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

## TL;DR

This study shows that pulsed low-dose-rate radiotherapy causes less damage to healthy tissues in mice compared to conventional radiotherapy.

## Contribution

The study demonstrates that PLDR has a significantly higher lethal dose than CRT, suggesting it is safer for normal tissues.

## Key findings

- PLDR caused less tissue toxicity and higher survival rates in mice compared to CRT.
- The lethal dose for PLDR was 29 Gy, over 60% higher than the 18 Gy for CRT.
- Mice treated with PLDR recovered weight after initial loss, while CRT-treated mice did not.

## Abstract

Pulsed low-dose-rate radiotherapy (PLDR) is a radiotherapy technique believed to reduce damage to healthy tissues while maintaining cancer-killing efficacy comparable to conventional radiotherapy (CRT). In this study, we evaluated the effectiveness of PLDR in reducing normal tissue toxicity compared to CRT using a mouse model. Healthy mice were subjected to whole-abdominal irradiation with either CRT or PLDR. We assessed toxicity by monitoring survival rates and weight changes. The results demonstrate that PLDR induces significantly lower toxicity, with the lethal dose for PLDR being approximately 60% higher than that of CRT.

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.