Toxicity Related to Radiotherapy Dose and Targeting Strategy: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Locally Advanced Non–Small Cell Lung Cancer

Abstract

Objective: Concurrent chemoradiotherapy (CRT) was the standard treatment for locally advanced NSCLC (LA‐NSCLC). This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on adverse events (AEs). Methods: We collected individual patient data from 3600 patients with LA‐NSCLC who participated in 16 cooperative group trials of concurrent CRT. The TRT parameters examined included field design strategy (elective nodal irradiation [ENI] versus involved‐field [IF] TRT [IF‐TRT]) and TRT dose (60 Gy versus ≥60 Gy). The primary end point of this analysis was the occurrence of AEs. ORs for AEs were calculated with univariable and multivariable logistic models. Results: TRT doses ranged from 60 to 74 Gy. ENI was not associated with more grade 3 or higher AEs than IF‐TRT was (multivariable OR = 0.77, 95% confidence interval [CI]: 0.543–1.102, p = 0.1545). Doses higher than 60 Gy (high‐dose TRT) were associated with significantly more grade 3 or higher AEs (multivariable OR = 1.82, 95% CI: 1.501–2.203, p < 0.0001). In contrast, ENI was associated with significantly more grade 4 or higher AEs (multivariable OR = 1.33, 95% CI: 1.035–1.709, p = 0.0258). Doses higher than 60 Gy were also associated with more grade 4 or higher AEs (multivariate OR = 1.42, 95% CI: 1.191–1.700, p = 0.0001). Grade 5 AEs plus treatment‐related deaths were more frequent with higher‐dose TRT (p = 0.0012) but not ENI (p = 0.099). Conclusions: For patients with LA‐NSCLC treated with concurrent CRT, IF‐TRT was not associated with the overall risk of grade 3 or higher AEs but was associated with significantly fewer grade 4 or higher AEs than ENI TRT. This is likely the result of irradiation of a lesser amount of adjacent critical normal tissue. Higher TRT doses were associated significantly with grade 3 or higher and grade 4 or higher AEs. On the basis of these findings and our prior report on survival, CRT using IF‐TRT and 60 Gy (conventionally fractionated) were associated with more favorable patient survival and less toxicity than was the use of ENI or higher radiotherapy doses.