Michael G Nix1, Carl G Rowbottom2, Sindu Vivekanandan3, Maria A Hawkins4, John D Fenwick5. 1. Department of Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, United Kingdom. Electronic address: michael.nix@nhs.net. 2. Department of Physics, Clatterbridge Cancer Centre, Wirral, United Kingdom; Department of Physics, University of Liverpool, Oliver Lodge Laboratory, Liverpool, United Kingdom. 3. Guy's Hospital Cancer Centre, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. 4. Department of Oncology, University of Oxford, United Kingdom. 5. Department of Physics, Clatterbridge Cancer Centre, Wirral, United Kingdom; Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, United Kingdom.
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.
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.
Authors: Louise Turtle; Neeraj Bhalla; Andrew Willett; Robert Biggar; Jonathan Leadbetter; Georgios Georgiou; James M Wilson; Sindu Vivekanandan; Maria A Hawkins; Michael Brada; John D Fenwick Journal: Radiat Oncol Date: 2021-06-03 Impact factor: 3.481
Authors: Huei-Tyng Huang; Michael G Nix; Douglas H Brand; David Cobben; Crispin T Hiley; John D Fenwick; Maria A Hawkins Journal: Cancers (Basel) Date: 2022-10-05 Impact factor: 6.575