Relative Biological Effect/Linear Energy Transfer in Proton Beam Therapy: A Primer Gulliford, S. L., & Prise, K. M. (2019). Relative Biological Effect/Linear Energy Transfer in Proton Beam Therapy: A Primer. Clinical Oncology. https://doi.org/10.1016/j.clon.2019.06.009 Published in: Clinical Oncology Document Version: Peer reviewed version Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2019 Elsevier. This manuscript is distributed under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited. 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Article Type: Editorial-commissioned Keywords: Linear Energy Transfer (LET) Relative Biological Effect (RBE) Proton Beam Therapy Corresponding Author: Dr. Sarah Gulliford, PhD Corresponding Author's Institution: University College Hospital London First Author: Sarah Gulliford, PhD Order of Authors: Sarah Gulliford, PhD; Kevin M Prise, PhD Manuscript Region of Origin: UNITED KINGDOM *Title Page Title: RBE/LET in Proton Beam Therapy: A Primer Sarah L Gulliford PhD [1] & Kevin M Prise PhD [2] [1] Department of Radiotherapy University College Hospitals London 250 Euston Road London NW1 2PG [2] Centre for Cancer Research & Cell Biology Queen’s University Belfast Belfast BT9 7AE, Keywords Linear Energy Transfer (LET) Relative Biological Effect (RBE) Proton Beam Therapy (PBT) Acknowledgments KMP acknowledges support from EPSRC (Ep/K022415/1). *Manuscript (without Author details) 1 2 RBE/LET in Proton Beam Therapy: A Primer 3 4 5 6 Keywords 7 8 9 10 Linear Energy Transfer (LET) 11 12 Relative Biological Effect (RBE) 13 14 Proton Beam Therapy 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 Introduction and aim of paper 3 4 Proton beam therapy is a rapidly developing tool in cancer treatment. This educational piece will 5 outline the key physical, biological and clinical parameters that give a basic understanding of the 6 radiobiology of proton therapy (Fig. 1). In particular it will focus on the important parameters of 7 8 linear energy transfer (LET) and relative biological effectiveness (RBE). 9 10 Proton vs. photon physical characteristics 11 12 Radiotherapy is based on the concept of delivering physical dose, in the form of ionizing radiation, to 13 cause a biological response. We know that the main target for damage is cellular DNA. High energy 14 photons are used globally for radiotherapy. They are indirectly ionizing particles which means that 15 16 the photons interact to produce secondary electrons which then impart dose to the medium. At the 17 photon energies used for external beam radiotherapy (≥6 MV) the dominant interaction is Compton 18 scattering where incoming photons eject an atomic electron [1]. In contrast, protons are directly 19 20 ionizing particles and predominantly interact with atomic electrons through multiple coulomb 21 scattering. The mass advantage of the protons means that little energy is lost by the proton during 22 23 an interaction but with the sheer number of interactions the proton loses energy with depth in the 24 patient [2]. As the energy decreases, the velocity of the proton decreases and the number of 25 interactions increases, consequently increasing the local dose deposition. The dose deposited 26 27 increases steeply in a short distance at the end of the protons range with a sharp fall off beyond the 28 peak. This dose distribution with depth is known as the Bragg curve. 29 30 Proton therapy is comparatively expensive to deliver relative to linac-based photons [3]; however 31 the difference in interactions results in a preferential dose-distribution which has the potential to 32 33 reduce the dose to normal tissues relative to optimal photon. We know that protons are 34 radiobiologically more effective than photons, however, quantification of this difference is a current 35 active area of research [4]. 36 37 38 Absorbed Dose 39 Absorbed Dose is defined as the mean energy imparted by ionising radiation to matter of mass m in 40 a finite volume v. The unit of absorbed dose is the gray (Gy) where 1 Gy is equivalent to 1 joule per 41 42 kilogram (J/kg). 43 44 Linear Energy Transfer 45 Linear Energy Transfer (LET) is defined as the average energy locally imparted to the absorbing 46 47 medium by a charged particle of specified energy traversing a given distance of the medium. Most 48 typically expressed in units of kiloelectronvolts per micrometre (keV/μm). As with dose, LET 49 increases with depth for protons with the maximum just beyond the Bragg peak. 50 51 52 Relative Biological Effectiveness (RBE) 53 RBE is the defined as the ratio of dose required to produce the same biological effect between a 54 radiation beam (often charged particles) and a reference radiation usually defined as 250 kVp X-rays 55 60 56 or a Co γ-rays (RBE=1). RBE depends on the conditions under which the effect is measured [5]. 57 58 Experimental evidence has shown that RBE is related to LET, increasing towards the end of the range 59 of a proton, in and just slightly beyond the Bragg peak. Although clinically, a constant value of 1.1 is 60 61 62 63 64 65 used to relate proton dosimetry to biological effect, this is an oversimplification for both tumour and 1 normal tissue responses [6]. 2 3 4 5 6 Photons vs. protons biological characteristics 7 The increased ionization density of particles relative to photons (i.e. increased LET), leads to more 8 9 densely ionizing clusters of energy interacting with cells and particular with the nuclear DNA leading 10 to a high probability of clusters of DNA damage being produced locally on the DNA. These can 11 consist of multiple DNA lesions, such as base damage, single-strand breaks, double-strand breaks 12 13 (dsb) and crosslinks as part of what is termed clustered (or complex) DNA damage [7]. This damage 14 is thought to be more difficult to repair and with increasing LET more DSB are left unrepaired and 15 have a higher probability to lead to cell death. This leads to an increased RBE for cell killing with 16 17 increasing LET, typically up to a maximum value (dependent on ion species) beyond which energy 18 then becomes wasted (overkill effect). RBE however is dependent on many additional factors, such 19 20 as dose, dose-rate and individual radiosensitivity. Oxygen is also a major modifier of response which 21 is LET dependent. For low LET radiations such as X-rays and γ-rays, regions of tumours which are 22 hypoxic (at reduced oxygen) are more radioresistant. Oxygen rapidly converts radicals produced 23 24 after irradiation to damaging peroxy-radicals which are the precursors of DNA damage. In the 25 absence of oxygen, cells are ~ 3 times more radioresistant. This is measured in clonogenic survival 26 assays as an Oxygen Enhancement Ratio (OER). This is defined as the ratio of the radiation dose 27 28 under anoxic conditions to produce a given effect relative to the radiation dose under fully 29 oxygenated conditions to produce the same effect. OER also decreases with increasing LET making 30 ion beams more effective against hypoxic tumours. 31 32 33 Calculating RBE - cell survival curve 34 RBE is found experimentally by plotting the cell survival curves for a single cell line comparing the 35 36 survival fraction using the reference beam and the particle beam. The dose required to produce a 37 specific survival is compared. These measurements are sensitive to a large number of experimental 38 factors including the choice of reference beam, the cell line, the choice of survival fraction, dose rate 39 [5]. 40 41 The review article by Paganetti which collated preclinical data found the RBE to be 1.1 at the 42 43 entrance of the beam, 1.3 at the distil edge and 1.7 in the distil fall off region. It also noted the large 44 variation in experimental setup and the large uncertainty in the derived values. 45 46 47 48 49 Current data for protons-models 50 Mathematical models relating physical dose to relative biological effect are numerous and remain 51 largely unvalidated. Models based on the Linear Quadratic model are widely cited when considering 52 53 proton beams [8] [9] [10] [11]. It is beyond the remit to describe in full each implementation but 54 generally each model requires the dose averaged LET and α/β value of the tissue (photons). The 55 models have been fitted to mostly pre-clinical data to derive the relevant parameter values.