ESTRO 2024 - Abstract Book

S91 ESTRO 2024 England). This emphasises the importance of RT and the importance of continuing to work hard on ways to reduce and mitigate toxicity. Invited Speaker

Physics and biology are inextricably linked in daily practice of RT, and developments in both contribute to reducing toxicity.

In the earliest days of radiotherapy, more than 100 years ago, radiotherapy was prescribed based on the ‘dose’ (really time) to produce just perceptible reddening in 80% of patients. This was the Erythema Dose (ED or HED (Haut Einheits Dosis) in German). Implicit in this is variability in normal tissue response between patients. This approach was soon replaced by the development of physical measurement of ionisation. However, this early demonstration of individual variation in normal tissue response was largely forgotten. The first formal, quantitative description of normal tissue dose response, and so of individual variation, was reported by Holthusen from Hamburg in 1936. Interestingly, he worked on both physical aspects of ionisation and its measurement as well as on biological processes, which underlines the fundamental linkage between the 2 areas. In the 1980s, Ingela Turesson and colleagues in Göteborg described individual variation again. There followed the demonstration that this was likely linked to variation in cellular sensitivity and then, with the advent of radiogenomics using new genotyping techniques, to underlying genetic variation (polymorphisms). One important finding is that genes being implicated in individual variation could not be predicted beforehand. For some acute toxicities the same polymorphisms appear to predict side effects in different tissues but for late effects the genetic variants appear to be tissue-specific. Radiogenomics requires very large numbers of treated patients to be analysed so this presents challenges for rarer tumour types and for newer radiation modalities such as proton beam therapy. The extraordinary developments in radiotherapy technology over the last 25 years have led to huge reductions in side effects, both in the numbers of patients affected and the severity of toxicities in those who are affected. We often concentrate on grade 2+ toxicities, which are considered the most ‘clinically relevant’ (by us). However, patients do find even Grade 1 toxicities troublesome. For the next ‘phase’ of toxicity reduction, I suggest that we should aim to reduce these grade 1 toxicities. Clinical trials have been (and continue to be) central to improvements for patients, including toxicity reduction. These improvements have included newer hypofractionation schedules for some tumour types (especially breast and prostate). A particularly powerful tool for investigating clinical schedules is the Three Arm Randomised Trial with Two Experimental Arms, which I call the ‘TART with TEA’ design. This has been highly effective for breast (START A) and prostate (CHHiP) in particular. Traditional values of a/b ratios for tumours were high (10 - 20 Gy) and for normal tissues were low (2 - 5 Gy), favouring smaller doses per fraction. Clinical data supports this for some sites, e.g. CNS and Head & Neck. However, in other sites, e.g. breast and prostate, clinical trials have suggested that the tumour a/b ratio may be similar to or lower than the normal tissue values, therefore favouring hypofractionation. All values of a/b derived from clinical studies are averages for a population of patients. However, individual variation exists in normal tissue sensitivity. If there is also individual variation in a/b ratios then in theory more extreme fractionation schedules (hypo- or hyper-) could be detrimental to some patients; and there is some limited evidence for individual differences in normal tissue a/b ratios. One of the products of TART with TEA trials is the derivation of robust estimates of the alpha:beta (a/b) ratios of tumour and normal tissue and these a/b ratios are vital for optimising dose/fractionation schedules.