Recovery from sublethal damage during intermittent exposures in cultured tumor cells: Implications for dose modification in radiosurgery and IMRT

Purpose: In stereotactic irradiation using a linear accelerator and intensity-modulated radiation therapy (IMRT), radiation is administered intermittently, and 30 min or longer is often required in one treatment session. The purpose of the present study was to determine how different the dose delivered with such intermissions is from that delivered continuously and to estimate dose-modifying factors. Methods and Materials: Murine EMT6 and SCCVII cells in culture were used. First, two doses of 4 Gy were given with an interruption of 15 min to 6 h or 1-10 min, or without interruption. Next, five fractions of 1.6 Gy were given with interfraction intervals of 1 to 5 min each. Doses of 6.5-8 Gy were also given without interruption to estimate dose-modifying factors. Cell survival was determined by a colony assay. Furthermore, a total dose of 2 Gy was given in 5 or 10 even fractions at intervals of 1-5 min or 30 s-3 min each, respectively, and the results were compared with those obtained after 1.6-2 Gy delivered continuously by using a cytokinesis-block micronucleus assay. Results: In the two-fraction experiments, a significant increase in cell survival resulting from recovery from sublethal damage (SLDR) was observed when the interruption time was 2 min or longer in EMT6 cells and 3 min or longer in SCCVII. With a 5-min interval, cell survival increased by 13% in EMT6 and by 18% in SCCVII. In the five-fraction experiments, SLDR was evident when the interfraction interval was 2 min or longer in both 8-Gy and 2-Gy dose experiments. In the 10-fraction experiment using a dose of 2 Gy, SLDR was evident when the interfraction interval was 1 min or longer. In the 5-fraction and 10-fraction experiments, the dose-modifying factors were between 1.08 and 1.16 when the total time for irradiation was between 20 and 30 min. Conclusions: The effects of stereotactic radiosurgery and IMRT that require considerably long beam interruption (e.g., 8 min or longer in total) may be less than those of the same dose administered continuously. In treatments that take 20 min or longer, dose modification appears necessary based on biologically estimated dose-modifying factors. (C) 2004 Elsevier Inc.