Investigation of Normal Tissue Toxicity in Pulsed Low Dose Rate Radiotherapy.

Abstract

Purpose: Pulsed low dose rate radiotherapy (PLDR) is a radiotherapy approach expected to reduce normal tissue toxicity while maintaining equivalent tumor control as conventional radiotherapy (CRT). This preliminary study evaluates the effectiveness of PLDR in reducing normal tissue toxicity in vivo. Materials and Methods: In the initial phase, C57BL/6 mice underwent histological examination following single-fraction, total-body irradiation. Observations were conducted at 3 and 5 days post-treatment. Mice were divided into control, PLDR, and CRT groups, receiving varying doses ranging from 4 to 12 Gy. Building upon the histological findings, the second phase centered on whole-abdominal irradiation (WAI) and determining the lethal dose for WAI using CRT. Subsequently, this dose was applied in PLDR settings to compare survival rates and changes in body weight. The experiment was replicated to collect histology samples at 1-, 3-, 5-, 7-, and 9-day endpoints, enabling the assessment and comparison of tissue toxicity. Finally, exploration into PLDR's lethal WAI dose was conducted. Results: Histology results showed the abdominal region as the main site of difference between PLDR and CRT, with both methods causing a dose-dependent increase in atrophy and hyperplasia. However, CRT led to higher tissue toxicity compared to PLDR. In the survival study, the fatal dose for WAI treatment was 18 Gy, with mice in the CRT group experiencing substantial weight loss and dying within 9-12 days post-treatment. In contrast, mice in the PLDR group, despite an initial weight loss, recovered their weight and survived. Histology results also showed that the PLDR group had less tissue toxicity. Furthermore, the fatal dose of WAI for PLDR was revealed to be 29 Gy, which is over 60% higher than the dose required for CRT, indicating a substantial difference in tolerance and potential safety margin provided by PLDR treatment. Conclusions: PLDR demonstrated a reduced normal toxicity compared to CRT, potentially beneficial in re-treatment scenarios or for tumors where CRT-induced toxicity limits tumor control, such as in liver cases.