Normal tissue radiosensitivity: prediction on deterministic or stochastic basis?

Abstract

For the same standardized physical radiation dose there is considerable variation, among different patients, of the magnitude of early and late normal tissue reactions. Technical and clinical factors account for about one third only of these variations. Genetic or epigenetic differences between patients account for the greater proportion of interpatient radiosensitivity differences. Attempts have been made to correlate differences in the tissue radiosensitivity with the in vitro radiosensitivity of fibroblasts or lymphocytes as well as with other biological cellular processes related to cell death (mainly DNA repair and chromosomal aberrations). Apart from some genetic diseases such as ataxia telangiectasia, there were positive results in some studies that could not be reproduced in others. It is now realized that for normal tissue radiation-induced morbidity (a) cell kill is not the only factor, (b) interaction with a large number of gene products, such as IL-2, IL-6, TGF-beta, is involved, and (c) radiosensitivity differences can reflect genetic differences. Polymorphism in a wide range of genes can now be demonstrated and analyzed as a source of variations in the radiation response. cDNA microarray procedures can also allow simultaneous measurement, in the same sample, of thousands of genes and thus avoiding basing the investigation on a restricted number of genes. Preliminary results could show retrospectively a correlation between late normal tissue reactions and expression of certain genes. Using cDNA microarray before radiotherapy to predict the occurrence of serious late reactions is still under consideration. Theoretically, an efficient predictor procedure may serve in (a) detection of hypersensitive patients before submitting them to highly toxic radiotherapy regimes such as whole body irradiation, (b) detection of hypersensitive patients in clinical situations where radiotherapy can be effectively replaced by other modalities, and (c) selection of patients for elaborate radiotherapy techniques involving dose escalation to high levels.