^a

•. Target populations were HER2-negative or TNBC, but HER2-positive populations were also included

•. Early disease (stage I–III)

•. First-line treatment

•. Eribulin mesylate (Halaven®)

•. Carboplatin (Paraplatin®)

•. Cisplatin (Platinol®; Platinol®-AQ)

•. Cyclophosphamide (Cytoxan®; Neosar®)

•. Doxorubicin (Adriamycin®; Rubex®)

•. Doxorubicin liposomal (Doxil®)

•. Epirubicin (Ellence®)

•. Capecitabine (Xeloda®)

•. Fluorouracil (Adrucil®)

•. Gemcitabine (Gemzar®)

•. Methotrexate (amethopterin)

•. Docetaxel (Taxotere®)

•. Ixabepilone (Ixempra®)

•. Paclitaxel (Taxol®; Onxal™)

•. Protein-bound paclitaxel (Abraxane®)

•. Vinorelbine (Navelbine®)

•. Efficacy: OS, PFS, response (including ORR, CR, PR, SD, PD)

•. Safety: AEs, SAEs, discontinuation, and death

Abbreviations: AE Adverse event, BSC Best supportive care, CR Complete response, HER2 Human epidermal growth factor receptor 2, LABC Locally advanced breast cancer, MBC Metastatic breast cancer, NA Not applicable, NMA Network meta-analysis, ORR Objective response rate, OS Overall survival, PD Progressive disease, PFS Progression-free survival, PICOS Population, interventions, comparisons, outcomes, and study design, PR Partial response, RCT Randomized controlled trial, SAE Serious adverse event, SD Stable disease, SLR Systematic literature review, TNBC Triple-negative breast cancer

^a Any size, with or without nearby lymph node involvement, spread to distant organs or distal lymph nodes