BACKGROUND AND PURPOSE: This study presents a multi-center comparison of in vitro cell survival measurements and RBE calculations following proton irradiations conducted under harmonized experimental conditions across six European institutions participating in the INSPIRE framework. MATERIALS AND METHODS: V79-4 cells were irradiated using spread-out Bragg peak (SOBP) proton fields of two configurations delivering 6 and 8 Gy with widths of 6 and 4 cm, respectively. Each center adhered to a standardized protocol, utilizing the same phantom design to minimize uncertainties related to sample positioning. X-ray reference irradiations were also performed to assess cell radiosensitivity across the participating centers. RESULTS: Despite the consistent protocol, significant inter-institutional variability was observed in the survival measurements. For both treatment plans, the largest variation was detected in the most distal points of the SOBP (coefficients of variation of 43 % and 60 % for the 6 Gy and 8 Gy plans, respectively). Kruskal-Wallis statistical test confirmed the significant differences between the centers for each of the measured position in the proton field for both SOBP configurations. Discrepancies were observed in calculated RBE data as well, albeit preserving the expected trend for the values to slightly increase towards the distal edge of the SOBP (up to 1.5 and 1.3 for the 6 Gy and 8 Gy plans, respectively). CONCLUSION: The results of the study highlight the minimal biological variation one could expect performing proton RBE measurements in well-aligned experimental conditions and challenges in conducting large-scale, multi-center radiobiological experiments and inter-comparisons between literature data sets.

CIMAP CEA CNRS ENSICAEN UNICAEN Normandie Université Caen France

Danish Centre for Particle Therapy Aarhus University Hospital Aarhus Denmark

Department of Experimental Clinical Oncology Aarhus University Hospital Aarhus Denmark

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Radiotherapy and Radiation Oncology Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Division of Cancer Sciences Faculty of Biology Medicine and Health The University of Manchester Manchester UK

GSI Helmholtz Centre for Heavy Ion Research Darmstadt Germany

Helmholtz Zentrum Dresden Rossendorf Institute of Radiation Physics Dresden Germany

Helmholtz Zentrum Dresden Rossendorf Institute of Radiooncology OncoRay Dresden Germany

Inserm U1021 CNRS UMR 3347 Institut Curie PSL Research University University Paris Saclay Orsay France

Inserm U1288 Laboratory of Translational Imaging in Oncology Institut Curie PSL Research University University Paris Saclay Orsay France

Institut Curie PSL Research University Radiation Oncology Department Proton Therapy Centre Centre universitaire Orsay France

Institute for Condensed Matter Physics Technische Universität Darmstadt Darmstadt Germany

Institute of Nuclear Physics Polish Academy of Sciences Krakow Poland

Manchester Academic Health Science Centre The Christie NHS Foundation Trust Manchester UK

Nuclear Physics Institute of the Czech Academy of Sciences Řež Czech Republic

OncoRay National Center for Radiation Research in Oncology Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Helmholtz Zentrum Dresden Rossendorf Dresden Germany

OncoRay National Center for Radiation Research in Oncology Faculty of Medicine Dresden Germany

The Skandion Clinic Uppsala Sweden

Translational Research Department Institut Curie Experimental Radiotherapy Platform University Paris Saclay Orsay France

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