Time factor for acute tissue reactions following fractionated irradiation: a balance between repopulation and enhanced radiosensitivity.

Experimental data for acute radiation-induced skin reactions are reviewed. These show that for dose fractionation schedules with gaps, repopulation is initiated after a lag period. After this lag period, the isoeffective dose for a given level of skin reaction first increases rapidly, but then slows. The timing of the lag period is related to the total turnover time of the tissue under investigation and, for example, is shorter in rodent skin than in pig or human skin. At the point when accelerated repopulation is initiated, there is a major shortening of the turnover time of the target cell population. At this time, there is evidence, for a short period, for an increase in radiosensitivity of the surviving stem cells in a number of acutely responding normal tissues. This effect is clearly illustrated by the results of experiments using sequential dose fractionation schedules. Prolongation of the schedule from 'short' to schedules that include irradiation over the period when the cell turnover is accelerated is associated with a marked increase in tissue radiosensitivity. Clinically, this is best illustrated by a comparison of the effects of accelerated fractionation schedules, involving multiple fractions/day, with daily fractionation schedules. The increase in radiosensitivity produced by the prolongation of the treatment from 2 to 4-5 weeks was equivalent to > or =1 Gy day(-1). Comparable findings were obtained from animal studies. In the oral mucosa of mice, the initiation of accelerated cell proliferation in surviving cells is associated with the loss of dose sparing by subsequent dose fractionation due to the loss of the capacity to repair sublethal damage. Studies in pig and human skin have indicated that increased radiosensitivity is associated with a loss of cells in the G1 phase of the cell cycle. A collation of these two sets of findings suggests that the repair of sublethal damage takes place over this phase of the cell cycle. One clinical implication of these findings is that the alpha/beta ratio for acute skin reaction changes with the length of the overall treatment time; it is approximately 4.0 Gy for 'short' fractionation schedules that avoid any shortening of the cell cycle time. This increases to 11.2-13.3 Gy for schedules given in 3-4 weeks and to approximately 35 Gy for schedules given in 5-6 weeks. Results for pig skin were in total agreement with those for human skin.