Repopulation kinetics during fractionated irradiation and the relationship to the potential doubling time, Tpot

Therapeutic outcome may be adversely affected by repopulation in solid tumors during fractionated irradiation. It has been proposed that the repopulation rate of the surviving cells may be reflected by the pretreatment potential doubling time (Tpot). This concept has been examined by comparing pretreatment Tpot measurements to repopulation monitored in five transplantable murine tumors during fractionated radiation treatment.

Up to nine fractions of 2 Gy were given to clamped tumors on a 6 h schedule, which allowed adequate time for repair, or on a 24 h schedule, which incorporated more time for repopulation. Tumors were removed from treatment at various times and tumor cell survival was analyzed using an excision assay. The ratio of the cell survival in tumors treated with the same total dose on the two different fractionation schedules (24 h/6 h) was used to calculate an effective doubling time for repopulation during the treatment (Teff). Potential doubling time was assessed in untreated tumors by giving the tumor-bearing animals 5-bromodeoxyuridine (BrdUrd) and, at various times later, removing the tumors for flow cytometric analysis. Tpot values were calculated by two different widely used methods.

For four tumors (RIF-1, KHT-C, KHT-LP1, and B16-F1), the Teff was greater than Tpot indicating that repopulation was not as rapid as suggested by Tpot. For SCC-VII, the only carcinoma tested, Teff was smaller than Tpot indicating that repopulation was more rapid than predicted by Tpot. Individual estimates of Tpot made from single tumor samples taken at different times after BrdUrd administration varied by factors of 2 to 7 for the different tumors.

These findings indicate a need for caution in applying measurements of Tpot for prediction of regrowth rates in individual patients' tumors.