title: Investigating the Implications of a Variable RBE on Proton Dose Fractionation Across a Clinical Pencil Beam Scanned Spread-Out Bragg Peak.
abstract: OBJECTIVE
  To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited.
  
  
  METHODS
  Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfraction period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism.
  
  
  RESULTS
  Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens.
  
  
  CONCLUSIONS
  The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Marshall
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Department of Radiation Dosimetry, Nuclear Physics Institute CAS, Prague, Czech Republic; Proton Therapy Center Czech, Prague, Czech Republic; Department of Dosimetry and Application of Ionizing Radiation, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Michaelidesová
authors.affiliation: Department of Radiation Dosimetry, Nuclear Physics Institute CAS, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Vachelová
authors.affiliation: Department of Radiation Dosimetry, Nuclear Physics Institute CAS, Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Davídková
authors.affiliation: Proton Therapy Center Czech, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vondráček
authors.affiliation: Radiation Dosimetry, National Physical Laboratory, Teddington, UK. Electronic address: giuseppe.schettino@npl.co.uk.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Schettino
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
mesh_terms: D002470:Cell Survival; D003114:Colony-Forming Units Assay; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D006801:Humans; D018499:Linear Energy Transfer; D009010:Monte Carlo Method; D061766:Proton Therapy / Q000379:methods*; D011522:Protons; D012062:Relative Biological Effectiveness; D035501:Uncertainty
chemical_list: D011522:Protons