Introduction: Non-small cell lung cancer (NSCLC) radiotherapy has undergone substantial technical advances. However, issues remain unanswered, including: 1) optimum radiation dose-fractionation schedules for concurrent chemoradiotherapy (cCRT); 2) the effects of adding immune checkpoint blockade (ICB) immunotherapy above cCRT alone on overall survival (OS); 3) how radiotherapy schedules can be optimised with cCRT-ICB treatment; 4) the impact of cardiac toxicity, and how cardiac-sparing might change OS. In this thesis, I test a series of hypotheses to answer these questions.//
Methods: Two meta-analytic lung radiotherapy datasets were used, containing 4866 and 2196 NSCLC patients treated via radiotherapy alone, sequential CRT (sCRT), cCRT and cCRT-ICB. Models were maximum likelihood fitted. A series of radiotherapy dose-response models were used, taken hypotheses considering the effects of chemotherapy, immunotherapy, and cardiac toxicity. Chapter 3 informed the optimised prescribed dose, dose-per-fraction, and duration for cCRT. Chapter 4 identified factors influencing outcomes with cCRT-ICB. Chapter 5 optimised radiation schedules with cCRT/sCRT-ICB. Chapter 6 modelled OS effects of cardiac-sparing with photons and protons.//
Results: For cCRT, accelerated repopulation began late (day 24) and was clinically significant (1.47Gy/day). The addition of ICB to cCRT improved 2-year OS by 9.9%, with tumour PDL1 ≥1%, stage IIIB/C, and longer planned ICB duration being significant predictors of benefit. Neither dose-escalation nor de-escalation relative to 60Gy in 30 fractions influenced survival with cCRT-ICB, while dose de-escalation of 5Gy might benefit patients with heavily irradiated organs at risk. Mean heart dose cardiac-sparing improved OS, and protons offered additional benefit over photons for tumours overlapped or lay below the 7th thoracic vertebra.//
Conclusion: This work furthers our understanding about mechanistic processes influencing outcomes after NSCLC radiotherapy. Findings could be translated into future clinical studies, such as hypofractionation for cCRT alone, extending ICB administration to 2 years for cCRT-ICB treatment, and cardiac-sparing using photons or protons.