Distribution of the number of clonogens surviving fractionated radiotherapy: a long-standing problem revisited.

ABSTRACT

PURPOSE: A long-standing problem is addressed what form of the probability distribution for the number of clonogenic tumor cells remaining after fractionated radiotherapy should be used in the analysis aimed at evaluating the efficacy of cancer treatment? Over a period of years, a lack of theoretical results leading to a closed-form analytic expression for this distribution, even under very simplistic models of cell kinetics in the course of fractionated radiotherapy, was the most critical deterrent to the development of relevant methods of data analysis. MATERIALS AND METHODS: Rigorous mathematical results associated with a model of fractionated irradiation of tumors based on the iterated birth and death stochastic process are discussed. RESULTS: A formula is presented for the exact distribution of the number of clonogenic tumor cells at the end of treatment. It is shown that, under certain conditions, this distribution can be approximated by a Poisson distribution. An explicit formula for the parameter of the limiting Poisson distribution is given and sample computations aimed at evaluation of the convergence rate are reported. Another useful limit that retains a dose-response relationship in the distribution of the number of clonogens has been found. Practical implications of the key theoretical findings are discussed in the context of survival data analysis. CONCLUSIONS: This study answers some challenging theoretical questions that have been under discussion over a number of years. The results presented in this work provide mechanistic motivation for parametric regression models designed to analyze data on the efficacy of radiation therapy.