Radiobiology in clinical radiation therapy part II: current practice and new horizons

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 multifraction regimens used in conventional radiotherapy were developed empirically, but can be understood in terms of radiobiological principles. Dividing the dose into many fractions reduces biological effectiveness due to repair of sublethal damage; this occurs in both tumors and normal tissues. Fractionation allows re-oxygenation to occur in tumors and so increases the effectiveness of a given total dose. Fractionation also leads to sensitization by reassortment of cycling tumor cells into radiosensitive phases of the cycle. Laboratory research also provides a rationale for modifications of existing fractionation protocols. The dose response relationship for late responding tissues is more 'curved' than for acute or early effects. Consequently the use of multiple fractions allows a greater separation of early and late effects in normal tissues. This has led to the introduction of hyperfractionation and accelerated treatment. Both involve two treatments per day (BID) but based on quite different rationales. The limitation of protraction is cell proliferation in the tumor, which may be accelerated as the tumor shrinks. Measurements of cell kinetics can identify fast growing tumors that may benefit from accelerated treatment. Hypoxia was early identified as a cause of resistance to cell killing x-rays. This led to development of electron affinic compounds as radiosensitizers of hypoxic cells. The new trend is the development of bioreductive drugs that are specifically cytotoxic to hypoxic cells i.e. hypoxic cytotoxins, but which still need to be combined with radiation. Fast neutrons were initially introduced, too, in an attempt to overcome the perceived problems of hypoxia, but clinical trials now are based on the premise that neutron RBE values are larger for slowly proliferating tumors which is in closer accord with the clinical observation that neutrons offer a clear advantage over x-rays only in the case of a few tumor sites. Boron Neutron Arpture Therapy remains an attractive possibility if suitable compounds can be developed. An important new horizon is the development of predictive assays to individualize treatment, and to identify patients that might benefit from new treatment strategies. Three predictive assays have already reached the clinic and have been proven to have some usefulness in clinical trials. First, there is the attempt to identify patients who may be unusually sensitive or resistant to radiation by measuring the fraction of cells (from a tumor or normal tissue specimen) surviving a dose of 2 Gy. Second, there are several methods available to identify those tumors that contain a significant proportion of hypoxia cells. Third, estimates of the proliferative potential of a tumor are now possible from a single tumor biopsy (Tpot). The future of cancer therapy is likely to be revolutionized by developments in molecular biology. The radiosensitivity of cells is determined by repair genes and molecular checkpoint genes. The malignant process is governed by oncogenes and suppressor genes which may also influence response to radiation. A radiation exposure appears to 'turn on' early responding genes, many of which involve cytokines, i.e. growth factors that control movement through the cell cycle. Many of these genes are being identified and characterized. In addition, there is increasing evidence that some (and maybe most) common cancers do not occur at random in the population, but are a consequence of inherited susceptibility genes. In the near future it may be possible to identify alterations in these genes early in life which would dictate strategies for treatment