Skip to main content
Top
Published in: Radiation Oncology 1/2020

Open Access 01-12-2020 | Hepatocellular Carcinoma | Research

Clinical impact of Hypofractionated carbon ion radiotherapy on locally advanced hepatocellular carcinoma

Authors: Shintaro Shiba, Kei Shibuya, Masahiko Okamoto, Shohei Okazaki, Shuichiro Komatsu, Yoshiki Kubota, Takashi Nakano, Tatsuya Ohno

Published in: Radiation Oncology | Issue 1/2020

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein is in a locally advanced stage and remains difficult to cure. This study aimed to evaluate the clinical effects of carbon ion radiotherapy (C-ion RT) in locally advanced HCC (LAHCC).

Methods

The data of 11 consecutive patients with LAHCC who received C-ion RT were analyzed. The C-ion RT doses of 52.8 Gy (relative biological effectiveness [RBE]) and 60.0 Gy (RBE) were delivered in 4 fractions for standard cases, and the 60.0 Gy dose was delivered in 12 fractions for close-to-gastrointestinal-tract cases. Survival and local control probabilities were calculated using the Kaplan-Meier method.

Results

The median follow-up duration after C-ion RT was 36.4 months. The median age at the time of registration for C-ion RT was 76 years. The median tumor size was 53 mm. The numbers of treatment-naive and recurrent HCC patients were 1 and 10, respectively. Direct invasion of the major branch of the portal vein, hepatic vein, or both portal and hepatic veins was observed in three, five, and three patients, respectively. The 3-year overall survival, local control, and progression-free survival rates were 64, 78, and 18%, respectively. No patient developed radiation-induced liver diseases or grade 3 or higher toxicities in the acute and late phases.

Conclusions

C-ion RT showed favorable clinical outcomes with a high rate of local control and minimal toxicities in LAHCC. Our findings suggest that C-ion RT is a promising multidisciplinary treatment option in LAHCC.
Literature
1.
go back to reference EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.
2.
go back to reference Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRef Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRef
3.
go back to reference Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.CrossRef Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.CrossRef
4.
go back to reference Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.CrossRef Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.CrossRef
5.
go back to reference Yoon SM, Ryoo BY, Lee SJ, Kim JH, Shin JH, An JH, et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial. JAMA Oncol. 2018;4:661–9.CrossRef Yoon SM, Ryoo BY, Lee SJ, Kim JH, Shin JH, An JH, et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial. JAMA Oncol. 2018;4:661–9.CrossRef
6.
go back to reference Kasuya G, Kato H, Yasuda S, Tsuji H, Yamada S, Haruyama Y, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: combined analyses of 2 prospective trials. Cancer. 2017;123:3955–65.CrossRef Kasuya G, Kato H, Yasuda S, Tsuji H, Yamada S, Haruyama Y, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: combined analyses of 2 prospective trials. Cancer. 2017;123:3955–65.CrossRef
7.
go back to reference Shiba S, Abe T, Shibuya K, Katoh H, Koyama Y, Shimada H, et al. Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. BMC Cancer. 2017;17:721.CrossRef Shiba S, Abe T, Shibuya K, Katoh H, Koyama Y, Shimada H, et al. Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. BMC Cancer. 2017;17:721.CrossRef
8.
go back to reference Shibuya K, Ohno T, Katoh H, Okamoto M, Shiba S, Koyama Y, et al. A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3cm or larger. Radiother Oncol. 2019;132:230–5.CrossRef Shibuya K, Ohno T, Katoh H, Okamoto M, Shiba S, Koyama Y, et al. A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3cm or larger. Radiother Oncol. 2019;132:230–5.CrossRef
9.
go back to reference Shibuya K, Ohno T, Terashima K, Toyama S, Yasuda S, Tsuji H, et al. Short-course carbon-ion radiotherapy for hepatocellular carcinoma: a multi-institutional retrospective study. Liver Int. 2018;38:2239–47.CrossRef Shibuya K, Ohno T, Terashima K, Toyama S, Yasuda S, Tsuji H, et al. Short-course carbon-ion radiotherapy for hepatocellular carcinoma: a multi-institutional retrospective study. Liver Int. 2018;38:2239–47.CrossRef
10.
go back to reference Shiba S, Shibuya K, Kawashima M, Okano N, Kaminuma T, Okamoto M, et al. Evaluation of advantages in dose-distribution with carbon ion radiotherapy versus intensity-modulated radiation therapy for hepatocellular carcinoma with macroscopic vascular invasion. Anticancer Res. 2020;40:459–64.CrossRef Shiba S, Shibuya K, Kawashima M, Okano N, Kaminuma T, Okamoto M, et al. Evaluation of advantages in dose-distribution with carbon ion radiotherapy versus intensity-modulated radiation therapy for hepatocellular carcinoma with macroscopic vascular invasion. Anticancer Res. 2020;40:459–64.CrossRef
11.
go back to reference Abe T, Saitoh J, Kobayashi D, Shibuya K, Koyama Y, Shimada H, et al. Dosimetric comparison of carbon ion radiotherapy and stereotactic body radiotherapy with photon beams for the treatment of hepatocellular carcinoma. Radiat Oncol. 2015;10:187.CrossRef Abe T, Saitoh J, Kobayashi D, Shibuya K, Koyama Y, Shimada H, et al. Dosimetric comparison of carbon ion radiotherapy and stereotactic body radiotherapy with photon beams for the treatment of hepatocellular carcinoma. Radiat Oncol. 2015;10:187.CrossRef
12.
go back to reference Tsujii H, Kamada T, Shirai T, et al. Carbon-Ion Radiotherapy: Springer; 2014. Tsujii H, Kamada T, Shirai T, et al. Carbon-Ion Radiotherapy: Springer; 2014.
13.
go back to reference Nakano T, Suzuki Y, Ohno T, Kato S, Suzuki M, Morita S, et al. Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia. Clin Cancer Res. 2006;12(7 Pt 1):2185–90.CrossRef Nakano T, Suzuki Y, Ohno T, Kato S, Suzuki M, Morita S, et al. Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia. Clin Cancer Res. 2006;12(7 Pt 1):2185–90.CrossRef
14.
go back to reference Cui X, Oonishi K, Tsujii H, Yasuda T, Matsumoto Y, Furusawa Y, et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res. 2011;71:3676–87.CrossRef Cui X, Oonishi K, Tsujii H, Yasuda T, Matsumoto Y, Furusawa Y, et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res. 2011;71:3676–87.CrossRef
15.
go back to reference Kudo M, Izumi N, Kubo S, Kokudo N, Sakamoto M, Shiina S, et al. Report of the 20th Nationwide follow-up survey of primary liver Cancer in Japan. Hepatol Res. 2020;50:15–46.CrossRef Kudo M, Izumi N, Kubo S, Kokudo N, Sakamoto M, Shiina S, et al. Report of the 20th Nationwide follow-up survey of primary liver Cancer in Japan. Hepatol Res. 2020;50:15–46.CrossRef
16.
go back to reference Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.CrossRef Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.CrossRef
17.
go back to reference Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550–8.CrossRef Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550–8.CrossRef
18.
go back to reference Kanematsu N. Dose calculation algorithm of fast fine-heterogeneity correction for heavy charged particle radiotherapy. Phys Med. 2011;27:97–102.CrossRef Kanematsu N. Dose calculation algorithm of fast fine-heterogeneity correction for heavy charged particle radiotherapy. Phys Med. 2011;27:97–102.CrossRef
19.
go back to reference Inaniwa T, Kanematsu N, Matsufuji N, Kanai T, Shirai T, Noda K, et al. Reformulation of a clinical-dose system for carbon-ion radiotherapy treatment planning at the National Institute of Radiological Sciences, Japan. Phys Med Biol. 2015;60:3271–86.CrossRef Inaniwa T, Kanematsu N, Matsufuji N, Kanai T, Shirai T, Noda K, et al. Reformulation of a clinical-dose system for carbon-ion radiotherapy treatment planning at the National Institute of Radiological Sciences, Japan. Phys Med Biol. 2015;60:3271–86.CrossRef
20.
go back to reference Tashiro T, Ishii T, Koya J, Okada R, Kurosawa Y, Arai K, et al. Technical approach to individualized respiratory-gated carbon-ion therapy for mobile organs. Radiol Phys Technol. 2013;6:356–66.CrossRef Tashiro T, Ishii T, Koya J, Okada R, Kurosawa Y, Arai K, et al. Technical approach to individualized respiratory-gated carbon-ion therapy for mobile organs. Radiol Phys Technol. 2013;6:356–66.CrossRef
21.
go back to reference Kubota Y, Tashiro M, Shinohara A, Abe S, Souda S, Okada R, et al. Development of an automatic evaluation method for patient positioning error. J Appl Clin Med Phys. 2015;16:100–11.CrossRef Kubota Y, Tashiro M, Shinohara A, Abe S, Souda S, Okada R, et al. Development of an automatic evaluation method for patient positioning error. J Appl Clin Med Phys. 2015;16:100–11.CrossRef
22.
go back to reference Abe S, Kubota Y, Shibuya K, Koyama Y, Abe T, Ohno T, et al. Fiducial marker matching versus vertebral body matching. Dosimetric impact of patient positioning in carbon ion radiotherapy for primary hepatic cancer. Phys Med. 2017;33:114–20.CrossRef Abe S, Kubota Y, Shibuya K, Koyama Y, Abe T, Ohno T, et al. Fiducial marker matching versus vertebral body matching. Dosimetric impact of patient positioning in carbon ion radiotherapy for primary hepatic cancer. Phys Med. 2017;33:114–20.CrossRef
23.
go back to reference Kubota Y, Katoh H, Shibuya K, Shiba S, Abe S, Sakai M, et al. Comparison between bone matching and marker matching for evaluation of intra- and inter-fractional changes in accumulated of carbon ion radiotherapy for hepatocellular carcinoma. Radiother Oncol. 2019;137:77–82.CrossRef Kubota Y, Katoh H, Shibuya K, Shiba S, Abe S, Sakai M, et al. Comparison between bone matching and marker matching for evaluation of intra- and inter-fractional changes in accumulated of carbon ion radiotherapy for hepatocellular carcinoma. Radiother Oncol. 2019;137:77–82.CrossRef
24.
go back to reference US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. In: National Institutes of Health: National Cancer Institute; 2009. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. In: National Institutes of Health: National Cancer Institute; 2009.
25.
go back to reference Kodama K, Kawaoka T, Aikata H, Uchikawa S, Nishida Y, Inagaki Y, et al. Comparison of outcome of hepatic arterial infusion chemotherapy combined with radiotherapy and sorafenib for advanced hepatocellular carcinoma patients with major portal vein tumor thrombosis. Oncology. 2018;94:215–22.CrossRef Kodama K, Kawaoka T, Aikata H, Uchikawa S, Nishida Y, Inagaki Y, et al. Comparison of outcome of hepatic arterial infusion chemotherapy combined with radiotherapy and sorafenib for advanced hepatocellular carcinoma patients with major portal vein tumor thrombosis. Oncology. 2018;94:215–22.CrossRef
26.
go back to reference Zhang X, Wang K, Wang M, Yang G, Ye XF, Wu MC, et al. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. Oncotarget. 2017;8:29416–27.CrossRef Zhang X, Wang K, Wang M, Yang G, Ye XF, Wu MC, et al. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. Oncotarget. 2017;8:29416–27.CrossRef
27.
go back to reference Liu PH, Lee YH, Hsia CY, Hsu CY, Huang YH, Chiou YY, et al. Surgical resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis. Ann Surg Oncol. 2014;21:1825–33.CrossRef Liu PH, Lee YH, Hsia CY, Hsu CY, Huang YH, Chiou YY, et al. Surgical resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis. Ann Surg Oncol. 2014;21:1825–33.CrossRef
28.
go back to reference Shi J, Lai EC, Li N, Guo WX, Xue J, Lau WY, et al. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus. Ann Surg Oncol. 2010;17:2073–80.CrossRef Shi J, Lai EC, Li N, Guo WX, Xue J, Lau WY, et al. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus. Ann Surg Oncol. 2010;17:2073–80.CrossRef
29.
go back to reference Komatsu S, Kido M, Asari S, Toyama H, Ajiki T, Demizu Y, et al. Particle radiotherapy, a novel external radiation therapy, versus liver resection for hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus: a matched-pair analysis. Surgery. 2017;162:1241–9.CrossRef Komatsu S, Kido M, Asari S, Toyama H, Ajiki T, Demizu Y, et al. Particle radiotherapy, a novel external radiation therapy, versus liver resection for hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus: a matched-pair analysis. Surgery. 2017;162:1241–9.CrossRef
30.
go back to reference Liang SX, Zhu XD, Xu ZY, Zhu J, Zhao JD, Lu HJ, et al. Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance. Int J Radiat Oncol Biol Phys. 2006;65:426–34.CrossRef Liang SX, Zhu XD, Xu ZY, Zhu J, Zhao JD, Lu HJ, et al. Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance. Int J Radiat Oncol Biol Phys. 2006;65:426–34.CrossRef
31.
go back to reference Komatsu S, Fukumoto T, Demizu Y, Miyawaki D, Terashima K, Niwa Y, et al. The effectiveness of particle radiotherapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus. J Gastroenterol. 2011;46:913–20.CrossRef Komatsu S, Fukumoto T, Demizu Y, Miyawaki D, Terashima K, Niwa Y, et al. The effectiveness of particle radiotherapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus. J Gastroenterol. 2011;46:913–20.CrossRef
Metadata
Title
Clinical impact of Hypofractionated carbon ion radiotherapy on locally advanced hepatocellular carcinoma
Authors
Shintaro Shiba
Kei Shibuya
Masahiko Okamoto
Shohei Okazaki
Shuichiro Komatsu
Yoshiki Kubota
Takashi Nakano
Tatsuya Ohno
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2020
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-020-01634-z

Other articles of this Issue 1/2020

Radiation Oncology 1/2020 Go to the issue