A systematic review of clinical studies on variable proton Relative Biological Effectiveness (RBE)

  • Tracy S.A. Underwood
    Corresponding author at: Leo Cancer Care Ltd, Unit 1, Woodbridge House, Chapel Road, Smallfield, Horley, RH6 9NW, UK.
    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Leo Cancer Care Ltd, Unit 1, Woodbridge House, Chapel Road, Smallfield, Horley, UK
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  • Aimee L. McNamara
    Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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  • Ane Appelt
    Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, UK

    Department of Medical Physics, Leeds Cancer Centre, St James’s University Hospital, Leeds, UK
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  • Joanne S. Haviland
    Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
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  • Brita Singers Sørensen
    Danish Centre for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark

    Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark
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  • Esther G.C. Troost
    Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    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

    National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany

    Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Institute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden – Rossendorf (HZDR), Dresden, Germany

    German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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      • Many clinical studies have analysed patient toxicities/image changes to investigate proton RBE.
      • Clinical evidence for variable proton RBE remains statistically weak.
      • Expert statistical advice should be sought during study planning.
      • Proton centres should collaborate on follow-up, enabling larger patient cohorts to be considered.


      Recently, a number of clinical studies have explored links between possible Relative Biological Effectiveness (RBE) elevations and patient toxicities and/or image changes following proton therapy. Our objective was to perform a systematic review of such studies. We applied a “Problem [RBE], Intervention [Protons], Population [Patients], Outcome [Side effect]” search strategy to the PubMed database. From our search, we retrieved studies which: (a) performed novel voxel-wise analyses of patient effects versus physical dose and LET (n = 13), and (b) compared image changes between proton and photon cohorts with regard to proton RBE (n = 9). For each retrieved study, we extracted data regarding: primary tumour type; size of patient cohort; type of image change studied; image-registration method (deformable or rigid); LET calculation method, and statistical methodology. We compared and contrasted their methods in order to discuss the weight of clinical evidence for variable proton RBE. We concluded that clinical evidence for variable proton RBE remains statistically weak at present. Our principal recommendation is that proton centres and clinical trial teams collaborate to standardize follow-up protocols and statistical analysis methods, so that larger patient cohorts can ultimately be considered for RBE analyses.


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