The Time Factor and Repopulation in Tumors and Normal Tissues.

Abstract

Summary The tolerance of most normal tissues and the radioresistance of some and maybe most tumors increases as overall treatment time increases. In most cases this increase appears to be proportional to time. The time factor is measured by the additional dose that has to be delivered for a given additional time period to achieve the same effect, and is quantitated as Gy/d. Typical values for the time factor in human tumors, particularly squamous cell carcinomas, are between 0.4 and 1 Gy/d, but with great heterogeneity among different tumor types and among different patients suffering from similar tumors. In acutely responding normal tissues of patients, particularly in skin and oral mucosa, the time factor depends more on time after the start of radiotherapy and on dose intensity than on the proliferative characteristics of the tissue. It may vary, in the same tissue, between 0 and 2 Gy/d. Typical values for the time factor for chronically responding normal tissues in patients are between 0.1 and 0.4 Gy/d. The mechanisms underlying the time factor are different for the three types of response. In tumors the main cause of the time factor is accelerated repopulation of tumor "stem" cells. In acutely responding normal tissues, the main cause of the time factor is accelerated repopulation of the entire population of stem and transit cells. In chronically responding normal tissues the cause is unlikely to be related to repopulation of any target cell population, but no convincing mechanism has emerged. The most detailed studies on repopulation have been performed on acutely responding normal tissues. Acceleration occurs after a delay that depends both on the proliferation kinetics of the tissue and on the dose intensity of irradiation. The main features are a shift from asymmetrical to symmetrical stem cell division and an expansion of the transit compartment. Accelerated repopulation in acutely responding normal tissues is a well regulated process. The mechanism and timing of acceleration of repopulation in tumors is not yet well understood. However, some similarities may exist in the patterns of response to radiotherapy of tumors and the respective normal tissue from which they arose.