Radiobiology in clinical radiation therapy part I - Systems and principles

Objective: This course is designed for residents in radiation oncology, preparing for their boards. It includes the physics and chemistry of the absorption of radiation, a description of the biological systems used to obtain a quantitative relationship between dose and biological effect, as well as a review of the basic principles in radiation biology that have been established. The biological effects of radiation may result from the direct action, which refers to ionizations in the DNA itself, or the indirect action which is mediated by free radicals. For x or gamma rays, about 70% of the damage is by the indirect action, which can be modified by oxygen and various chemical agents. Radiation-induced DNA damage may lead to carcinogenesis and hereditary effects, which are important in personnel protection, or to cell lethality which is the basis of radiotherapy. Chromosome aberrations and cell lethality appear to result from the interaction of two lesions (probably double strand breaks) which leads to the linear-quadratic relationship. This refers to mitotic death, which is the most common form of radiation induced death. Programmed cell death orApoptosis also occurs which appears to be important in more radiosensitive tumors, and relatively unimportant in radioresistant tumors. A number of quantitative biological test systems have been developed to quantify the effects of radiation as a function of dose. Cells may be cultured in vitro, of normal and neoplastic origin, and survival curves produced with reproductive integrity plotted as a function of dose. Normal tissue systems where reproductive integrity can be scored as an endpoint include skin, gut, colony forming units in the bone marrow, as well as breast, thyroid and testis. The response of some normal tissues depends, not only on the fraction of cells killed, but on the tissue architecture in terms of functional subunits, this will be discussed in Part III. A range of transplantable tumors have been studied with endpoints of tumor cure, growth delay, or cell survival. In addition, many human tumor cells grow as multicellular spheroids, or as xenografts in immuno-deficient nude mice. Based on laboratory data, the basic principles of radiation biology have been established; these include: (1) The shape of the cell survival curve for sparsely and densely ionizing radiations. (2) The difference in the shapes of the dose response relationships for early and late responding tissues. (3) The variation of cellular response with the quality of the radiation. (4) The age-response function, i.e., the variation of cellular radiosensitivity with the phase of the cell cycle. (5) Fractionation, the repair of sublethal damage and potentially lethal damage and the dose rate effect. (6) The effect of the presence of absence of molecular oxygen on radiation response, and the wider question of the chemical modification of radiation injury by sensitizers and protectors. (7) The kinetics of cells, tissues and tumors; cell cycle, growth fraction, cell loss factor and the process of reoxygenation. Multifraction radiotherapy protocols were developed empirically, but can now be understood in terms of principles derived from laboratory data. The importance of fraction size and overall time as separate variables has been made clear from experiments with cells and animals. Many of the new initiatives to be discussed in Part II are also a development of ideas that originated in the laboratory