title: Variable RBE in proton therapy: comparison of different model predictions and their influence on clinical-like scenarios.
abstract: BACKGROUND
  In proton radiation therapy a constant relative biological effectiveness (RBE) of 1.1 is usually assumed. However, biological experiments have evidenced RBE dependencies on dose level, proton linear energy transfer (LET) and tissue type. This work compares the predictions of three of the main radio-biological models proposed in the literature by Carabe-Fernandez, Wedenberg, Scholz and coworkers.
  
  
  METHODS
  Using the chosen models, a spread-out Bragg peak (SOBP) as well as two exemplary clinical cases (single field and two fields) for cranial proton irradiation, all delivered with state-of-the-art pencil-beam scanning, have been analyzed in terms of absorbed dose, dose-averaged LET (LET D ), RBE-weighted dose (D RBE) and biological range shift distributions.
  
  
  RESULTS
  In the systematic comparison of RBE predictions by the three models we could show different levels of agreement depending on (α/β) x and LET values. The SOBP study emphasizes the variation of LET D and RBE not only as a function of depth but also of lateral distance from the central beam axis. Application to clinical-like scenario shows consistent discrepancies from the values obtained for a constant RBE of 1.1, when using a variable RBE scheme for proton irradiation in tissues with low (α/β) x , regardless of the model. Biological range shifts of 0.6- 2.4 mm (for high (α/β) x ) and 3.0 - 5.4 mm (for low (α/β) x ) were found from the fall-off analysis of individual profiles of RBE-weighted fraction dose along the beam penetration depth.
  
  
  CONCLUSIONS
  Although more experimental evidence is needed to validate the accuracy of the investigated models and their input parameters, their consistent trend suggests that their main RBE dependencies (dose, LET and (α/β) x ) should be included in treatment planning systems. In particular, our results suggest that simpler models based on the linear-quadratic formalism and LETD might already be sufficient to reproduce important RBE dependencies for re-evaluation of plans optimized with the current RBE = 1.1 approximation. This approach would be a first step forward to consider RBE variations in proton therapy, thus enabling a more robust choice of biological dose delivery. The latter could in turn impact clinical outcome, especially in terms of reduced toxicities for tumors adjacent to organs at risk.
authors.affiliation: Ludwig-Maximilians-Universität München, Am Coulombwall 1, D-85748, Garching b. München, Germany.|University of Pavia, Department of Physics, Via Bassi 6, I-27100, Pavia, Italy.|Department of Radiation Oncology, Heidelberg University Clinic, Im Neuenheimer, Feld 400, D-69120, Heidelberg, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Giovannini
authors.affiliation: Ludwig-Maximilians-Universität München, Am Coulombwall 1, D-85748, Garching b. München, Germany.|European Organization for Nuclear Research CERN, CH-1211, Geneva, 23, Switzerland.|Now with Medical Physics Division, EBG MedAustron GmbH, Marie Curie-Straβe 5, Wiener Neustadt, A-2700, Austria.
authors.forename: Till
authors.initials: T
authors.lastname: Böhlen
authors.affiliation: Ludwig-Maximilians-Universität München, Am Coulombwall 1, D-85748, Garching b. München, Germany.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Cabal
authors.affiliation: Department of Radiation Oncology, Heidelberg University Clinic, Im Neuenheimer, Feld 400, D-69120, Heidelberg, Germany.|Heidelberg Ion Beam Therapy Center, Im Neuenheimer Feld 450, D-69120, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Department of Radiation Oncology, Heidelberg University Clinic, Im Neuenheimer, Feld 400, D-69120, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tessonnier
authors.affiliation: Ludwig-Maximilians-Universität München, Am Coulombwall 1, D-85748, Garching b. München, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Frey
authors.affiliation: Department of Radiation Oncology, Heidelberg University Clinic, Im Neuenheimer, Feld 400, D-69120, Heidelberg, Germany.|Heidelberg Ion Beam Therapy Center, Im Neuenheimer Feld 450, D-69120, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Heidelberg Ion Beam Therapy Center, Im Neuenheimer Feld 450, D-69120, Heidelberg, Germany. mairani@cnao.it.|Medical Physics Unit, CNAO Foundation, Via Strada Campeggi 53, I-27100, Pavia, Italy. mairani@cnao.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mairani
authors.affiliation: Ludwig-Maximilians-Universität München, Am Coulombwall 1, D-85748, Garching b. München, Germany.|Department of Radiation Oncology, Heidelberg University Clinic, Im Neuenheimer, Feld 400, D-69120, Heidelberg, Germany.|Heidelberg Ion Beam Therapy Center, Im Neuenheimer Feld 450, D-69120, Heidelberg, Germany.
authors.forename: Katia
authors.initials: K
authors.lastname: Parodi
mesh_terms: D000465:Algorithms; D006801:Humans; D018499:Linear Energy Transfer; D016014:Linear Models; D009010:Monte Carlo Method; D061766:Proton Therapy / Q000379:methods*; D011522:Protons; D011874:Radiometry; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods*; D012062:Relative Biological Effectiveness
chemical_list: D011522:Protons
keywords: FLUKA; Monte Carlo; Proton therapy; Relative biological effectiveness