Progressive hypofractionated carbon‐ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials

• Published in: Cancer Vol. 123; no. 20; pp. 3955 - 3965
• Main Authors: Kasuya, Goro, Kato, Hirotoshi, Yasuda, Shigeo, Tsuji, Hiroshi, Yamada, Shigeru, Haruyama, Yasuo, Kobashi, Gen, Ebner, Daniel K., Okada, Naomi Nagatake, Makishima, Hirokazu, Miyazaki, Masaru, Kamada, Tadashi, Tsujii, Hirohiko
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.10.2017; John Wiley and Sons Inc
• Subjects: Adult; adverse effect; Aged; Aged, 80 and over; Biological effects; Cancer; Carbon; carbon‐ion radiotherapy; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - radiotherapy; Clinical trials; Data processing; Effectiveness; Female; Heavy Ion Radiotherapy - methods; Hepatocellular carcinoma; Humans; Lesions; Liver cancer; Liver Neoplasms - mortality; Liver Neoplasms - radiotherapy; local control; Male; Maximum Tolerated Dose; Middle Aged; Mortality; Multivariate Analysis; Oncology; Original; overall survival; Patients; prognostic factor; prospective study; Radiation Dose Hypofractionation; Radiation therapy; Relative biological effectiveness (RBE); Safety; Severity of Illness Index; Side effects; Survival; Thrombosis; Thrombosis - epidemiology; Toxicity; adverse effect; carbon-ion radiotherapy; prognostic factor; local control; prospective study; mortality; overall survival; hepatocellular carcinoma
• ISSN: 0008-543X; 1097-0142; 1045-7410; 1097-0142
• DOI: 10.1002/cncr.30816

BACKGROUND The objective of this study was to evaluate the safety and efficacy of carbon‐ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials. METHODS Sequential phase 1/2 (protocol 9603) and phase 2 (protocol 0004) trials were conducted for patients with histologically proven HCC. The phase 1 component of protocol 9603 was a dose‐escalation study; CIRT was delivered in 12, 8, or 4 fractions. After determination of the recommended dose, 2 phase 2 trials were performed in an expanded cohort, and the data were pooled to analyze toxicity, local control, and overall survival. RESULTS In the phase 1 component of protocol 9603, 69.6, 58.0, and 52.8 Gy (relative biological effectiveness [RBE]) in 12, 8, and 4 fractions, respectively, constituted the maximum tolerated doses, and 52.8 Gy (RBE) in 4 fractions was established as the recommended dose regimen for the 2 phase 2 studies. In 124 patients with a total of 133 lesions, few severe adverse effects occurred, and local‐control and overall survival rates at 1, 3, and 5 years were 94.7% and 90.3%, 91.4% and 50.0%, and 90.0% and 25.0%, respectively; this included 1‐, 3‐, and 5‐year local‐control rates of 97.8%, 95.5%, and 91.6%, respectively, in the phase 2 study. In a multivariate analysis, Child‐Pugh class B and the presence of a tumor thrombus were significant factors for mortality. CONCLUSIONS The safety and efficacy of CIRT in 12, 8, and 4 fractions were confirmed, with 52.8 Gy (RBE) in 4 fractions established as the recommended treatment course for eligible HCC patients. Cancer 2017;123:3955‐65. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Sequential phase 1/2 and phase 2 prospective trials including 133 lesions in 124 patients with histologically proven hepatocellular carcinoma have been performed to evaluate the safety and efficacy of carbon‐ion radiotherapy hypofractionation with 12, 8, and 4 fractions. Few severe adverse effects have been found, and the 3‐year local‐control rate is 91.4% for all lesions with a 3‐year local‐control rate of 95.5% in the phase 2 trial.