Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low α/β ratio

Purpose: To analyse changes in 2-year overall survival (OS_2yr) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC).

Material and methods: OS_2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation.

Results: A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (p < 10^-14), and had better AIC and cross-validation scores. The fitted α/β ratio for LA-NSCLC was 4.0 Gy (95%CI: 2.8-6.0 Gy), repopulation negated 0.38 (95%CI: 0.31-0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16-31%). For schedules delivered in 2 Gy fractions over 40 days, maximum modelled OS_2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87 Gy (RT or sequential CRT) and 67 and 73 Gy (concurrent CRT). Modelled OS_2yr rates fell at higher doses.

Conclusions: Fitted dose-response curves indicate that gains of ~10% in OS_2yr can be made by escalating RT and sequential CRT beyond 64 Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5-10% improvement in OS_2yr. Further 10-20% OS_2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared.