Cheng-En Hsieh1, Bhanu Prasad Venkatesulu2, Ching-Hsin Lee3, Sheng-Ping Hung3, Pei-Fong Wong4, Sathvik Panambur Aithala4, Byung Kyu Kim5, Arvind Rao6, Joseph Tung-Chieh Chang3, Ngan-Ming Tsang7, Chun-Chieh Wang8, Chung-Chi Lee9, Chen-Chun Lin10, Jeng-Hwei Tseng11, Wen-Chi Chou12, Yu-Chao Wang13, Sunil Krishnan14, Ji-Hong Hong15. 1. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China; Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center-UT Health Graduate School of Biomedical Sciences, Houston, Texas. 2. Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 4. Department of Radiation Physics, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center-UT Health Graduate School of Biomedical Sciences, Houston, Texas. 6. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. 7. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China; School of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 8. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China; Department of Medical Imaging and Radiological Science, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 9. Department of Medical Imaging and Radiological Science, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 10. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 11. Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 12. Department of Medical Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 13. Department of Surgery, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. 14. Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center-UT Health Graduate School of Biomedical Sciences, Houston, Texas; Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 15. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China; Department of Institute for Radiological Research, Chang Gung Memorial Hospital, Linkou and College of Medicine, Chang Gung University, Taoyuan City, Taiwan, China. Electronic address: jihong@cgmh.org.tw.
Abstract
PURPOSE: To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS: This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving <1 GyE; the standard liver volume (SLV) was calculated using body surface area. Possible correlations of clinicodosimetric parameters with RILD were examined. RESULTS: The mean pretreatment LV was 85% of SLV, and patients with a history of hepatectomy (P < .001) or hepatitis B virus infection (P = .035) had significantly smaller LV/SLV. Nineteen (14%) patients developed RILD. Multivariate logistic regression analysis identified ULV/SLV (P = .001), gross tumor volume (P = .001), and Child-Pugh classification (P = .002) as independent RILD predictors, and mean liver dose and target-delivered dose were not associated with RILD occurrence. A "volume-response" relationship between ULV/SLV and RILD was consistently observed in both eastern and western cohorts. In Child-Pugh class-A patients whose ULV/SLV were ≥50%, 49.9%-40%, 39.9%-30% and <30%, the RILD incidences were 0%, 6%, 16%, and 39% (P < .001), respectively. For the Child-Pugh class-B group, the RILD incidences in patients with ≥60%, 59.9%-40%, and <40% of ULV/SLV were 0%, 14%, and 83% (P = .006), respectively. CONCLUSIONS: The ULV/SLV, not mean liver dose, independently predicts RILD in patients with HCC undergoing PBT. The relative and absolute contraindications for Child-Pugh class-A patient's ULV/SLV are <50% and <30%, and <60% and <40% for Child-Pugh class-B patients, respectively. Our results indicate that the likelihood of hepatic complications for PBT is dictated by similar metrics as that for surgery.
PURPOSE: To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS: This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving <1 GyE; the standard liver volume (SLV) was calculated using body surface area. Possible correlations of clinicodosimetric parameters with RILD were examined. RESULTS: The mean pretreatment LV was 85% of SLV, and patients with a history of hepatectomy (P < .001) or hepatitis B virus infection (P = .035) had significantly smaller LV/SLV. Nineteen (14%) patients developed RILD. Multivariate logistic regression analysis identified ULV/SLV (P = .001), gross tumor volume (P = .001), and Child-Pugh classification (P = .002) as independent RILD predictors, and mean liver dose and target-delivered dose were not associated with RILD occurrence. A "volume-response" relationship between ULV/SLV and RILD was consistently observed in both eastern and western cohorts. In Child-Pugh class-A patients whose ULV/SLV were ≥50%, 49.9%-40%, 39.9%-30% and <30%, the RILD incidences were 0%, 6%, 16%, and 39% (P < .001), respectively. For the Child-Pugh class-B group, the RILD incidences in patients with ≥60%, 59.9%-40%, and <40% of ULV/SLV were 0%, 14%, and 83% (P = .006), respectively. CONCLUSIONS: The ULV/SLV, not mean liver dose, independently predicts RILD in patients with HCC undergoing PBT. The relative and absolute contraindications for Child-Pugh class-A patient's ULV/SLV are <50% and <30%, and <60% and <40% for Child-Pugh class-B patients, respectively. Our results indicate that the likelihood of hepatic complications for PBT is dictated by similar metrics as that for surgery.
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