Cardiac Disease and COVID-19 in Lung Cancer Radiotherapy

Abstract

COVID-19, ischaemic heart disease (IHD) and lung cancer were three of the five main causes of death in the United Kingdom in 2020. These conditions may co-exist in the same patient and population-based studies report that approximately 30% of patients undergoing thoracic radiotherapy for lung cancer have a known pre-existing cardiac comorbidity. A seminal dose escalation study published in 2015 found that radiotherapy dose escalation in stage 3 NSCLC is associated with poorer survival and that this may be due to increased heart dose. This study initiated a worldwide interest in the field of radiation-related cardiac toxicity. Subsequently a number of studies have suggested different cardiac dose parameters to reduce cardiac toxicity. This thesis uses large, real world datasets and prospective patient cohorts to define the optimal approach to minimising cardiac toxicity following thoracic radiotherapy and to examine the changes brought about by the COVID-19 pandemic on radiotherapy for lung cancer. First, a review of the current literature on whole heart and substructure dose constraints, the pathophysiology and management of radiation induced heart disease was carried out. This review identified that the volume of heart receiving 30Gy (V30Gy), V5Gy, V50Gy and mean heart dose (MHD) to be the cardiac dose parameters found to be significantly associated with cardiac events and mortality. The relationship between these dose parameters and death with a cardiac cause was then investigated in a retrospective cohort of 967 patients treated with curative hypofractionated radiotherapy for lung cancer. The dataset used in this study was created by linking national data from Public Health England on hospital admission and death with local individual patient radiotherapy dose distributions. This analysis showed that 30% of patients with lung cancer have a known pre-existing cardiac comorbidity prior to radiotherapy and these patients had an increased risk of death with a cardiac cause following treatment. The variables associated with cardiac death following lung cancer radiotherapy were different in patients with and those without pre-existing cardiac comorbidities. In both groups the V30Gy was the heart dose parameter that was most frequently associated with cardiac-related death. 12 In order to elucidate potential mechanisms of RIHD, a prospective cohort trial of cardiac blood biomarkers and cardiac imaging was performed. In the trial, blood was taken from 38 patients for high sensitivity troponin I (hsTnI) and N-terminal pro-brain natriuretic peptide prior to, at the end of and 4 months after curative radiotherapy for stage 1-3 lung cancer. Patients also had cardiac computed tomography (CCT) and cardiac echocardiograms before and 4 months after radiotherapy. The trial found that there was an increase in hsTnI at the end of radiotherapy but that this returned to baseline levels by 4 months after radiotherapy. There was no change in CCT or echocardiograms following radiotherapy. Following previous work reported here and further research carried out by our group and others, a cardiac avoidance area (CAA) is described. This consists of the right atrium, aortic valve root and proximal coronary arteries. A radiotherapy planning study was then carried out with the plans from 15 patients with lung cancer. Standard lung radiotherapy volumetric modulated arc therapy (VMAT) photon plans of were compared to VMAT photon plans in patients with stage 3 lung cancer (66Gy in 33 fractions in both groups) with a maximum dose constraint to 1cc (D1cc) of less than 23Gy on the CAA. The study found that it is possible to achieve this D1cc CAA dose constraint with photon radiotherapy in all cases. It can, however, be difficult to achieve the constraint with proton radiotherapy if the tumour is very close to the CAA. Photon cardiac avoidance achieved a 1843cGy median reduction in CAA D1cc and 1590cGy with proton cardiac avoidance planning. The median MHD was 1

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Alan Mcwilliam (Supervisor), Corinne Faivre-Finn (Supervisor) & Marcel Van Herk (Supervisor)