No Survival Advantage of Intermediate Radiotherapy Dose Escalation in Stage III NSCLC Receiving Delayed Immunotherapy after Chemoradiation

Whether intensifying the radiotherapy dose for unresectable stage III NSCLC that is later managed with immunotherapy provides any advantage remains poorly understood. This analysis was designed to explore whether intermediate-dose escalation (IDE) yields a survival benefit in stage III NSCLC treated with definitive concurrent chemoradiation (dcCRT) and subsequent immunotherapy. The study extracted information from the National Cancer Database. All-cause mortality was evaluated through multivariable Cox regression, contrasting a standard RT dose (SD) (60 Gy ± 10%) against IDE (64–74 Gy). Within the pre-immunotherapy timeframe, 47,315 individuals were diagnosed and managed exclusively with dcCRT, while 4,947 received dcCRT in combination with immunotherapy. Among the dcCRT-only subset, SD was associated with a statistically significant increase in mortality but a clinically trivial difference compared with IDE (HR: 1.09, 95% CI: 1.07-1.12; P < 0.0001). During the immunotherapy period, SD remained associated with lower mortality than IDE (HR: 1.17, 95% CI: 1.03-1.33; P = 0.02). The survival benefit linked to IDE, however, applied exclusively to patients whose immunotherapy began within six weeks of completing RT (HR: 1.26, 95% CI: 1.05-1.6; P = 0.01). No mortality divergence emerged between SD and IDE for those starting immunotherapy at 7–10 weeks (HR: 1.13, 95% CI: 0.88-1.45; P = 0.35) nor for delays exceeding 10 weeks after RT completion (HR: 0.74, 95% CI: 0.51-1.07; P = 0.11). For stage III unresectable NSCLC patients who do not initiate immunotherapy more than 6 weeks after dcCRT, the IDE of RT is unwarranted.