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Cynthia De la Garza-Ramos,1 S Ali Montazeri,1 Kaitlyn R Musto,1 Melissa D Kapp,1 Andrew R Lewis,1 Gregory Frey,1 Ricardo Paz-Fumagalli,1 Sumera Ilyas,2 Denise M Harnois,3 Umair Majeed,4 Tushar Patel,3 Beau Toskich1 1Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA; 3Department of Transplant, Mayo Clinic, Florida, FL, USA; 4Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, USACorrespondence: Beau Toskich, Division of Interventional Radiology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, Tel +1 904-953-1496, Email Toskich.Beau@mayo.eduPurpose: To compare the outcomes of radiation segmentectomy for early-stage hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) versus hepatitis C virus (HCV).Materials and Methods: A retrospective analysis of consecutive patients with NAFLD- or HCV-related HCC treated with radiation segmentectomy from 01/2017-06/2022 was performed. Eligibility criteria included solitary tumor ≤ 8 cm or up to 3 HCC ≤ 3 cm, ECOG 0– 1, and absence of vascular invasion or extrahepatic spread. Imaging best response was assessed per modified Response Evaluation Criteria in Solid Tumors. Target tumor and overall progression, time-to-progression (TTP), and overall survival (OS) were calculated. All outcomes were censored for liver transplantation (LT). Complete pathologic response (CPN) was assessed in patients who underwent LT.Results: Of 142 patients included (NAFLD: 61; HCV: 81), most had cirrhosis (NAFLD: 87%; HCV: 86%) and small tumors (median size NAFLD: 2.3 cm; HCV: 2.5 cm). Patients with NAFLD had higher BMI (p< 0.001) and worse ALBI scores (p=0.003). Patients with HCV were younger (p< 0.001) and had higher AFP levels (p=0.034). Median radiation dose (NAFLD: 508 Gy; HCV: 452 Gy) and specific activity (NAFLD: 700 Bq; HCV: 698 Bq) were similar between cohorts. Objective response was 100% and 97% in the NAFLD and HCV cohorts, respectively. Target tumor progression occurred in 1 (2%) NAFLD and 8 (10%) HCV patients. Target tumor TTP was not met for either cohort. Overall progression occurred in 23 (38%) NAFLD and 39 (48%) HCV patients. Overall TTP was 17.4 months (95% CI 13.5– 22.2) in NAFLD and 13.5 months (95% CI 0.4– 26.6) in HCV patients (p=0.86). LT was performed in 27 (44%) NAFLD and 33 (41%) HCV patients, with a CPN rate of 63% and 54%, respectively. OS was not met in the NAFLD cohort and was 53.9 months (95% CI 32.1– 75.7) in the HCV cohort (p=0.15).Conclusion: Although NAFLD and HCV are associated with different mechanisms of liver injury, patients with early-stage HCC treated with radiation segmentectomy achieve comparable outcomes.Keywords: hepatocellular carcinoma, radiation segmentectomy, NAFLD, viral hepatitis

Belal Abousaida,1,&ast; Danushka Seneviratne,1,&ast; Bradford S Hoppe,1 Stephen J Ko,1 Aroumougame Asaithamby,2 Francis A Cucinotta,3 Jessica M Kirwan,4 Kabir Mody,5 Beau Toskich,6 Jonathan B Ashman,7 Christopher L Hallemeier,8 Sunil Krishnan1 1Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3School of Integrated Health Sciences, University of Las Vegas, Las Vegas, NV, USA; 4Department of Radiation Oncology, University of Florida, Gainesville, FL, USA; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, USA; 6Division of Interventional Radiology, Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 7Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA; 8Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, MN, USA&ast;These authors contributed equally to this workCorrespondence: Sunil KrishnanDepartment of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USATel +1 713-202-8063Email krishnan.sunil@mayo.eduAbstract: Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.Keywords: carbon ion therapy, hepatocellular carcinoma, hypofractionation