Treatment modelling: The influence of micro-environmental conditions

Abstract

The interest in theoretical modelling of radiation response has grown steadily from a fast method to estimate the gain of new treatment strategies to an individualisation tool that may be used as part of the treatment planning algorithms. While the advantages of biological optimisation of plans are obvious, accurate theoretical models and realistic information about the micro-environmental conditions in tissues are needed.This paper aimed to investigate the clinical implications of taking into consideration the details of the tumour microenvironmental conditions. The focus was on the availability of oxygen and other nutrients to tumour cells and the relationship between cellular energy reserves and DNA repair ability as this is thought to influence the response of the various hypoxic cells. The choice of the theoretical models for predicting the response (the linear quadratic model or the inducible repair model) was also addressed.The modelling performed in this project has shown that the postulated radiobiological differences between acute and chronic hypoxia have some important clinical implications which may help to understand the mechanism behind the current success rates of radiotherapy. The results also suggested that it is important to distinguish between the two types of hypoxia in predictive assays and other treatment simulations.

Modelling Tumour Oxygenation, Reoxygenation and Implications on Treatment Outcome

“…This comes as a confirmation of studies showing an improvement of control in experimental systems in the presence of chronically hypoxic cells [64]. In contrast, the presence of acute hypoxia in tumours leads to a worsening of the response to radiation therapy [56, 65, 66]. However, while the fluctuating character of the perfusion disturbances in tumour capillaries does not lead to a full “washout” of the radioresistance of acutely hypoxic cells, the fluctuations are essential for the success of fractionated therapy.…”

“…Experimental studies have shown that chronically hypoxic cells may have low or depleted energy reserves which would impair their repair mechanisms [52–55], in contrast with acutely hypoxic cells that are repair competent. Correlating these findings with calculated oxygen distributions in tumours has suggested that the added biochemical sensitisation of chronically hypoxic cells could provide an explanation for the success of radiotherapy, as the chemical radioresistance conferred by hypoxia in general would otherwise require unrealistically high doses to control tumours containing hypoxic cells [49, 50, 56]. This comes as a confirmation of studies showing an improvement of control in experimental systems in the presence of chronically hypoxic cells [64].…”

“…Consequently, differentiating between the two types of hypoxia as well as the time-dependent variation of the oxygen and nutrient availability might be needed for studies aiming to quantify the impact of certain treatment approaches on tumour containing both types of hypoxic cells. In this case, simulations would have to account for the perfusion status of the blood vessels in the tumour at various time points during the treatment and the impact on cellular radiosensitivity [56]. …”

“…Theoretical simulations using (9)–(13) have shown significant differences in the predicted response depending on the assumed oxygenation of the tissue and these results indicate that full distributions of p O 2 values, not only the hypoxic fraction, are needed for modelling [25, 56, 63]. This is particularly important in light of the equivocal relationship between tumour oxygenation and the above-mentioned parameters.…”

Impact of SBRT fractionation in hypoxia dose painting — Accounting for heterogeneous and dynamic tumor oxygenation

“…In NSCLC, several studies have investigated dose painting based on different tracers such as 18 F‐labeled flurorodeoxyglucose (FDG), fluoromisonidazole (FMISO), and flortanidazole (HX4) . Furthermore, several modeling studies investigated the influence of heterogeneous tumor hypoxia on the treatment outcome . However, given the qualitative information obtained from PET imaging, the determination of the prescribed dose still presents a challenge to the concept of dose painting in general.…”