Impact of chemotherapy dose reduction during concurrent chemoradiotherapy on survival outcomes in limited-stage small-cell lung cancer

BACKGROUND: Dose reduction during concurrent chemoradiotherapy (cCRT) is frequently required in patients with limited-stage small-cell lung cancer (LS-SCLC) because of treatment-related toxicities or poor tolerance. However, the impact of chemotherapy dose reduction on long-term outcomes in LS-SCLC remains unclear. We aimed to evaluate whether chemotherapy dose reduction compromises survival in patients with LS-SCLC receiving definitive cCRT. METHODS: We retrospectively analyzed patients with LS-SCLC treated with definitive cCRT across multiple centers. Patients were categorized into a dose-maintained group and a dose-reduced group according to whether chemotherapy dose reduction occurred during cCRT. To minimize baseline imbalances, inverse probability of treatment weighting (IPTW) based on propensity scores was applied using clinical covariates including age, sex, T stage, N stage, ECOG performance status, smoking status, weight loss, gross tumor volume, and chemotherapy regimens. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis and Cox proportional hazards models in both unweighted and IPTW-weighted cohorts. Exploratory analyses were additionally performed within the dose-reduced group according to the timing of first dose reduction and the magnitude of dose reduction. RESULTS: A total of 1,013 patients were included, comprising 627 patients in the dose-maintained group and 386 patients in the dose-reduced group. After IPTW adjustment, baseline characteristics were well balanced between groups. For OS, the median OS after IPTW adjustment was 57.8 months (95% CI 42.9-70.1) in the dose-maintained group and 42.8 months (95% CI 37.5-67.5) in the dose-reduced group. Chemotherapy dose reduction was not associated with a statistically significant difference in OS (HR = 1.17, 95% CI 0.95-1.44, P = 0.132).For PFS, the median PFS after IPTW adjustment was 25.0 months (95% CI 20.7-31.0) in the dose-maintained group and 20.5 months (95% CI 17.1-26.9) in the dose-reduced group. Chemotherapy dose reduction was associated with a modest but statistically significant decrease in PFS (HR = 1.19, 95% CI 1.00-1.40, P = 0.047). Within the dose-reduced group, exploratory analyses suggested that patients whose first dose reduction occurred at cycle ≥ 3 had significantly better PFS and OS than those whose first dose reduction occurred during cycles 1-2.Treatment-related adverse events were broadly comparable between groups, with no statistically significant reduction observed in the dose-reduced group. CONCLUSIONS: In this multicenter real-world cohort of patients with LS-SCLC treated with definitive cCRT, chemotherapy dose reduction was not associated with a statistically significant difference in OS after IPTW adjustment but was associated with a modestly shorter PFS. Given the absence of an apparent reduction in treatment-related toxicity, chemotherapy dose reduction should not be considered an ideal strategy when full-dose treatment is feasible, although it may remain a pragmatic option for selected patients with limited treatment tolerance. The exploratory association between early dose reduction and poorer survival should be interpreted cautiously, as it may reflect greater frailty or poorer treatment tolerance rather than a direct causal effect of dose-reduction timing.