Toward improving the therapeutic ratio in stereotactic radiosurgery: selective modulation of the radiation responses of both normal tissues and tumor.

A review of the radiobiological factors that influence the response of the brain to radiation is provided in relation to stereotactic radiosurgery (SRS). The prospects for intervention after radiation treatment to selectively modulate the expression of late central nervous system (CNS) injury is considered, as well as an account of recent interest in the use of radiation enhancers to selectively increase the response of tumors to radiation. Brain necrosis in humans, after conventional irradiation, indicates that the risk of necrosis increases rapidly after an equivalent single dose of 12 or 13 Gy. When single-dose treatments are extended due to 60Co decay or planned extension of treatment times, account should be taken of the effects of the repair of sublethal radiation damage to DNA on the efficacy of treatment. Both repair capacity and repair kinetics will also influence tumor control, but parameters to quantify this effect have not yet been established. The volume of CNS tissue that has been irradiated affects the tissue response, but this effect is only significant for volumes less than 0.05 cm3. The gain obtained from irradiation of small volumes is reduced, however, when focal irradiation is given within a wider field of irradiation. Based on a vascular hypothesis explaining the pathogenesis of late CNS damage, approaches designed to selectively modulate the frequency of late CNS damage have been validated. Given the high intrinsic radioresistance of some tumors, as opposed to the presence of hypoxia, an interest has developed in the use of selective radiation enhancers in the treatment of tumors. The compound presently available has proved to be disappointing clinically due to toxicity at effective doses, when repeated administration is required. However, when given at high single doses it is less toxic and may be more effective. Less toxic radiation enhancers need to be developed.