Cellular signalling effects in high precision radiotherapy

Abstract

Radiotherapy is commonly planned on the basis of physical dose received by the tumour and surrounding normal tissue, with margins added to address the possibility of geometric miss. However, recent experimental evidence suggests that intercellular signalling results in a given cell's survival also depending on the dose received by neighbouring cells. A model of radiation-induced cell killing and signalling was used to analyse how this effect depends on dose and margin choices. Effective Uniform Doses were calculated for model tumours in both idealised cases with no delivery uncertainty and more realistic cases incorporating geometric uncertainty. In highly conformal irradiation, a lack of signalling from outside the target leads to reduced target cell killing, equivalent to under-dosing by up to 10% compared to large uniform fields. This effect is significantly reduced when higher doses per fraction are considered, both increasing the level of cell killing and reducing margin sensitivity. These effects may limit the achievable biological precision of techniques such as stereotactic radiotherapy even in the absence of geometric uncertainties, although it is predicted that larger fraction sizes reduce the relative contribution of cell signalling driven effects. These observations may contribute to understanding the efficacy of hypo-fractionated radiotherapy.

Effects of Charged Particles on Human Tumor Cells

“…( 23 , 24 )], it remains far from clear whether non-targeted effects are similar or different after irradiation with photons versus charged particles ( 25 – 27 ). Furthermore, the role of non-targeted effects or intercellular signaling in response of tumors to radiation remains under investigation ( 28 , 29 ), with very little work having been done with charged particles. This review is limited to discussion of targeted effects of charge particles.…”

Radiation, a two-edged sword: From untoward effects to fractionated radiotherapy

“…As an example, normal oxygenated tissues will experience greater cell death due to bystander-related mechanisms (Marín et al, 2014); the bystander effects are one of the complications in radiation exposure, potentially causing chromosomal damages that could lead to near future carcinogenic risk (Dent et al, 2000). Conversely, bystandereffects signalling (McMahon et al, 2015), autoimmune diseases or chronic inflammation may also be beneficial to radiotherapy (Schaue, 2017). Thus, modification of bystander signalling could in principle be used to modify radiation responses, but this does not appear to have been realised so far.…”

Modelling responses to spatially fractionated radiation fields using preclinical image-guided radiotherapy

“…In previous work, we have assumed simple linear diffusion between neighbouring voxels, 26,27 which is again applied in this work.…”

“…The diffusion coefficient within the mouse was set to simulate different signal ranges-this is the maximum distance from an irradiated volume at which a cell may see a signalling-induced damage response, as described previously. 27 For each irradiation condition and range, the level of survival has been calculated for each voxel within the tumour volume and compared with that predicted from a standard linear-quadratic dose response, assuming no interaction between neighbouring voxels. The dose which gives that level of survival in the linearquadratic model is defined as the "signalling-adjusted dose", for ease of comparison between different dose-volume histograms (DVHs).…”