External Validation of a Predictive Model for Acute Skin Radiation Toxicity in the REQUITE Breast Cohort

Tim Rattay, Petra Seibold, Miguel E. Aguado-Barrera, Manuel Altabas, David Azria, Gillian C. Barnett, Renée Bultijnck, Jenny Chang-Claude, Ananya Choudhury, Charlotte E. Coles, Alison M. Dunning, Rebecca M. Elliott, Marie-Pierre Farcy Jacquet, Sara Gutiérrez-Enríquez, Kerstie Johnson, Anusha Müller, Giselle Post, Tiziana Rancati, Victoria Reyes, Barry S. Rosenstein, Dirk De Ruysscher, Maria C. de Santis, Elena Sperk, Hilary Stobart, R. Paul Symonds, Begoña Taboada-Valladares, Ana Vega, Liv Veldeman, Adam J. Webb, Catharine M. West, Riccardo Valdagni, Christopher J. Talbot, REQUITE consortium, Yolande Lievens, Marc van Eijkeren, Piet Ost, Valérie Fonteyne, Christel Monten, Wilfried De Neve, Stephanie Peeters, Karin Haustermans, Caroline Weltens, Gilles Defraene, Maarten Lambrecht, Erik van Limberghen, Erik Briers, Celine Bourgier, Muriel Brengues, Roxana Draghici, Francoise Bons, Thomas Blaschke, Christian Weiß, Irmgard Helmbold, Christian Weißenberger, Petra Stegmaier, Johannes Claßen, Ulrich Giesche, Marie-Luise Sautter-Bihl, Burkhard Neu, Thomas Schnabel, Michael Ehmann, Benjamin Gauter-Fleckenstein, Carsten Herskind, Marlon Veldwijk, Jörg Schäfer, Tommaso Giandini, Marzia Franceschini, Claudia Sangalli, Barbara Avuzzi, Sara Morlino, Laura Lozza, Gabriele Pietro, Elena Delmastro, Elisabetta Garibaldi, Alessandro Cicchetti, Ben Vanneste, Bibiana Piqué-Leiva, Meritxel Molla, Alexandra Giraldo, Monica Ramos, Ramon Lobato-Busto, Paloma Sosa-Fajardo, Laura Torrado Moya, Isabel Dominguez-Rios, Irene Fajardo-Paneque, Patricia Calvo-Crespo, Ana Carballo, Paula Peleteiro, Olivia-Fuentes-Rios, Antonio Gomez-Caamano, Victoria Harrop, Debbie Payne, Manjusha Keni, Samuel Lavers, Simon Wright, Sridhar Thiagarajan, Luis Aznar-Garcia, Kiran Kancherla, Christopher Kent, Subramaniam Vasanthan, Donna Appleton, Monika Kaushik, Frances Kenny, Hazem Khout, Jaroslaw Krupa, Kelly V. Lambert, Simon Pilgrim, Sheila Shokuhi, Kalliope Valassiadou, Ion Bioangiu, Kufre Sampson, Ahmed Osman, Corinne Faivre-Finn, Karen Foweraker, Abigail Pascoe, Claire P. Esler, Tim Ward, Daniel S. Higginson, Richard G. Stock, Sheryl Green

Background: Acute skin toxicity is a common and usually transient side-effect of breast radiotherapy although, if sufficiently severe, it can affect breast cosmesis, aftercare costs and the patient's quality-of-life. The aim of this study was to develop predictive models for acute skin toxicity using published risk factors and externally validate the models in patients recruited into the prospective multi-center REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve QUalITy of lifE in cancer survivors) study. Methods: Patient and treatment-related risk factors significantly associated with acute breast radiation toxicity on multivariate analysis were identified in the literature. These predictors were used to develop risk models for acute erythema and acute desquamation (skin loss) in three Radiogenomics Consortium cohorts of patients treated by breast-conserving surgery and whole breast external beam radiotherapy (n = 2,031). The models were externally validated in the REQUITE breast cancer cohort (n = 2,057). Results: The final risk model for acute erythema included BMI, breast size, hypo-fractionation, boost, tamoxifen use and smoking status. This model was validated in REQUITE with moderate discrimination (AUC 0.65), calibration and agreement between predicted and observed toxicity (Brier score 0.17). The risk model for acute desquamation, excluding the predictor tamoxifen use, failed to validate in the REQUITE cohort. Conclusions: While most published prediction research in the field has focused on model development, this study reports successful external validation of a predictive model using clinical risk factors for acute erythema following radiotherapy after breast-conserving surgery. This model retained discriminatory power but will benefit from further re-calibration. A similar model to predict acute desquamation failed to validate in the REQUITE cohort. Future improvements and more accurate predictions are expected through the addition of genetic markers and application of other modeling and machine learning techniques.