ESTRO 2021 Abstract Book

S590

ESTRO 2021

Engineering, London, United Kingdom

Purpose or Objective Prostate external beam radiotherapy (EBRT) is increasingly being delivered using hypofractionated radiotherapy. The fraction size sensitivity of genitourinary (GU) endpoints is of interest to permit comparison of dose-fractionation regimens. This is usually calculated as Equivalent Dose in 2 Gy per fraction (EQD2) which relies upon the α/β ratio, a parameter inversely related to the fraction size sensitivity. While for late GU endpoints, α/β ratios are often thought to be between 3-5 Gy, fitted α/β ratios <1 Gy have been reported for severe (G3+) incontinence and haematuria in the post-prostatectomy setting [ Fiorino et al, IJROBP, 2014 ]. This study estimates α/β ratios with Normal Tissue Complication (NTCP) models for several common late GU toxicity endpoints following primary prostate EBRT. Materials and Methods The CHHiP trial randomised (1:1:1) men with localised prostate cancer to: 74 Gy in 37 fractions (Fr) or 60 Gy in 20 Fr or 57 Gy in 19 Fr; all delivered daily. This study includes 2206 patients with adequate DICOM data and >50% late toxicity assessment completion. Amalgamated late GU endpoints were made from the simultaneously recorded clinician reported scales: Radiation Therapy Oncology Group (RTOG), Late Effects in Normal Tissues Subjective, Objective, Management (LENTSOM) and Royal Marsden Hospital (RMH) toxicity scales for Dysuria, Frequency, Haematuria, Incontinence and Reduced Flow/Stricture. Only patients with zero baseline toxicity were included in each respective endpoint. Both G1+ and G2+ models were made; event rates ranged: G1+ 9.5 – 20.5%; G2+ 4.6 – 9.8%. Lyman-Kutcher-Burman (LKB) models with EQD2 correction were fitted by grid search then Nelder-Mead Simplex search (estimating n , m , TD50 & α/β). Bootstrapping provided percentile 95% confidence intervals (CIs). Results Model fits with reasonably narrow 95% CIs were produced for four endpoints, each with α/β estimates below 3 Gy: Dysuria G1+ α/β 2.0 Gy (95% CI 1.2 – 3.2 Gy); Haematuria G1+ α/β 0.9 Gy (95% CI 0.1 – 2.2 Gy); Haematuria G2+ α/β 0.6 Gy (95% CI 0.1 – 1.7 Gy); Incontinence G2+ α/β 1.5 Gy (95% CI 0.1 – 6.2 Gy). Across these four models, the LKB parameters showed strong seriality of response ( n = 0.02 – 0.07), with reasonable steepness of dose-response ( m = 0.19 – 0.32) and expectedly high doses for 50% toxicity ( TD50 = 90 – 120 Gy). Several endpoints modelled poorly, with very wide confidence intervals (upper 95% CI for α/β ratio > 400 Gy): Reduced Flow/Stricture G1+/G2+ and Urinary Frequency G1+/G2+. Additionally, the fits for Dysuria G2+ and Incontinence G1+ did not improve on the fit of a non-EQD2 corrected LKB model. Conclusion Using data from a large, prospectively collected phase III trial of moderate hypofractionation, we have shown that low α/β ratios provide the best fit for LKB models of several late GU endpoints. This supports the data previously observed for severe incontinence and haematuria in the post-prostatectomy setting. PD-0759 Immune and cell cycle differentially expressed pathways underlie late skin radiotherapy toxicity E. Aguado Flor 1 , M.J. Fuentes-Raspall 2 , R. Gonzalo 3 , C. Alonso 4 , T. Ramon y Cajal 4 , D. Fisas 4 , A. Seoane 5 , Á. Sánchez Pla 3 , J. Giralt 6 , O. Díez 7 , S. Gutiérrez-Enríquez 1 1 Vall Hebron Institute of Oncology, Hereditary Cancer Genetics, Barcelona, Spain; 2 Santa Creu i Sant Pau Hospital, Radiation Oncology Department, Barcelona, Spain; 3 Vall Hebron Institute of Research, Statistics and Bioinformatics Unit, Barcelona, Spain; 4 Santa Creu i Sant Pau Hospital, Medical Oncology Department, Barcelona, Spain; 5 Vall Hebron Barcelona Hospital Campus, Medical Physics Department, Barcelona, Spain; 6 Vall Hebron Barcelona Hospital Campus, Radiation Oncology Department, Barcelona, Spain; 7 Vall Hebron Barcelona Hospital Campus, Area of Clinical and Molecular Genetics, Barcelona, Spain Purpose or Objective Despite advances of modern radiotherapy, radiation-induced late effects remain a common cause of morbidity amongst cancer survivors. There is still no optimization of biomarker-based radiation therapy to reduce the risk of side effects. The purpose of this study was to identify the molecular basis underlying the radiotherapy- induced late skin toxicity in breast cancer patients by profiling blood gene expression. Gene sets differentially expressed between patients with or without side effects might be used as predictors of radiotherapy-induced toxicity. Materials and Methods Peripheral blood mononuclear blood cells of 10 patients with severe late complications from radiotherapy and 10 patients without symptoms were mock-irradiated or irradiated with 8-Gy. The 48-h response was analysed by gene expression profiling with Affymetrix Human Exon 1.0 ST arrays. Irradiated and non-irradiated gene expression profiles were compared between both groups of patients. Gene set enrichment analysis (GSEA) was performed to identify the biological pathways associated with the differentially expressed genes. Results Regardless of patient toxicity status, the 8-Gy irradiation leads to a significant gene expression signature. Although the group of differentially expressed mRNAs did not reach a significant adjusted p-value between patients with or without clinical toxicity, the discriminative power was enhanced by using GSEA approach. Thus, in basal conditions, the differentially expressed genes were mainly involved in interferon signaling and transport of small molecules pathways (Figure 1). In contrast, after 8Gy the genes were enriched in cell cycle and DNA replication as well as G protein coupled receptor signalling process (Figure 2). Posterior qPCR analysis revealed that APOBEC3H (a ssDNA deoxycytidine deaminase with antiretroviral activity) was significantly overexpressed after 8Gy in the non-toxicity patients.