Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint.Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed.Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ~1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ~1.1 in the entrance region, to ~1.15 in the center, ~1.35 at the distal edge and ~1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ~1.1.This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels.

https://iopscience.iop.org/article/10.1088/0031-9155/59/22/R419/pdf

Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer

Proton therapy treatments are currently planned and delivered using the assumption that the proton relative biological effectiveness (RBE) relative to photons is 1.1. This assumption ignores strong experimental evidence that suggests the RBE varies along the treatment field, i.e. with linear energy transfer (LET) and with tissue type. A recent review study collected over 70 experimental reports on proton RBE, providing a comprehensive dataset for predicting RBE for cell survival. Using this dataset we developed a model to predict proton RBE based on dose, dose average LET (LETd) and the ratio of the linear-quadratic model parameters for the reference radiation (α/β)x, as the tissue specific parameter. The proposed RBE model is based on the linear quadratic model and was derived from a nonlinear regression fit to 287 experimental data points. The proposed model predicts that the RBE increases with increasing LETd and decreases with increasing (α/β)x. This agrees with previous theoretical predictions on the relationship between RBE, LETd and (α/β)x. The model additionally predicts a decrease in RBE with increasing dose and shows a relationship between both α and β with LETd. Our proposed phenomenological RBE model is derived using the most comprehensive collection of proton RBE experimental data to date. Previously published phenomenological models, based on a limited data set, may have to be revised.

/pdf/a-phenomenological-relative-biological-effectiveness-rbe-2tusstsaye.pdf

A phenomenological relative biological effectiveness (RBE) model for proton therapy based on all published in vitro cell survival data.

Experimental and theoretical radiation damage studies on crystalline silicon solar cells

Purpose The aim of this study was to evaluate the induction and rejoining of DNA double strand breaks (DSBs) in melanoma cells exposed to low and high linear energy transfer (LET) radiation. Methods and Materials DSBs and survival were determined as a function of dose in melanoma cells (B16-F0) irradiated with monoenergetic proton and lithium beams and with a gamma source. Survival curves were obtained by clonogenic assay and fitted to the linear-quadratic model. DSBs were evaluated by the detection of phosphorylated histone H2AX (γH2AX) foci at 30 min and 6 h post-irradiation. Results Survival curves showed the increasing effectiveness of radiation as a function of LET. γH2AX labeling showed an increase in the number of foci vs. dose for all the radiations evaluated. A decrease in the number of foci was found at 6 h post-irradiation for low LET radiation, revealing the repair capacity of DSBs. An increase in the size of γH2AX foci in cells irradiated with lithium beams was found, as compared with gamma and proton irradiations, which could be attributed to the clusters of DSBs induced by high LET radiation. Foci size increased at 6 h post-irradiation for lithium and proton irradiations in relation with persistent DSBs, showing a correlation with surviving fraction. Conclusions Our results showed the response of B16-F0 cells to charged particle beams evaluated by the detection of γH2AX foci. We conclude that γH2AX foci size is an accurate parameter to correlate the rejoining of DSBs induced by different LET radiations and radiosensitivity.

Induction and rejoining of DNA double strand breaks assessed by H2AX phosphorylation in melanoma cells irradiated with proton and lithium beams.

Background
Little is known about the cellular effects of exposure to mixed beams of high and low linear energy transfer radiation. So far, the effects of combined exposures have mainly been assessed with clonogenic survival or cytogenetic methods, and the results are contradictory. The gamma-H2AX assay has up to now not been applied in this context, and it is a promising tool for investigating the early cellular response to mixed beam irradiation.

/pdf/gamma-h2ax-foci-in-cells-exposed-to-a-mixed-beam-of-x-rays-1b5b0mzxy1.pdf

Gamma-H2AX foci in cells exposed to a mixed beam of X-rays and alpha particles

External proton and 6,7 Li beams, of energies around 24 and 48 MeV respectively, were produced and characterized dosimetrically at the Tandem accelerator TANDAR in Buenos Aires and used for radiobiology studies on tumor and normal cell cultures. The beam monitoring instrumentation of a dedicated beam line is discussed. Relative biological effectiveness (RBE) values (at 10% survival) have been measured as functions of projectile energy (0–21 MeV) for protons and 6,7 Li ions for different tumor (PDV, PDVC57) and reference cell lines (V79). The RBE values for these cell lines have been determined here for the first time but are similar to those reported in the literature for other cell lines.

Relative biological effectiveness measurements of low energy proton and lithium beams on tumor cells

The aim of this study was to evaluate the DNA damage induced by low and high linear energy transfer radiation in two related cell lines with different radiation sensitivity, CHO10B2 and irs-20 cells (defective in DNA-PKcs). Double-strand breaks were assessed by the detection of phosphorylated histone H2AX foci (γH2AX). The number of foci increased as a function of dose for both cell lines and types of radiation. However, irs-20 cells showed a higher number of foci than the parental CHO10B2. An increase in the foci size was observed for both cell lines after lithium irradiation. This could be attributed to clusters of DNA damage. Moreover, the number of lithium-induced larger foci per nuclei increased with dose and fitted with the expected number of hits per nucleus. Concluding, γH2AX foci size provides a potential tool to characterise the intrinsic radiosensitivity of cells related to DNA damage and to compare the effects of different quality radiations.

Assessment of γH2AX nuclear foci number and size in normal and repair-deficient cells irradiated with low and high linear energy transfer radiation

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Relative biological effectiveness measurements of low energy proton and lithium beams on tumor cells

Assessment of γH2AX nuclear foci number and size in normal and repair-deficient cells irradiated with low and high linear energy transfer radiation