The impact of hypofractionation on simultaneous dose-boosting to hypoxic tumor subvolumes

In a previous study, the dependence of the therapeutic ratio on the number of fractions (n), including both acute and chronic hypoxia, was investigated for homogeneously irradiated tumors. The present study further develops the model to include simultaneous dose-boosting to the hypoxic tumour subvolumes. The acutely hypoxic (ah) tumor subvolume was partitioned into a large number (10(2)-10(3)) of oxygenation subvolumes, modelled through rectangular pO(2)(t) waves all with the same frequency and fractional time spent below the hypoxic threshold, but with randomly distributed phases. Three quite different assumptions were considered for the effect of prolonged hypoxia on the radio sensitivity (alpha) of the chronically hypoxic (ch) clonogens, ranging from equal radiosensitivity to that of the ah-cells to an even greater radio sensitivity than that of the well-oxygenated (ox) cells. The linear-quadratic model, including, tumor repopulation, intertumor a-heterogeneity, and dependence of the oxygen enhancement ratio on the dose per fraction, was adopted for tumor control probability (TCP) computation. To include a consideration of therapeutic ratio, lung irradiation was considered and the mean normalized total lung dose (NTDL) was used as a risk indicator. For those 1(fr/d)(.)5(d/w) schedules yielding 50% TCP with homogeneous irradiation (our reference benchmark), we estimated the gain in TCP and the corresponding NTDL from dose boosting only the ch-subvolume, both the ah- and the ch-subvolumes, or 50% of the pretreatment tumor volume without specific targeting to tumor hypoxia. For two of the three assumptions for the radiosensitivity of the ch-clonogens, dose-boosting the ch-subvolume was associated with a substantial gain in TCP, and with a trend including minima in NTDL, for severely hypofractionated schedules only, whereas when dose-boosting both the ah- and the ch-subvolumes a substantial gain in TCP was always obtained for multifractionated schedules. By contrast, the "blind" dose-boosting strategy was generally inferior, although an appreciable gain in TCP for severely hypofractionated schedules was obtained. In conclusion, a strategy of dose-boosting tumor hypoxia, guided by nuclear medicine techniques that substantially map chronic hypoxia, is expected, to yield optimal gains in TCP via severely hypofractionated delivery. (c) 2006 American Association of Physicists in Medicine.