TOTALDOSE,PRACIIONDOSEAND -SPACINGVS INCOMPLETEREPAIRAND PROLIFERATION IN ACCELERATEDRADIOTHERAPY

An analysis is presented of the relative impact of incomplete repair, proliferation of clonogenic tumor cells and repopulation of normal tissues, under various conditions of conventional and accelerated treatment fractionation, taking into account reasonably estimated values of several tumor and tissue kinetic parameters. The Linear-Quadratic model for single-dose response is extended to include correction for incomplete repair and exponential proliferation of tumor clonogens, and homeostatically controlled repopulation of stem cells and functioning early reacting (ER) normal tissue. The description of the influence of increased lethal damage due to incomplete sublethal damage repair, and the influence of residual sublethal damage upon proliferation and repopulation is based on principles developed by Dale[ 11. The description of proliferation of clonogenic tumor cells, repopulation of the stem cell/transition cell compartment and recovery of early reacting normal tissue functionality follows recent work by Van de Geijn[2]. The potential of the model is demonstrated by computed time-dose response patterns and tabulated survival data, inter-comparing the conventional regimen of 30 x 2 Gy in 6 weeks, the Mt. Vernon 36 x 1.50 Gy in 12 days, the MD Anderson concomitant boost regimen, the MGH 40 x 1.60 Gy (2x daily) split course schedule and finally the EORTC (18 -I 27) x 1.60 Gy (3x daily) split course regimen, for a reference tumor and normal tissue conditions. Using consistent sets of estimated kinetic parameter values, provisional simulations suggest that 1) assuming an 18-day overall renewal of laryngeal/oral mucosa, and an acute stem cell doubling time of 24 h starting after 5 - 7 days, the severity of early reactions to the MtV should be somewhat more serious than to the MDA and EORTC schemes, and all three should be considerably more than the regular tolerance level; 2) shortening of the interfraction interval, which should improve tumor control, is generally not very critical as to ER tissue response; this is in part due to the fact that for practical reasons only one-half (2x daily) to two thirds (3x daily) of all the intervals can be “short”; 3) shortening of the overall treatment time generally becomes useful only in tumors with a substantial proportion of active clonogens of T t shorter than about 5 days; 4) the initial proportion of (fast) clonogenic cells is probably by far the most important (and elusive) factor, 5 p” the tumor control rate improvement should be appreciable, but not very different between the MtV, MGH and MDA schemes; the EORTC scheme could probably drop a number of fractions; 6) it is questionable whether even for tumors with TPt < 4 days the effort of weekend-less courses (MtV) is justified. Although we use estimated kinetic parameter values, the present method could become useful with regular acquisition and documentation of time-severity of (early) reactions data, and the rate and time scale of (local) tumor recurrence as a function of treatment parameters. References: 1. Dale, R.G., 1985, The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. Brit. J. Radiol. 58: 515-528 2. Van de Geijn, J., 1988. Time-dose response of human tumors and normal tissues during and after fractionated radiation treatment. A new model. Radiother. and Oncol. 12: 57-78