Inter-tumor heterogeneity and radiation dose-control curves.

This communication presents a theoretical analysis of the influence of inter-tumor heterogeneity on clinical radiation dose-response curves. Any clinically defined group of tumors consists of individuals each having a unique individual dose-control relation (I-TCP/D). This I-TCP/D relation is steep and is based on Poisson statistics. The population as a whole possesses a heterogeneous dose-control relation (H-TCP/D relation) that is a resultant of the weighted summation of the I-TCP/D curves, each weighted according to its relative frequency in the population. This summation leads to an H-TCP/D curve that is considerably flatter than the steep portion of any I-TCP/D curve. For any specified radiation regimen, three subclasses of tumors exist in any population: the stochastic fraction, which consists of those tumors whose individual tumor control probability lies between 99% and 1% and individual outcome is probabilistic; the refractory fraction, which consists of those tumors each of which has no prospect for control with the specified treatment; and the sensitive fraction, which consists of tumors each of which is absolutely controllable with the specific treatment. Based on plausible parameters, it is estimated that, for tumors associated with an overall tumor control probability of approximately 50%, some 70-85% of failures come from a predictably radioresistant fraction. To optimize and improve the radiation therapy of tumors with unsatisfactory local control, it is necessary to predictably identify the location of each individual in one of the three subclasses.