Computed 88% TCP dose for SBRT of NSCLC from tumour hypoxia modelling

In small NSCLC, 88% local control at three years from SBRT was reported both for schedule (20-22 Gy x 3) (Fakiris et al 2009 Int. J. Radiat. Oncol. Biol. Phys. 75 677-82), actually close to (18-20 Gy x 3) if density correction is properly applied, and for schedules (18 Gy x 3) and (11 Gy x 5) (Palma et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 82 1149-56). Here, we compare our computed iso-TCP = 88% dose per fraction (d(88)) for three and five fractions (n) with such clinically adopted ones. Our TCP model accounts for tumour repopulation, at rate lambda (d(-1)), reoxygenation of chronic hypoxia (ch-), at rate a (d(-1)) and fluctuating oxygenation of acute hypoxia (ah-), with hypoxic fraction (C) of the acutely hypoxic fractional volume (AHF). Out of the eight free parameters whose values we had fitted to in vivo animal data (Ruggieri et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 83 1603-8), we here maintained (a(d(-1)), C, OERch, OERah/OERch, AHF, CHF) = (0.026, 0.17, 1.9, 2.2, 0.033, 0.145) while rescaling the initial total number of clonogens (N-o) according to the ratio of NSCLC on animal median tumour volumes. From the clinical literature, the usually assumed (alpha(o)/beta(o)(Gy), lambda(d(-1))) = (10, 0.217) for the well-oxygenated (o-) cells were taken. By normal (lognormal) random sampling of all parameter values over their 95% C. I., the uncertainty on present d(88)(n) computations was estimated. Finally, SBRT intra-tumour dose heterogeneity was simulated by a 1.3 dose boost ratio on 50% of tumour volume. Computed d(88)(+/- 1 sigma) were 19.0 (16.3; 21.7) Gy, for n = 3; 10.4 (8.7; 12.1) Gy, for n = 5; 5.8 (5.2; 6.4) Gy, for n = 8; 4.0 (3.6; 4.3) Gy, for n = 12. Furthermore, the iso-TCP = 88% total dose, D-88(n)= d(88)(n)* n, exhibited a relative minimum around n = 8. Computed d88(n = 3, 5) are strictly consistent with the clinically adopted ones, which confirms the validity of LQ-model-based TCP predictions at the doses used in SBRT if a highly radioresistant cell subpopulation is properly modelled. The computed minimum D-88(n) around n = 8 suggests the adoption of 6 <= n <= 10 instead of n = 3 in SBRT of small NSCLC tumours.