21 years of Biologically Effective Dose

In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for “biologically equivalent dose”, from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be “triangulated” to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion “How Fractionation Really Works”. BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.In 1989 the British Journal of Radiology (BJR) published an article 1] that introduced the term BED, biologically effective dose, as a linear quadratic (LQ)-based formula with an overall time factor included, to replace Dr Frank Ellis''s (1969) nominal standard dose (NSD) and the Orton and Ellis (1973) time–dose factor (TDF) tables.(1)Where n fractions of d Gy are given in an overall time of T days and tumour repopulation doesn''t start until day Tk (using k for kick-off, or onset, of the delayed repopulation during fractionated irradiation).Dr Ellis had designed NSD as a much-needed concept, distinct from physical dose, because dose alone obviously fails to represent the effect on biological tissues if it is delivered in one instead of 30 daily fractions, or at a different dose rate or radiation quality. NSD was for normal tissues only; repopulation had been discovered in tumours in rats and mice but was thought not to occur in human tumours during continued “daily” irradiation, until nearly a decade later (“Labelling indices go to zero...” Tubiana, oral comment in a conference in Rome, 1969). The main contribution of BED was just to add a simple overall time factor on to the equally simple LQ equation, log cell kill = αd+ βd², which had been in regular, but not universal, use in radiotherapy since before 1980. Somehow, BED stuck and continues to be useful. Does it need modifying yet? Its record, of mainly avoiding accidental overdoses for late complications, has remained intact for nearly 30 years because those effects of late complications didn''t depend on overall time, but only on dose-per-fraction if intervals between fractions were more than 6 h.