title: Relative biological effectiveness variation along monoenergetic and modulated Bragg peaks of a 62-MeV therapeutic proton beam: a preclinical assessment.
abstract: OBJECTIVE
  The biological optimization of proton therapy can be achieved only through a detailed evaluation of relative biological effectiveness (RBE) variations along the full range of the Bragg curve. The clinically used RBE value of 1.1 represents a broad average, which disregards the steep rise of linear energy transfer (LET) at the distal end of the spread-out Bragg peak (SOBP). With particular attention to the key endpoint of cell survival, our work presents a comparative investigation of cell killing RBE variations along monoenergetic (pristine) and modulated (SOBP) beams using human normal and radioresistant cells with the aim to investigate the RBE dependence on LET and intrinsic radiosensitvity.
  
  
  METHODS
  Human fibroblasts (AG01522) and glioma (U87) cells were irradiated at 6 depth positions along pristine and modulated 62-MeV proton beams at the INFN-LNS (Catania, Italy). Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and the local effect model (LEM).
  
  
  RESULTS
  We observed significant cell killing RBE variations along the proton beam path, particularly in the distal region showing strong dose dependence. Experimental RBE values were in excellent agreement with the LEM predicted values, indicating dose-averaged LET as a suitable predictor of proton biological effectiveness. Data were also used to validate a parameterized RBE model.
  
  
  CONCLUSIONS
  The predicted biological dose delivered to a tumor region, based on the variable RBE inferred from the data, varies significantly with respect to the clinically used constant RBE of 1.1. The significant RBE increase at the distal end suggests also a potential to enhance optimization of treatment modalities such as LET painting of hypoxic tumors. The study highlights the limitation of adoption of a constant RBE for proton therapy and suggests approaches for fast implementation of RBE models in treatment planning.
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Marshall
authors.affiliation: Department of Physics, University of Naples Federico II and INFN Naples Section University of Naples, Naples, Italy.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Perozziello
authors.affiliation: Department of Physics, University of Naples Federico II and INFN Naples Section University of Naples, Naples, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Manti
authors.affiliation: Centre for Plasma Physics, School of Mathematics and Physics, Queen's University Belfast, Belfast, UK.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Currell
authors.affiliation: Centre for Plasma Physics, School of Mathematics and Physics, Queen's University Belfast, Belfast, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Hanton
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McMahon
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Joy N
authors.initials: JN
authors.lastname: Kavanagh
authors.affiliation: Istituto Nazionale di Fisica Nucleare, LNS, Catania, Italy.
authors.forename: Giuseppe Antonio Pablo
authors.initials: GA
authors.lastname: Cirrone
authors.affiliation: Istituto Nazionale di Fisica Nucleare, LNS, Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Romano
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. Electronic address: k.prise@qub.ac.uk.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; National Physical Laboratory, Teddington, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Schettino
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D017357:Cyclotrons; D005347:Fibroblasts / Q000502:physiology / Q000528:radiation effects; D005910:Glioma / Q000532:radiotherapy; D006801:Humans; D018499:Linear Energy Transfer; D061766:Proton Therapy; D011522:Protons; D011836:Radiation Tolerance; D012062:Relative Biological Effectiveness
chemical_list: D011522:Protons