ESTRO 36 Abstract Book

S41 ESTRO 36 _______________________________________________________________________________________________

4 Alfred Hospital, William Buckland Radiotherapy Centre, Melbourne, Australia Purpose or Objective Microbeam Radiotherapy (MRT) is a pre-clinical synchrotron radiotherapy modality characterised by fields of high intensity, parallel beams which form 25-50 micron (µm) wide ‘peak dose’ regions spaced by 100 - 400µm ‘valley’ regions. The aim of this study was to assess the safety profile of MRT compared to high dose-rate broad- beam radiotherapy based on in vivo normal tissue toxicity. Material and Methods A dose-escalation study using MRT and high dose-rate synchrotron broad-beam radiotherapy (SBBR) was performed on C57BL/6 mice (male and female, 8-10 weeks old). Mice received either Total Body Irradiation (TBI) or Partial Body Irradiation to their entire abdomen (PBI). MRT was performed at the Australian Synchrotron with an array of microbeams 50 µm wide and spaced by 400 µm. SBBR was delivered at the Australian Synchrotron using a dose rate of 40 Gy/second. For TBI, the broad-beam doses were 4, 6, 8 and 10 Gy and the MRT peak doses were 48, 64, 96 and 144 Gy. For PBI, the broad-beam doses were 6, 9, 12 and 15 Gy and the MRT peak doses were 180, 270, 360 and 450 Gy. Five mice were irradiated per group. Mice were monitored twice per day for one month following irradiation for signs of weight loss and other gastrointestinal toxicities such as diarrhoea, and were euthanized according to strict intervention criteria. Results For TBI, all mice survived with no signs of diarrhoea up to peak MRT doses of 144 Gy. There was a dose-dependent increase in the incidence of sustained weight loss, with four out of five mice in the 144 Gy group showing at least 10% weight loss two weeks following irradiation. All mice in the 48 Gy and 64 Gy groups returned to within 5% of their pre-experimental weight eight days following irradiation. In the SBBR groups, 10 Gy led to irreversible weight loss and euthanasia for all mice within two weeks of irradiation. All mice in the 6 and 4 Gy SBBR groups returned to their pre-experimental weight within nine days of irradiation. For PBI, all mice in the 450 Gy group experienced 20% weight loss, severe diarrhoea and dehydration within six days of irradiation, consistent with gastrointestinal syndrome, and were euthanized. All mice in the 360 Gy MRT and 15 Gy SBBR groups also lost 20% of their pre-experimental body weight, showed signs of dehydration and were euthanized. All mice in the 270 and 180 Gy MRT groups and the 9 and 6 Gy SBBR groups survived, experiencing reversible weight loss and showing no signs of diarrhoea. Conclusion These are the first systematic dose-escalation toxicity data for MRT and high dose-rate SBBR for the gastrointestinal tract. The threshold for catastrophic acute gastro-intestinal toxicity lies between 270 and 360 Gy for MRT and between 10 and 15 Gy for high dose-rate synchrotron broad-beam radiotherapy when irradiating the entire abdomen. A comparison with toxicity data for conventional dose-rate broad beam radiotherapy is required to determine whether ultra-high dose-rates provide a normal tissue sparing effect.

experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. Increasing the therapeutic window of radiotherapy may be achieved by using molecularly targeted therapies against pathways that are altered in cancer. The complement system is an important pathway in immunity composed of soluble and cell surface proteins. Several members of this pathway are upregulated in cancer and complement inhibition is under investigation as a therapeutic strategy, including in combination with radiotherapy. Interestingly, our data suggests that in response to radiotherapy, expression of complement regulators CD55 and CD59 is decreased in normal colon. Importantly, these expression changes correlate with an increase in the C5b-9 complex (thought to be responsible for cell lysis) in irradiated colon in vivo . Furthermore, our results suggest that targeting the complement system (either genetically or pharmacologically) can result in increased survival of mice following radiotherapy, through protection of the gastrointestinal tract from radiation-induced toxicity. Together, these findings suggest that targeting the complement system could be a promising approach to reduced radiation-induced gastrointestinal toxicity thereby increasing the therapeutic window of radiotherapy. SP-0079 Bowel radiation injury: complexity of the pathophysiology and promises of cell and tissue engineering L. Moussa 1 , P. Weiss 2 , M. Benderitter 1 , C. Demarquay 1 , J. Guicheux 2 , G. Réthoré 2 , N. Mathieu 1 1 Institut de Radioprotection et de Sûreté Nucléaire, SRBE, Fontenay-aux-Roses- Paris, France 2 Institut National de la Santé et de la Recherche Médicale, LIOAD, Nantes, France Radiation therapy is crucial in the therapeutic arsenal to cure cancers; however, normal tissue situated in the irradiation field can be damaged by ionizing radiation, leading some specialists to define these specific gastrointestinal complications as “pelvic radiation disease”. This is particularly important as the number of patients suffering from this disease is increasing with increased life expectancy of patients treated for cancer. Mesenchymal Stromal Cells (MSCs) represent a promising strategy to treat radiation-induced intestinal damage. Indeed, we previously demonstrated in rats, mini-pigs then patients over-irradiated during radiotherapy for prostate cancer, that intravenous injection of MSCs reduces severe colorectal lesions. However, this effect seems temporary and repeated injections have been recommended. The beneficial effects of MSCs have been related to their capacity to engraft, survive and secrete bioactive factors in the host tissue. We need to optimize the efficacy of the injected cells, particularly, with regard to extending their life span in the irradiated tissue. Here, we propose to use a colonoscope to deliver MSCs embedded in a biocompatible hydrogel (Si-HPMC) directly into the colon. We demonstrated in vivo using a rat model of radiation-induced severe colonic damage that MSC+Si- HPMC improve colonic epithelial structure and function. These results could open up new perspectives in regenerative medicine in particular with the co- administration of MSC and ex-vivo expended “mini-gut”. OC-0080 Normal tissue toxicity and in vivo dose- equivalence of synchroton radiotherapy modalities L. Smyth 1,2 , J. Crosbie 3,4 , J. Ventura 1 , J. Donoghue 1,3 , S. Senthi 4 , P. Rogers 1 1 University of Melbourne, Obstetrics & Gynaecology, Melbourne, Australia 2 Epworth HealthCare, Radiation Oncology, Melbourne, Australia 3 RMIT University, School of Science, Melbourne, Australia

Proffered Papers: Skin

OC-0081 Patient Safety Is Improved With An Extensive Incident Learning System—9 Years Of Clinical Evidence C. Deufel 1 , L. McLemore 1 , L. Fong de los Santos 1 , K. Classic 2 , S. Park 1 , K. Furutani 1 1 Mayo Clinic MN, Radiation Oncology, Rochester, USA 2 Mayo Clinic MN, Radiation Safety, Rochester, USA