ESTRO 38 Abstract book

S340 ESTRO 38

Teaching Lecture: The DNA damage response to radiotherapy: mechanisms and therapeutic opportunities

Teaching Lecture: Recent insights into radiotherapy tolerance from the REQUITE Consortium

SP-0639 Recent insights into radiotherapy tolerance from the REQUITE Consortium C. West 1 1 The University of Manchester, Translational Radiobiology, Manchester, United Kingdom Abstract text Logic dictates that the needs of the many outweigh the needs of the few. Radiotherapy is given to maximise the probability of local control while accepting that a small proportion of patients might suffer with long-term side- effects that impact negatively on their health-related quality-of-life. Although toxicity is reduced with modern radiotherapy techniques, it is increased with multi- modality treatment. Worldwide, the total number of people who are alive within 5 years of a cancer diagnosis was estimated to be 43.8 million in 2018. If 40% of survivors received radiotherapy as part of their treatment, many people could be suffering with late effects even if the overall percentage is small. The importance of survivorship issues is increasingly recognised and includes the need for research to identify patients at risk of long- term side-effects. Many models and biomarker have been reported and few validated. Some are starting to be implemented clinically. The ability to develop and validate models requires insights into radiotherapy tolerance. Accurate insight is only possible with high- quality data. The EU funded REQUITE consortium established a high- quality resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. An international, prospective cohort study recruited patients in 26 hospitals in eight countries. Eligible patients had breast, prostate or lung cancer and planned potentially-curable radiotherapy. To reflect real- world patients versus patients selected for inclusion in randomised trials, radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Between April 2014 and March 2017 REQUITE recruited 2,069 breast, 1,808 prostate and 561 lung cancer patients. Patients were followed for up to 2 years. The data highlight heterogeneity in patients and treatments across centres/countries that might pose a challenge when attempting to validate predictive models and biomarkers. For example, cancer patients tended to have a higher body mass index in Spain and the UK than in the other countries; the percentage of breast cancer patients who received intensity modulated radiotherapy ranged from <20% (France, Italy, Spain, US) to >80% (Belgium, UK); and the percentage of prostate patients having hormones ranged from 13% (Germany) to ~80% (Belgium, UK). The pre-radiotherapy baseline adverse effect data highlight that across all cancers and toxicities healthcare professional graded scores were lower than patients’ grades. Baseline patient-reported grade ≥2 adverse effects varied between 12% (USA) and 41% (UK) for breast pain (breast patients); between 1% (Netherlands) and 13% (Belgium) for urinary incontinence (prostate patients); and 9% (Italy) to 38% France) for dyspnoea (lung patients). Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Data from the REQUITE consortium highlight differences in patient characteristics and treatments that will affect radiotherapy tolerance.

SP-0636 The DNA damage response to radiotherapy: mechanisms and therapeutic opportunities M. Morgan 1 1 University of Michigan, Department of Radiation Oncology, Ann Arbor, USA Abstract text Cellular responses to radiation-induced DNA damage include cell cycle arrest, a transient delay in DNA synthesis, and activation of DNA repair pathways. In addition, emerging data suggest that DNA damage response (DDR) pathways may also modulate innate immunity. Research characterizing the vital role these pathways play in determining tumor cell survival has led to tremendous enthusiasm for the development of small molecule inhibitors which target critical proteins within DDR pathways, many of which are in clinical development in combination with radiation. This talk will provide an overview of current strategies designed to maximize the therapeutic efficacy of DDR inhibitors in combination with radiation, including incorporation with standard-of-care chemoradiation, novel combinations of DDR inhibitors targeting multiple steps in the DDR pathway, and integration of DDR inhibitors with immune checkpoint therapy.

Teaching Lecture: Are adolescents and young adults (AYA) a specific patients' population?

SP-0637 D.Walker 1 1 University Hospital, Queens Medical Center,Department of Radiotherapy, Nottingham United Kingdom

Abstract not received

Teaching Lecture: Hypofractionation; Is there rationale from biology (a/b ratio)?

SP-0638 Hypofractionation: can the DNA damage response deliver a biological rationale? K. Rothkamm 1 1 University Medical Center Hamburg - Eppendorf UKE, Department of Radiotherapy / Laboratory of Radiobiology and Experimental Radiation Oncology, Hamburg, Germany Abstract text The delivery of large radiation doses in a reduced number of fractions is becoming more and more popular in the treatment of primary tumours such as breast and prostate cancer as well as in stereotactic body radiotherapy (SBRT) of oligometastases. While clinical trials data provide increasingly robust evidence supporting hypofractionation in certain therapeutic settings, the underlying biology is still poorly understood. Vascular damage, immunogenic and dose volume effects as well as the “Rs” of classical radiobiology may shape the overall response of tumours and normal tissues to altered fractionation. Cell cycle checkpoint control and DNA damage repair have recently been proposed as important biological modulators of cellular fraction size sensitivity. These recent mechanistic insights may help us establish predictive biomarkers of tumour fractionation sensitivity.

Teaching Lecture: Integration of PET imaging in radiation treatment planning