Are half-times of repair reliably shorter for tumors than for late normal-tissue effects?

The important point is that Brenner et al. (1) and I agree about the calculations-which should be so because there is no difference in the linear quadratic (LQ) models assumed (1). We do not disagree that iftumors had short half-times of repair of sublethal injury (min) and lateresponding tissues had long half-times (h), then pulsed brachytherapy (and some other nonstandard schedules in radiotherapy) should give enhanced cell kill in tumors for no worse late complications. There is no argument here. We should just hope to be so lucky! It’s this big if1 wish to debate, before people run away with the assumption that such a trend is reliable. Radiobiologists went through the same process of reevaluating the trend in the late 1980s (5-7), but apparently the arguments need restating now. It is true that the shortest half-times of repair in normal tissues in situ occur in the rapidly proliferating cells of the small intestine, and the longest half-times in the late-responding tissues of the spinal cord, in several species. This divergence gave rise to the suspicion that the trend was uniform, but it has not been substantiated. There are notable exceptions to the trend. One is the long T,,* for repair in mouse skin, which is rapidly proliferating: 1.3 h or longer for larger doses per fraction (3, 5). By contrast, the T,,* for repair in lung (a slowly proliferating late-responding organ) has been determined by various experiments in mice as 0.7-0.9 h (7, 8). One group suspected two components for lung, with a very short T1,Z for one component (2, 7). Figure 6 of reference 5 summarizes a large number of measurements on many tissues very well, with great overlap. They reported their own results for mouse skin, kidney, and tumors. Their conclusion was that “half times for recovery from radiation injury for most tissues are between 1 and 2 h, irrespective of their proliferation kinetics. The clinical data showing increased early and late reactions for multiple-fraction-per-day regimes using interfraction intervals of 4.5 h or less support this” (5). More recently, this is also supported by the reported decrease in acute reactions in head and neck cancer patients when intervals between three fractions per day were increased from 4, 4, and 16 h to 8 h (J. C. Horiot, personal communication, October 1993). Because all T,,* determinations have wide confidence intervals, the one or two more recent values do not alter these conclusions. The most relevant departure from the “hoped-for trend” comes from several lines of human tumor cells from carcinoma of the uterine cervix, where half-times ranging from 0.26 up to 5.7 h were found by Kelland and Steel (4). A number of authors have documented the possibility of two components of repair. Brenner et al. (1) mention the evidence of Turesson and Thames for normal tissue effects (9), but they concentrate their discussion on the second, longer, component. The shorter components (25 min for both early and late responses) are also important, in proportion to their magnitudes relative to the slow components. Further, large variations of T1,Z with dose per fraction (given at high dose rate) are reported (5, 7). These have been interpreted in various ways, including saturation of repair processes after larger doses. There is clearly scope for variation here from any trend, depending, for example, on pulse size in pulsed brachytherapy (PB). Finally, it is well known that much shorter half-times of repair are regularly observed in experiments where dose rate is varied, than in split-dose experiments with varying intervals between two fractions at high dose rate (3,6,7). The mechanism may be debatable, but the results are not in doubt. Here again the discrepancy is relevant to PB given at different dose rates in the pulse. To the extent that half-times of repair mentioned by Brenner et al. for human tumors ( 1) include data obtained