Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

Abstract

BackgroundStereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT.MethodsA three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia.ResultsFor the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions.ConclusionsAlthough attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation.

High-dose and fractionation effects in stereotactic radiation therapy: Analysis of tumor control data from 2965 patients

“…Instead, multi-fraction brain SRT was predicted to produce slightly better TCPs than single-fraction treatments for brain metastases. These conclusions are consistent with expected effects on hypoxic tumors, where fractionation allows tumor reoxygenation between fractions [41][42][43].…”

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes

“…LOCs were assumed to take place, meaning that the oxygen tension was assumed to change at the cellular level as a result of changes in acute hypoxia. This was achieved by randomly shutting down a fraction of vessels at each treatment fraction, while the average intervessel distance within each tumor region remained the same throughout the full course of treatment, leading to a redistribution of the p O 2 values between voxels at each fraction [12, 17, 19, 20]. The overall geometry of the tumor with its hypoxic island, and the corresponding hypoxic fractions of the different regions, therefore, remained the same for all fractions (Fig.…”

“…However, another type of reoxygenation, resulting from changes in acute hypoxia between fractions, should also be considered [9–11]. In a recent study by Lindblom [12], the influence of such local oxygenation changes (LOCs) on the outcome of stereotactic body radiotherapy (SBRT) using photons was investigated. The study showed that extreme hypofractionation (using one single fraction) should be pursued with caution, since it might result in reduced local control as a result of the reduced possibilities of interfraction LOCs.…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…For example, there is evidence that single-fraction stereotactic RT lacks a dose-response relationship and achieves lower tumor control rates than 3 or more fractions even if the same ‘biologically effective doses' are applied [105,106], which is consistent with a detrimental effect of missing re-oxygenation [107]. Oxygen is required for the production of superoxide from cell water radiolysis products, which greatly enhances the toxicity of IR [57].…”