Evaluating the Fragility of Long-Term Outcomes for Neoadjuvant versus Adjuvant Chemotherapy Prescription in Early Breast Cancer: Pooled Data from 10 Randomised Clinical Trials

Introduction: Randomised clinical trials (RCTs) report similar outcomes following neoadjuvant (NAC) and adjuvant chemotherapy (AC) in breast cancer. “Fragility Indices” (FI) test significance reversal reported in RCTs. Aim: To evaluate the FI of findings from RCTs assessing outcomes of NAC and AC. Methods: A systematic review was performed as per PRISMA guidelines. RCTs of interest were identified and data pooled. Fisher’s exact test was used to calculate FI for reversal of statistical significance for dichotomous outcomes. “Fragility Quotient” (FQ) was calculated by division of the calculated FI by the sample size. Results: Ten RCTs including 4928 patients. Mean follow-up was 8.2 years. For breast conservation surgery (BCS), the FI was 500 and FQ was 0.10781. For local recurrence (LR), the FI was 42 and FQ was 0.00852. FI and FQ varied for LR at 0– 4 years (FI: 9), 5– 9 years (FI: 2), 10– 14 years (FI: 4), and 15+ years (FI: 3). Regarding distant recurrence (DR), the FI was 13 and FQ was 0.00264. FI and FQ trended downwards over time: 0– 4 years (FI: 56), 5– 9 years (FI: 18), 10– 14 years (FI: 4), and 15+ years (FI: 4). For breast-cancer-specific mortality (BCSM), the overall FI was 51 and FQ was 0.01035. FI and FQ varied for BCSM at 0– 4 years (FI: 5), 5– 9 years (FI: 19), 10– 14 years (FI: 8), and 15+ years (FI: 5). For overall survival (OS), the FI was 17 and FQ was 0.00345. FI and FQ were calculated with respect to OS at 0– 4 years (FI: 19), 5– 9 years (FI: 17), 10– 14 years (FI: 19), and 15+ years (FI: 1). Conclusion: FIs comparing survival following NAC and AC were of moderate-to-high fragility, indicating weak statistical significance. BCS eligibility following NAC was of low fragility, ratifying the oncological and surgical safety of NAC versus AC. Level of Evidence: Systematic Review of Level I Randomised Control Trials. Keywords: Fragility Index, breast cancer, statistics, chemotherapy, patient outcomes