Absolute benefit from adjuvant chemotherapy in contemporary clinical trials: A systemic review and meta-analysis

Background: Many adjuvant breast cancer trials have observed smaller than anticipated differences between experimental and control groups. Accurate estimation of the absolute benefits of treatment is essential for the planning of clinical trials. Methods: We searched PubMed to identify contemporary randomized trials comparing different adjuvant chemotherapy regimens in breast cancer. The absolute difference in 5-year disease-free survival (DFS) and overall-survival between experimental and control groups were extracted, weighted by individual study sample size and pooled. Analyses were performed for estrogen receptor (ER) negative and ER-positive disease. Meta-regression explored the influence of patients and tumor characteristics and median follow-up on the benefit from treatment. Results: Analysis included 19 studies comprising 41,564 patients. Studies comparing chemotherapy regimens of different generations showed the largest difference in 5-year DFS (+ 7.4% for 3rd vs. 2nd generation and + 5.9% for 2nd vs. 1st generation for ER-negative disease, and + 2.3% for 3rd vs. 2nd generation and + 1.8% for 2nd vs. 1st generation for ER-positive disease). Studies comparing chemotherapy regimens from the same generation showed smaller differences in DFS in both subgroups. Meta-regression showed that larger tumors and nodal involvement had significant greater magnitude of effect on 5-year DFS for ER-negative, but not ER-positive disease. Age and menopausal status had no effect in either subgroup. Conclusions: Absolute differences between adjuvant chemotherapy regimens of the same generation are small even in ER-negative disease. Enrichment of trials for patients with poor clinical features results in larger magnitudes of benefit from treatment at 5 years in ER-negative, but not ER-positive disease.