Introduction: Prognosis for locally advanced non-small cell lung cancer (LANSCLC) remain poor despite attempts with radiation dose escalation to improve overall survival (OS). A major limitation of radiation dose escalation is normal tissue toxicity. Here, I investigate the hypothesis that cardiac and its substructure irradiation impact OS in LA-NSCLC patients with a dose-volume-time effect. As cardiac avoidance can potentially increase lung toxicity (radiation pneumonitis (RP) acutely) the hypothesis that novel predictive models for RP combining clinical and dosimetric factors accounting for potential heart and lung irradiation synergistic effect are better than mean lung dose alone as a predictor was also tested. Methods: Complementary methodologies were utilised to provide additional knowledge and derive novel Cox regression OS models and logistic regression RP models. The highly correlated dose volume data were best analysed through principal component analysis. 1) A post hoc analysis of a prospective phase 1/2 isotoxic dose escalation study of 78 patients was conducted to derive an OS model incorporating clinical and cardiac substructure dosimetric factors, and electrocardiographic (ECG) changes. 2) OS model identified in part 1 was validated and refined in an independent retrospective 64 patient cohort where direct impact of cardiac dosimetry on cardiac-morbidity and cardiac-related-death was also assessed. 3) The further refined OS model from part 2 was validated in another independent cohort and the model refined using a large combined cohort and a dose-volume-time effect was tested. 4) A modelling study to predict ≥ grade 2 RP (G2RP) risk combining clinical and dosimetric factors including heart and lung irradiation interaction was conducted. Results: High volume of left atrial wall receiving high doses (64-73 Gy in equivalent 2 Gy per fraction (EQD2)), coronary ostia region receiving intermediate doses (29- 38 Gy EQD2), large planning target volume size, younger age and any ECG changes or recorded cardiac events after RT were associated with poorer OS. A prognostic index was derived from these factors with good performance. High whole heart volume receiving low doses (3-12 Gy EQD2) was associated with poorer OS with the low dose effect seen later than high or intermediate dose effects. Poorer performance status, higher baseline forced vital capacity, higher contralateral tumour free lung volumes, especially lower and middle sections, receiving 2-5 Gy EQD2 and high heart volume receiving 37-55 Gy EQD2 were associated with higher G2RP risk. A model combining these factors performed better at predicting G2RP than the standard mean lung dose model in isotoxically dose escalated patients. Conclusions: This work adds to the knowledge about the nature, magnitude and timing of cardiac and its substructure irradiation on OS and derived novel survival and lung toxicity models combining clinical and dosimetric factors. This can be used to help future management of LA-NSCLC and personalisation of radiation dose escalation. The planned in-silico study and the prospective cardiopulmonary functional imaging study will contribute further knowledge regarding the practical implications and underlying mechanism of damage.</p
