Repair capacity and kinetics for human mucosa and epithelial tumors in the head and neck: Clinical data on the effect of changing the time interval between multiple fractions per day in radiotherapy

Early mucosal reactions are a major concern in radiotherapy of tumors in the head and neck. With some of the current strategies for altered fractionation these reactions may become dose limiting, and this has created a renewed interest in their radiobiology. The present paper reviews data on the response of mucosa in the head and neck to a change in dose per fraction (repair capacity) and time interval between dose fractions (repair kinetics). A review of clinical data on repair capacity shows that the alpha/beta ratio of the linear-quadratic model is high, around 10 Gy. Also, the steepness of the dose-response curve for mucositis is high as quantified by the maximum value of the normalized dose-response gradient, gamma(50) = 6.9 +/- 2.1. Computer simulations illustrate how this high value may be explained by the structural and proliferative organization of the mucosa. Finally, data from the following four recent studies are analyzed: the Radiation Therapy Oncology Group studies 7913 and 8313, a study from the M.D. Anderson Cancer Center, and a study from the Center of Oncology in Warsaw. All of these studies showed a decrease in the incidence of mucosal reactions when the interval between fractions given in the same day was increased, typically from around 4 h to around 6 h. It is shown that the maximum dose-equivalent of repair in the time interval between 4 h and 6 h occurs for a repair halftime of about 3.2 h. A comparison between the steepness of dose-response curves from studies not involving incomplete repair and those derived from the above four studies shows that the repair halftime for human mucosa must be relatively long, probably in the range 2 to 4 h. The statistical resolution of the available data as well as a number of caveats in the design of the studies preclude a more rigorous estimation of the repair halftime for mucosa, Although the tumor data are less conclusive, a similar repair halftime cannot be excluded for epithelial tumors in the head and neck.