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



Nix, Michael G, Rowbottom, Carl G, Vivekanandan, Sindu, Hawkins, Maria A and Fenwick, John D
(2020) Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low alpha/beta ratio. RADIOTHERAPY AND ONCOLOGY, 143. 58 - 65.

[img] Text
Manuscript_final.pdf - Accepted Version

Download (906kB) | Preview

Abstract

Purpose To analyse changes in 2-year overall survival (OS2yr) 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 OS2yr 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 OS2yr 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 OS2yr rates fell at higher doses. Conclusions Fitted dose–response curves indicate that gains of ~10% in OS2yr 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 OS2yr. Further 10–20% OS2yr 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.

Item Type: Article
Uncontrolled Keywords: NSCLC, Radiotherapy, Dose-escalation, Chemotherapy, Toxicity
Depositing User: Symplectic Admin
Date Deposited: 02 Mar 2020 11:55
Last Modified: 02 Dec 2021 08:20
DOI: 10.1016/j.radonc.2019.07.026
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3076593