A general mechanistic model enables predictions of the biological effectiveness of different qualities of radiation

Abstract

Predicting the responses of biological systems to ionising radiation is extremely challenging, particularly when comparing X-rays and heavy charged particles, due to the uncertainty in their Relative Biological Effectiveness (RBE). Here we assess the power of a novel mechanistic model of DNA damage repair to predict the sensitivity of cells to X-ray, proton or carbon ion exposures in vitro against over 800 published experiments. By specifying the phenotypic characteristics of cells, the model was able to effectively stratify X-ray radiosensitivity (R 2 = 0.74) without the use of any cell-specific fitting parameters. This model was extended to charged particle exposures by integrating Monte Carlo calculated dose distributions, and successfully fit to cellular proton radiosensitivity using a single dose-related parameter (R 2 = 0.66). Using these parameters, the model was also shown to be predictive of carbon ion RBE (R 2 = 0.77). This model can effectively predict cellular sensitivity to a range of radiations, and has the potential to support developments of personalised radiotherapy independent of radiation type.

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

“…The key assumption is that the difference in biological efficacy, when comparing photons with protons, is caused by different microscopic dose deposition patterns. Other models consider radiation damage and repair more explicitly and are thus capable of describing a range of endpoints (eg, DNA repair, genetic aberration, and cellular survival) by incorporating the kinetics of different DNA repair processes, the spatial distribution of double-strand breaks and the resulting probability and severity of misrepair [79, 80]. …”

Clinical trials involving carbon‐ion radiation therapy and the path forward

“…With the use of heavier ions like carbon, high‐LET radiation effects translate into an increased relative biologic effectiveness (RBE) value by at least a factor of 2‐fold or 3‐fold relative to photons, depending on the treatment volume . Protons have RBE values that, for the most part, are only slightly higher than unity relative to photons . Although RBE is an important factor when selecting a radiation dose, there are additional advantages associated with high‐LET radiation that can contribute to survival benefits .…”

“…18 Protons have RBE values that, for the most part, are only slightly higher than unity relative to photons. 19 Although RBE is an important factor when selecting a radiation dose, there are additional advantages associated with high-LET radiation that can contribute to survival benefits. 8,20 For example, there are animal and human data suggesting that there is an increased immunestimulatory effect with CIRT compared with photons.…”

Proton relative biological effectiveness (RBE): a multiscale problem

“…By rigorously validating these models at each stage of the radiation response process, they could be linked more fundamentally to our knowledge of the underlying biology, and given greater predictive power. A number of frameworks exist which seek to make more mechanistic predictions of radiation sensitivity in a variety of end points, [33][34][35][36] but these models still lack the comprehensive coverage and validation required for clinical translation. A major challenge in this area is the availability of robust integrated validation data-while there are an abundance of experimental studies of changes in cell survival in terms of dose and LET, there are relatively few probing other intermediate end points such as DNA repair or chromosome aberrations.…”