Pulsed low dose rate brachytherapy in a rat model: Dependence of late rectal injury on radiation pulse size

Abstract

Clinical protocols utilizing pulsed low dose rate brachytherapy (PDR) to replace traditional continuous low dose rate brachytherapy (CLDR) employ irradiation in individual pulses given at intervals of a few hours. A critical factor in determining whether PDR will produce equivalent or greater late-occurring normal tissue toxicity is the dose per pulse. A rat rectal model was used to determine the role of pulse size in modifying dose effectiveness in producing late-occurring toxicity. A rat model in which the rectum is irradiated with 192Ir sources was used in conjunction with an intracavitary applicator. A section of rectum 1.3 cm in length was irradiated with either 0.75 Gy/h CLDR or one of five schemes of PDR. The schemes applied 0.375, 0.75, 1.5, 3.0, or 6.0 Gy pulses at 0.5, 1.0, 2.0, 4.0, or 8.0 h intervals, respectively. Rats were observed for up to 300 days after completion of irradiation for rectal obstruction. Rectal specimens were taken at the time of sacrifice for obstruction or at the end of follow-up and analyzed histologically for injury. Effectiveness of irradiation was analyzed by calculating the ED50 for incidence of obstruction and severe histological injury. The ED50 for obstruction after treatment with CLDR and pulse sizes of 0.375, 0.75, and 1.5 Gy were 70.5, 68.0, 68.6, and 68.8 Gy, respectively. These values were not significantly different. Compared to CLDR, the ED50 for obstruction after pulse sizes of 3.0 and 6.0 Gy were significantly different at 60.9 and 46.3 Gy, respectively. The relative changes in ED50 for the different radiation schemes in producing ulceration, fibrosis, and vascular sclerosis injury were similar to that observed for obstruction. The endpoints of colitis cystica profunda and atypical epithelial regeneration varied less with increasing pulse size. We have demonstrated that for late rat rectal injury, dose responses to PDR pulse sizes up to 1.5 Gy at 2-h intervals are not distinguishable from that seen with CLDR at a dose rate of 0.75 Gy/h.