A spatio-temporal simulation model of the response of solid tumours to radiotherapyin vivo: parametric validation concerning oxygen enhancement ratio and cell cycle duration

Abstract

Advanced bio-simulation methods are expected to substantially improve radiotherapy treatment planning. To this end a novel spatio-temporal patient-specific simulation model of the in vivo response of malignant tumours to radiotherapy schemes has been recently developed by our group. This paper discusses recent improvements to the model: an optimized algorithm leading to conformal shrinkage of the tumour as a response to radiotherapy, the introduction of the oxygen enhancement ratio (OER), a realistic initial cell phase distribution and finally an advanced imaging-based algorithm simulating the neovascularization field. A parametric study of the influence of the cell cycle duration Tc, OER, OERbeta for the beta LQ parameter on tumour growth. shrinkage and response to irradiation under two different fractionation schemes has been made. The model has been applied to two glioblastoma multiforme (GBM) cases, one with wild type (wt) and another one with mutated (mt) p53 gene. Furthermore, the model has been applied to a hypothetical GBM tumour with alpha and beta values corresponding to those of generic radiosensitive tumours. According to the model predictions, a whole tumour with shorter Tc tends to repopulate faster, as is to be expected. Furthermore, a higher OER value for the dormant cells leads to a more radioresistant whole tumour. A small variation of the OERbeta value does not seem to play a major role in the tumour response. Accelerated fractionation proved to be superior to the standard scheme for the whole range of the OER values considered. Finally, the tumour with mt p53 was shown to be more radioresistant compared to the tumour with wt p53. Although all simulation predictions agree at least qualitatively with the clinical experience and literature, a long-term clinical adaptation and quantitative validation procedure is in progress.

Low-Dose Hypersensitivity and Bystander Effect are Not Mutually Exclusive in A549 Lung Carcinoma Cells after Irradiation with Charged Particles

“…Some tumour models of tumour interaction with the environment included the quiescent state (Alarcon et al, 2004;Antipas et al, 2004). In the model by Antipas et al (2004), the quiescence was defined by a range of pH: cells became proliferative again if the concentration in ions H+ rose above the upper value of the range, and cells died if the concentration decreased below the lower limit.…”

“…Some tumour models of tumour interaction with the environment included the quiescent state (Alarcon et al, 2004;Antipas et al, 2004). In the model by Antipas et al (2004), the quiescence was defined by a range of pH: cells became proliferative again if the concentration in ions H+ rose above the upper value of the range, and cells died if the concentration decreased below the lower limit. Different approaches were taken for the cell division: in the model by Kansal et al (2000), cells died if there was no space in the neighbourhood, while in the model by Borkenstein et al (2004), cells could push the neighbours in random directions when they divided.…”

“…The direction of division could also depend on the distribution of nutrients surrounding 10 2.2. Classic Radiation Biology the cells: cells divided preferably where there is most nutrients (Antipas et al, 2004).…”

“…It was assumed that cells would cycle as long as the amount of nutrients stayed above a minimum value, but that cells would become quiescent as soon as the amount of nutrients fell below this minimum value. It was also assumed that quiescent cells would die if the amount of nutrients fell below a second lower minimum, but that they could become proliferative again if the amount of nutrients rose above the first minimum (Alarcon et al, 2004;Antipas et al, 2004). …”

“…" If there were several spaces free, the new daughter was where there was the most nutrients (Antipas et al, 2004); in the use of the model presented in this thesis, the nutrient was uniform, and cells choose randomly a direction of division. The influence of nutrient distribution would be critical for modelling the case of tumours.…”