Main Session
Sep 28
Pres Poster 01 - Presidential Science Poster Session Showcase

2501 - Investigating a Potential Prophylactic Role of eFLASH in a Murine Lung Metastatic Soft-tissue Sarcoma Model

04:00pm - 05:00pm ET
Poster Hall - Exhibit Hall A
Screen: 24
POSTER

Presenter(s)

Yomna Khamis, MD Headshot
Yomna Khamis, MD - University of Maryland, Baltimore, MD

Y. Khamis1,2, V. Ng3, K. Byrne4, Y. Poirier5, S. Pandey5, H. D. Shukla5, D. Newman4, K. Tighe6, X. Ma6, B. Carter-Cooper6, A. Casildo6, S. Azarbarzin4, K. Richard7, W. F. Regine Jr5, and F. Carrier5,8; 1University of Maryland, Department of Radiation Oncology, Baltimore, MD, 2Department of clinical oncology and nuclear medicine, Faculty of Medicine, Alexandria University, Alexandria, MD, 3University of Maryland, Sarcoma and Connective Tissue Surgical Oncology, Orthopedic Oncology, Baltimore, Maryland, USA, Baltimore, MD, 4Department of Radiation Oncology, University of Maryland School of Medicine, baltimore, MD, 5Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 6University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, baltimore, MD, 7University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center., baltimore, MD, 8University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD

Purpose/Objective(s): Pulmonary metastases are a leading cause of mortality in soft tissue sarcoma (STS). FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates (UHDR; >40 Gy/s), has demonstrated normal tissue sparing while maintaining tumor control. We hypothesized that prophylactic whole lung FLASH-RT could control STS pulmonary metastases while minimizing pulmonary toxicity. This study provides proof-of-principle for prophylactic electron FLASH (eFLASH) lung irradiation in a murine model of STS lung metastasis.

Materials/Methods: Thirty two female NRG mice (8-10 weeks) received injection of HT-1080-Luc human fibrosarcoma cells. Three days post-injection, mice were randomized to four groups (n=8 each): (1) Sham control; (2) Hemithoracic irradiation (HTI) with conventional dose rate (CONV, 0.4 Gy/s); (3) HTI with eFLASH (~80 Gy/s); (4) Whole lung irradiation (WLI) with eFLASH (~80 Gy/s). Radiation was delivered using a modified Varian 21EX LINAC with 16 MeV electrons to a prescribed dose of 15 Gy (mean doses: CONV-HTI 14.3 Gy, eFLASH-HTI 13.8 Gy, eFLASH-WLI 13.3 Gy). Tumor was assessed by bioluminescence imaging (BLI) Xenogen IVIS, up to three times weekly. Endpoints included survival, body weight, and histopathological analysis of lungs at necropsy including tumor presence, necrosis, TGF-ß1, CAIX, and CD31 immunohistochemistry. Animals were monitored and euthanized upon meeting alternative endpoint criteria (=20% body weight loss, respiratory distress, or moribund status). Survival was defined as time from radiation to endpoint and compared using Kaplan-Meier analysis with log-rank test (SPSS v. 29)

Results: WLI eFLASH significantly prolonged median survival (33.0 days; 95% CI: 30.9–35.1) compared to sham (18.0 days), HTI-CONV (21.0 days; 95% CI: 19.7–22.3), and HTI-eFLASH (24.0 days; 95% CI: 20.4–27.6) (p < 0.001). All groups demonstrated progressive weight loss; however, WLI-eFLASH mice-maintained body weight longer, consistent with delayed disease progression. BLI demonstrated effective tumor control in irradiated lung fields, with suppressed signal maintained through day 20 in all RT groups. However, contralateral lung progression in HTI groups and extrapulmonary metastases in all groups led to mortality. WLI-eFLASH uniquely controlled bilateral pulmonary disease, delaying systemic progression. Histopathology confirmed reduced tumor scores in irradiated lungs (WLI-eFLASH: 1.5–1.8 vs. Sham: 4.0) with decreased TGF-ß1 expression in eFLASH-treated tissues (HTI-eFLASH: 2.8; WLI-eFLASH: 3.0 vs. HTI-CONV: 4.0 in contralateral lung), suggesting reduced fibrotic potential.

Conclusion: This proof-of-principle study demonstrates that prophylactic eFLASH whole lung irradiation effectively controls STS pulmonary metastases and significantly prolongs survival compared to hemithoracic approaches in a mouse STS model. These findings warrant further investigation of FLASH-RT for prophylactic or therapeutic irradiation of pulmonary metastases in STS