The linear-quadratic formula and progress in fractionated radiotherapy

Clinical gains have been reported from the use of nonstandard fractionation schedules planned with a radiobiological basis. Hyperfractionation provides the leading example, as described below, with accelerated fractionation being developed more recently. Although examples of almost every kind of fractionated schedule can be found in the literature over the past 90 years, it is only within the last decade that the biological factors concerning overall time and delayed proliferation after irradiation, and the effect of dose per fraction, have been understood. Both these factors operate differently on late- and early-reacting tissues, because cell proliferation in late-reacting tissues is slow or absent, but early reacting tissues and tumours depend upon cells that proliferate rapidly. This basic knowledge is still diffusing through the radiotherapy community and I hope this review will help the diffusion process. The biological factors concerning fractionation seem to apply to the majority of tissues and tumours, so that new schedules can be planned that are effective in practice. Attempts to deal with hypoxic cells in tumours or to use high-linear-energy-transfer (LET) radiation have been less generally successful, probably because in those strategies we need to identify subpopulations that are smaller. Tumours that are resistant to conventional radiotherapy because they contain hypoxic cells and do not reoxygenate cannot be identifed yet.