Hypofractionation in non-small cell lung cancer (NSCLC): suggestions from modelling both acute and chronic hypoxia

Based on experimental estimates for acute and chronic tumour hypoxia, a speculative analysis of the therapeutic ratio dependence on the number of once-daily five-days-per-week fractions (n) for non-small cell lung cancer (NSCLC) radiotherapy is proposed. For this purpose an adapted formulation of the linear-quadratic model has been derived, including the effects of tumour repopulation, inter-tumour a-heterogeneity and oxygen enhancement ratio dependence on the dose per fraction. The relation between the curative dose D-50, assuring 50% tumour control probability, and n has been computed: for (n, D-50) fractionation schemes, the therapeutic ratios have been compared in terms of effective normalized total doses to the lungs (NTDeff (L)), estimated by a few supposed fractions of the normalized total dose to the tumour. Results suggest that D-50 is dominated by chronic hypoxia for shortly hypofractionated treatments and by acute hypoxia for multifractionated treatments. Furthermore, the optimum number of fractions depends on the rapidity of the reoxygenation from chronically hypoxic cells, almost independently of the extent of both chronic and acute hypoxia. For NSCLC, both the reduction of n until about 20 fractions in hypofractionated dose-escalation trials, and the extension of extra-cranial stereotactic radiotherapy schedules to include at least 5-10 fractions, seem to be supported by this model.