Dose-Response Analysis Describes Particularly Rapid Repopulation of Non-Small Cell Lung Cancer during Concurrent Chemoradiotherapy

Simple Summary Divergent results from trials of dose-escalation and acceleration suggest that optimal schedules have yet to be identified for radiotherapy of inoperable locally advanced non-small cell lung cancer. In this hypothesis-generating study radiation dose-response models were fitted to survival rates for 51 patient cohorts treated with schedules of varying total radiation dose, dose-per-fraction and duration. The best fit described repopulation running at 1.47 Gy/day for concurrent chemoradiotherapy and 0.30 Gy/day for radiotherapy alone and sequential chemoradiotherapy. The overall fitted tumour alpha/beta ratio was 3.0 Gy. These findings imply that moderate hypofractionation of chemoradiation, within normal tissue toxicity limits, should be efficacious. (1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low alpha/beta ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction <= 3 Gy over 16-60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and alpha/beta to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour alpha/beta ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low alpha/beta ratio suggests hypofractionation should be efficacious.