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

Abstract

Background: Stereotactic 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.

Methods: A 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.

Results: For 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.

Conclusions: Although 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.

Figure 1

Simulated tumours and their oxygenation. Two-dimensional pO₂-maps of cross-sections through the simulated tumours and the pO₂-histograms of the oxygen tension values for the whole (3D) tumours. i) Hypoxic tumour with a 13 mm hypoxic core, overall HF ≈ 20%, core HF ≈ 64%, ii) Oxic tumour with an overall HF < 1%.

Figure 2

Dose distribution for the simulation of SBRT treatments. The clinically relevant dose distribution normalized to the maximum dose so that the percentage dose at the PTV periphery (20 mm from the centre) is 69% and the maximum dose is 100%. The extents of the CTV and PTV are marked with red and blue lines respectively.

Figure 3

TCP curves using the LQ and USC models. TCP curves for a tumour with i) 20% overall hypoxic fraction located centrally and ii) 1% hypoxic fraction, heterogeneously distributed, with and without inter-fraction LOC calculated with the linear-quadratic model and the universal survival curve as a function of total dose prescribed to the PTV-encompassing 69% isodose.