Abstract
This thesis investigates the base-mediated radiation cardiotoxicity observed in the radical treatment of non-small cell lung cancer (NSCLC). The existing pre-clinical literature on this subject is restricted to non-targeted radiation exposures, objectives focussed on the cardiac ventricles, and little high-throughput experimentation. The published clinical experience is limited to small, single-centre clinical cohorts, or large, data-mining analyses, and typically include inadequate levels of cardiovascular co-morbidity and treatment detail. The overarching hypothesis of this thesis is that the base of the heart has quantifiable biophysical components.To address the gaps in the pre-clinical landscape of radiation cardiotoxicity, two mouse experiments were planned on the basis of results from a systematic review. Spatial transcriptomics was deployed to identify regional variation in the impact of base irradiation on gene expression at 30 weeks. Gene dysregulation was not restricted to the cardiac anatomy that was irradiated, demonstrating how the cardiac substructures are biologically inter-related.
The pre-clinical literature on statin therapy is consistent with a prophylactic role in radiation cardiotoxicity. Long-term follow-up data was generated in a second mouse study, and this confirmed persistent abrogation of radiation effects on functional endpoints. A cohort of 478 NSCLC cases was used to evaluate the relationship between statin therapy and cardiac outcomes in the clinical setting, accounting for incidental radiation dose to the heart base. A significant relationship was found to exist between statin therapy dose intensity and survival. Cardiac events did not differ by statin intensity in frequency or severity however.
Finally, the clinical data evidencing the base region of the heart as a key anatomical volume for dose-sparing is based on the endpoint of overall survival, a surrogate measure of radiation cardiotoxicity. In the clinical cohort above, cardiac substructures were auto-contoured with a validated tool for 4-dimensional planning scans. Additional substructures were manually delineated, including the pulmonary veins using an atlas presented here. Dose volume histogram metrics for the heart base were found to be associated with both survival and cardiac events. Furthermore, the dose to several cardiac substructures within the base corresponded to relevant clinical endpoints. Relationships were also observed for some substructures outside the formal base definition.
In conclusion, this work confirmed that the heart base radiation dose influences the cardiac response to irradiation, and that statin therapy partially off-sets deleterious radiation effects.
| Date of Award | Jul 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | Wellcome-HRB ICAT Programme |
| Supervisor | Karl Butterworth (Supervisor), Suneil Jain (Supervisor) & Aidan Cole (Supervisor) |
Keywords
- Lung cancer
- radiotherapy
- survival
- cardiotoxicity
- cardiac base
- spatial transcriptiomics
- statins
- auto-segmentation