Altering Radiation Response with Time, Volume and Fractionation

Sammanfattning: Radioresistance, the failure to achieve a desired outcome, is an obstacle in clinical radiotherapy. In this thesis we investigate factors affecting radioresistance and strategies to overcome it, both with established clinical approaches and by using novel pre-clinical discoveries. Study I & II concern the impact of tumour volume in patients with oropharyngeal cancer. In a large, pooled cohort of 654 patients from three clinical trials, we show that tumour volume is the predominant factor for local control, progression free survival and overall survival. The negative impact of large tumour volumes could, in exploratory analyses, be mitigated by intensified radiotherapy. The studies also confirm the prognostic role of HPV/p16- associated tumours, haemoglobin level and smoking status. Based on the results, individualized treatment based on tumour volume could be suggested. The second part of the thesis is based on pre-clinical experiments of novel discoveries. FLASH, the use of ultra-high dose rate radiotherapy where the irradiation is delivered in a fraction of a second, has been shown to spare normal tissue without hampering tumour control. Thereby, FLASH could be used to overcome radioresistance by escalating the dose to the tumour without increasing the risk of normal tissue complications. Oxygen has been proposed to play a key role in mediating the FLASH effect. We investigated the role of oxygen concentrations in a prostate cancer cell line and found that the FLASH effect appeared in hypoxic cells, but not in normoxic (study III). To further elucidate if FLASH effects are solely appearing in hypoxia, we investigated six additional cell lines under normoxic conditions and found that a FLASH effect may also appear in normoxia (study IV). We did not find any correlation between the FLASH effect and induction of DNA double strand breaks or cell cycle arrests. In the last two decades the discovery of bystander and rescue effects has broaden the understanding of radiation responses. Not only directly hit cells are affected by the irradiation, and cellular communications contribute to part of the radiation response. We investigated if cellular communications could induce radioresistance. By varying the number of irradiated cells, adding cell conditioned medium and irradiating only half of the cells, we found that cellular communications cause a rescue effect, hence radioresistance. In summary, the thesis underpins that radiation responses can be altered. To overcome radioresistance due to large tumour volumes, intensified radiotherapy for patients with large oropharyngeal cancers should be considered. The clinical exploitations of FLASH and bystander/rescue effects remain to be investigated.