S2560
Radiobiology – Normal tissue radiobiology
ESTRO 2026
Material/Methods: A total of 48 rectal cancer patients treated with neoadjuvant CRT were included. Female/male ratio was 14/34. Clinical T stage was T2 in 13 patients, T3 in 32, and T4 in 3. Forty-three patients had cN (+) disease. All patients received 50.4- 56 Gy to the primary tumor and 50.4 Gy to the regional lymph nodes, in 28 fractions, concurrent with daily Capecitabine. Blood samples obtained before CRT and a day after completion of CRT were centrifuged and serum samples were collected. Acute gastrointestinal, hematologic, and genitourinary toxicities were recorded weekly follow-ups during CRT. Serum NRF2 and HO1 (ng/mL), and KEAP1 (pg/mL) levels were measured using the ELISA method. Changes in NRF2, KEAP1, and HO1 levels (post-, pre-CRT) were defined as Δ NRF2, Δ KEAP1, and Δ HO1. Wilcoxon Signed Rank Test, Chi-Square and Mann-Whitney U tests were used for statistical analyses. Results: Median age was 58.5 (41-80). NRF2 (p<0.0001), KEAP1 (p=0.001), and HO1 (p<0.0001) levels were significantly increased during CRT. Median (min-max) pre- and post-CRT NRF2, HO1, and KEAP1 levels were 2.12 (1.96-3.0), 3.98 (1.58-8.72) ng/mL, and 202.02 (21.92- 1550.05) pg/mL, 2.14 (2.0-3.89), 5.24 (2.39-11.22) ng/mL, and 223.89 (43.46-1285.46) pg/mL, respectively. While pre-CRT HO1 and Δ NRF2 were significantly higher, Δ KEAP1 was significantly lower in patients suffered from gastrointestinal side effects. Similarly, pre-CRT HO1 and Δ NRF2 were significantly higher in patients with hematologic toxicity. Genitourinary toxicity was found affected with higher pre-and post-CRT KEAP1 and post-CRT NRF2 (Table).Table. Mean (± SD) values of variables by acute toxicity
increased KEAP1 levels which regulates NRF2. Increased pre-CRT HO1 level may be a predictor for gastrointestinal and hematologic side effects. Keywords: radioprotection, antioxidant, side effect
Poster Discussion 942 Reducing Inflammation and Macrophage Senescence by Metformin and Butyrate in Chronic Radiation Proctitis Mau-Shin Chi, Huan-I Jen, Shu-Yi Ho, Kwan-Hwa Chi Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Purpose/Objective: Chronic radiation proctitis (RP) is a debilitating late complication of pelvic radiotherapy, characterized by vascular ectasia, inflammation, and fibrosis. Current management options remain limited, particularly for refractory cases. This study aimed to establish a reproducible murine model of chronic RP using high- dose-rate (HDR) brachytherapy and to evaluate the therapeutic efficacy of a metformin–butyrate (MeBu) enema in mitigating radiation-induced injury. Material/Methods: BALB/c mice received a single 15 Gy fraction of HDR rectal brachytherapy to induce chronic RP. From weeks 4 to 8 post-irradiation, animals were treated with daily rectal enemas of metformin, butyrate, or MeBu. Histopathological changes were assessed using H&E and Masson’s Trichrome staining, while macrophage polarization was evaluated by iNOS (M1) and CD163 (M2) immunohistochemistry. Cellular senescence was analyzed using SA- β -gal staining and quantitative PCR for p16 and p21 in irradiated bone marrow–derived macrophages (BMDMs). Results: A single 15 Gy dose consistently produced chronic RP features, including mucosal erosion, transmural inflammation, and fibrosis, with an overall survival rate of 82%. MeBu treatment markedly reduced mucosal injury and fibrosis, and restored epithelial integrity. Immunohistochemistry revealed decreased M1 and increased M2 macrophages, indicating an anti- inflammatory phenotypic shift. In vitro, MeBu significantly decreased SA- β -gal–positive BMDMs, downregulated p21 expression (p = 0.0074), and showed a downward trend in p16 (p = 0.0568), demonstrating a pronounced anti-senescent effect. Conclusion: A reproducible murine model of chronic RP was established using single-fraction 15 Gy HDR brachytherapy. MeBu enema therapy exhibited potent anti-inflammatory, anti-fibrotic, and senolytic effects, highlighting its potential as a novel therapeutic strategy for chronic radiation proctitis.
Conclusion: NRF2/KEAP1/HO1 signaling pathway is activated with CRT in rectal cancer patients. NRF2 is overexpressed in patients with CRT related acute side effects despite
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