Tumour radiobiology beyond fractionation

Historically it has been shown repeatedly that single high doses of radiation do not allow a therapeutic differential between tumor and critical normal tissues but dose fractionation does. The purpose of conventional dose fractionation is to increase dose to the tumor while preserving normal tissue function. Tumors are generally irradiated with 2Gy dose per fraction delivered daily to a more or less homogeneous field over a 6-week time period to a specified total dose. In this treatment protocol, biological effect is based on a linear term and a quadratic term based on Lea and Catchside 1942; Radiation-induced chromosome aberrations as proposed by Kellerer and Rossi 1972 and theory of dual radiation action based on microdosimetry. Over 90% of radiation oncologists use the linear quadratic model. There are radiobiological mechanisms that impact the response to a fractionated course of radiation therapy. The classical 4R mechanisms act on every solid tumor following irradiation. Repair of sublethal damage spares late responding normal tissue preferentially. Redistribution of cells in the cell cycle increases acute and tumor damage but has no effect on late responding normal tissue. Repopulation spares acute responding normal tissue, no effect on late effects and Reoxygenation that increases tumor damage without any effect in normal tissues. However, Radiobiological parameters derived from clinical altered fractionation protocols such as hyperfractionation, accelerated fractionation and hypofractionation schedules may not follow these mechanisms. Moreover, other biological processes such as intrinsic radiosensitivity, radioadaptation and bystander effect, might alter radiation effects on tumor and normal tissue leading to an altered therapeutic gain factor. Some affected patients with various types of cancers show higher intrinsic radiosensitivity. Among these is breast cancer patients who show distinct radiosensitivity compared to normal individuals. This effect which is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. The other major concern in fractionation is the phenomenon of radioadaptation or radiation hormesis following first time irradiation of cells. Furthermore, radiation-induced bystander effect leads to perturbations to tissue social control and induction of genomic instability and delayed or immediate mutations in areas not receiving a direct deposition of energy. All these biological phenomena acting in low dose radiation response of tumor and normal tissues may lead to altered therapeutic gain in fractionation regimens will be discussed.