Spatio-temporal dependency of radiotherapy induced cardiac toxicity in a novel preclinical model

Radiotherapy is an excellent treatment for many types of cancer and about half of all patients can be cured by its use. Despite its success, radiotherapy can result in harmful side effects which can have severe consequences on the quality of life and survival of patients following treatment. In particular, patients who receive chest radiotherapy for different cancers may develop unwanted side effects in the heart which can be life threatening.

In this project, we will investigate different strategies that may be capable of minimizing the effects of radiotherapy by optimising radiotherapy is delivered. This will focus on avoiding structures in the heart that are very sensitive to radiation and will use a new technique to deliver radiotherapy at very high dose rates called FLASH-RT. We will use this information to design better ways of delivering radiotherapy that will reduce harmful effects in the heart, allowing even higher doses of radiotherapy to delivered which could improve outcomes for patients.

Radiation induced cardiac toxicity (RICT) is a major cause of morbidity and mortality in patients following radiotherapy for thoracic malignancies. The risk of developing RICT after treatment increases linearly with mean absorbed dose to the heart by >7% per Gy with an apparent low dose threshold. Consequently, no clear dose volume constraints can be defined & current radiotherapy planning recommendations advise dose to the heart be kept as low as possible.

Current clinical heart dose constraints remain poorly defined and are largely predicted on the heart being a uniformly radiosensitive organ. Recent clinical observations have shown a dose sensitive region in the base of the heart that is associated with poor survival outcomes in lung cancer. We have reverse translated these observations in a mouse model showing significant cardiac dysfunction following base irradiation of the heart.

In this project we will use this model to investigate the impact of spatio-temporal radiotherapy delivery parameters on RICT. Our overall aim to optimise treatment planning by integrating regional cardiac dose constraints based on radiosensitive sub-volumes, cardio-pulmonary interplay and effects at ultra-high dose rates (FLASH-RT).