Systematic Review of Radiation-Based Therapies for Hepatocellular Carcinoma

Namita E. Mathew; Mohammad Elsayed; Nariman Nezami; Bill S. Majdalany; Ripal Gandhi; Michael Haber; Zachary L. Bercu; Nima Kokabi

doi:10.1055/s-0041-1728807

Digestive Disease Interventions, Table of Contents

Digestive Disease Interventions 2021; 05(02): 123-136
DOI: 10.1055/s-0041-1728807

Review Article

Systematic Review of Radiation-Based Therapies for Hepatocellular Carcinoma

Namita E. Mathew

¹Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Mohammad Elsayed

²Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Nariman Nezami

²Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Bill S. Majdalany

²Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Ripal Gandhi

³Miami Cardiac and Vascular Institute, Miami, Florida

,

Michael Haber

⁴Department of Biostatistics and Bioinformatics, Emory Rollins School of Public Health, Atlanta, Georgia

,

Zachary L. Bercu

²Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Nima Kokabi

²Division of Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

› Author Affiliations

Abstract

Aim Despite the increasing trend to utilize radiation therapies for the treatment of hepatocellular carcinoma (HCC), there is limited analysis comparing treatment outcomes of various radiation-based therapies including selective internal radiation therapy (SIRT) to stereotactic body radiation therapy (SBRT) and proton beam therapy (PBT). This study aims to examine the heterogeneity of designs and outcomes in existing radiation therapy studies for the treatment of HCC.

Methods A systematic review was performed to compare the radiation therapies for HCC including SBRT, PBT, and yttrium-90 (Y90) SIRT by searching through PubMed, EMBASE, Medline, and Cochrane library databases. The main outcomes analyzed were overall survival rates, median overall survival, and progression-free survival with additional analysis of baseline patient characteristics, including Barcelona Clinic Liver Cancer stage, Child–Pugh class, and tumor size.

Results Eighty-seven studies comprising 7,462 patients were included. The pooled 1-year overall survival rates for the Y90 SIRT, SBRT, and PBT groups were 57.8, 83.1, and 78.7%, respectively. The rates of Barcelona Clinic Liver Cancer A, B, and C patients were 22.9, 32.2, and 42.5% in Y90 SIRT; 52.5, 20.2, and 25.1% in SBRT; and 36.3, 33.4, and 28.2% in PBT groups, respectively. The baseline intergroup differences were statistically significant (p < 0.0001). The median tumor sizes were 5.8, 3.1, and 4.5 cm in the Y90 SIRT, SBRT, and PBT groups, respectively.

Conclusion In the management of HCC, there is substantial heterogeneity in studies investigating Y90 SIRT, SBRT, and PBT, with Y90 SIRT patients having worse Barcelona Clinic Liver Cancer and tumor burden at baseline, which likely contributes to the observed lower survival outcome.

Keywords

HCC - radiation-based therapies - SIRT - SBRT - proton therapy

Full Text

References

References
1 Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology 2019; 156 (02) 477-491.e1
2 Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 2020; 72 (02) 250-261
3 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16 (10) 589-604
4 Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 2016; 150 (04) 835-853
5 Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (03) 329-338
6 Yu Y, Feng M. Radiotherapy for hepatocellular carcinoma. Semin Radiat Oncol 2018; 28 (04) 277-287
7 Eggert T, Greten TF. Current standard and future perspectives in non-surgical therapy for hepatocellular carcinoma. Digestion 2017; 96 (01) 1-4
8 Sangro B, Carpanese L, Cianni R. et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona Clinic Liver Cancer Stages: a European evaluation. Hepatology 2011; 54 (03) 868-878
9 Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology 2013; 58 (06) 2188-2197
10 Sanuki N, Takeda A, Kunieda E. Role of stereotactic body radiation therapy for hepatocellular carcinoma. World J Gastroenterol 2014; 20 (12) 3100-3111
11 Rim CH, Kim HJ, Seong J. Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: a systematic review and meta-analysis of observational studies. Radiother Oncol 2019; 131: 135-144
12 Qi W-X, Fu S, Zhang Q, Guo X-M. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 2015; 114 (03) 289-295
13 Han K, Kim JH. Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona Clinic Liver Cancer Staging System. World J Gastroenterol 2015; 21 (36) 10327-10335
14 Vilgrain V, Pereira H, Assenat E. et al; SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 2017; 18 (12) 1624-1636
15 Chow PKH, Gandhi M, Tan S-B. et al; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018; 36 (19) 1913-1921
16 Lewandowski RJ, Kulik LM, Riaz A. et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9 (08) 1920-1928
17 de la Torre MA, Buades-Mateu J, de la Rosa PA. et al. A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib. Liver Int 2016; 36 (08) 1206-1212
18 Gui B, Weiner AA, Nosher J. et al. Assessment of the albumin-bilirubin (ALBI) grade as a prognostic indicator for hepatocellular carcinoma patients treated with radioembolization. Am J Clin Oncol 2018; 41 (09) 861-866
19 Lance C, McLennan G, Obuchowski N. et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22 (12) 1697-1705
20 Golfieri R, Bilbao JI, Carpanese L. et al; European Network on Radioembolization with Yttrium-90 Microspheres (ENRY) study collaborators. Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma. J Hepatol 2013; 59 (04) 753-761
21 Kooby DA, Egnatashvili V, Srinivasan S. et al. Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2010; 21 (02) 224-230
22 Woo HY, Kim DY, Heo J. et al. Effect of yttrium-90 radioembolization on outcomes in Asian patients with early to advanced stage hepatocellular carcinoma. Hepatol Res 2017; 47 (05) 387-397
23 Moreno-Luna LE, Yang JD, Sanchez W. et al. Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol 2013; 36 (03) 714-723
24 El Fouly A, Ertle J, El Dorry A. et al. In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?. Liver Int 2015; 35 (02) 627-635
25 Salem R, Gabr A, Riaz A. et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 2018; 68 (04) 1429-1440
26 Pracht M, Edeline J, Lenoir L. et al. Lobar hepatocellular carcinoma with ipsilateral portal vein tumor thrombosis treated with yttrium-90 glass microsphere radioembolization: preliminary results. Int J Hepatol 2013; 2013: 827649
27 Kokabi N, Camacho JC, Xing M. et al. Open-label prospective study of the safety and efficacy of glass-based yttrium 90 radioembolization for infiltrative hepatocellular carcinoma with portal vein thrombosis. Cancer 2015; 121 (13) 2164-2174
28 Kolligs FT, Bilbao JI, Jakobs T. et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int 2015; 35 (06) 1715-1721
29 Xing M, Kokabi N, Camacho JC, Kim HS. Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization. BMC Cancer 2018; 18 (01) 75
30 Sangro B, Maini CL, Ettorre GM. et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies. Eur J Nucl Med Mol Imaging 2018; 45 (10) 1721-1730
31 Cho YY, Lee M, Kim H-C. et al. Radioembolization is a safe and effective treatment for hepatocellular carcinoma with portal vein thrombosis: a propensity score analysis. PLoS One 2016; 11 (05) e0154986
32 Gordon AC, Gabr A, Riaz A. et al. Radioembolization super survivors: extended survival in non-operative hepatocellular carcinoma. Cardiovasc Intervent Radiol 2018; 41 (10) 1557-1565
33 Iñarrairaegui M, Thurston KG, Bilbao JI. et al. Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2010; 21 (08) 1205-1212
34 Bhangoo MS, Karnani DR, Hein PN. et al. Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma. J Gastrointest Oncol 2015; 6 (05) 469-478
35 Kim DY, Park BJ, Kim YH. et al. Radioembolization with yttrium-90 resin microspheres in hepatocellular carcinoma: a multicenter prospective study. Am J Clin Oncol 2015; 38 (05) 495-501
36 Pitton MB, Kloeckner R, Ruckes C. et al. Randomized comparison of selective internal radiotherapy (SIRT) versus drug-eluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma. Cardiovasc Intervent Radiol 2015; 38 (02) 352-360
37 Padia SA, Johnson GE, Horton KJ. et al. Segmental yttrium-90 radioembolization versus segmental chemoembolization for localized hepatocellular carcinoma: results of a single-center, retrospective, propensity score-matched study. J Vasc Interv Radiol 2017; 28 (06) 777-785.e1
38 Mantry PS, Mehta A, Madani B, Mejia A, Shahin I. Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study. J Gastrointest Oncol 2017; 8 (05) 799-807
39 McDevitt JL, Alian A, Kapoor B. et al. Single-center comparison of overall survival and toxicities in patients with infiltrative hepatocellular carcinoma treated with yttrium-90 radioembolization or drug-eluting embolic transarterial chemoembolization. J Vasc Interv Radiol 2017; 28 (10) 1371-1377
40 She WH, Cheung TT, Yau TCC. et al. Survival analysis of transarterial radioembolization with yttrium-90 for hepatocellular carcinoma patients with HBV infection. Hepatobiliary Surg Nutr 2014; 3 (04) 185-193
41 Khor AY-K, Toh Y, Allen JC. et al. Survival and pattern of tumor progression with yttrium-90 microsphere radioembolization in predominantly hepatitis B Asian patients with hepatocellular carcinoma. Hepatol Int 2014; 8 (03) 395-404
42 Kwok PC-H, Leung KC, Cheung MT. et al. Survival benefit of radioembolization for inoperable hepatocellular carcinoma using yttrium-90 microspheres. J Gastroenterol Hepatol 2014; 29 (11) 1897-1904
43 Abdallah MA, Wongjarupong N, Hassan MA. et al. The efficacy, safety, and predictors of outcomes of transarterial radioembolization for hepatocellular carcinoma: a retrospective study. Expert Rev Gastroenterol Hepatol 2020; 14 (07) 619-629
44 Vouche M, Habib A, Ward TJ. et al. Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy. Hepatology 2014; 60 (01) 192-201
45 Salem R, Gordon AC, Mouli S. et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2016; 151 (06) 1155-1163.e2
46 Biederman DM, Titano JJ, Lee KM. et al. Yttrium-90 glass-based microsphere radioembolization in the treatment of hepatocellular carcinoma secondary to the hepatitis B virus: safety, efficacy, and survival. J Vasc Interv Radiol 2015; 26 (11) 1630-1638
47 Johnson GE, Monsky WL, Valji K, Hippe DS, Padia SA. Yttrium-90 radioembolization as a salvage treatment following chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2016; 27 (08) 1123-1129
48 Mazzaferro V, Sposito C, Bhoori S. et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 2013; 57 (05) 1826-1837
49 Saxena A, Meteling B, Kapoor J. et al. Yttrium-90 radioembolization is a safe and effective treatment for unresectable hepatocellular carcinoma: a single centre experience of 45 consecutive patients. Int J Surg 2014; 12 (12) 1403-1408
50 Meyer C, Pieper CC, Ahmadzadehfar H. et al. Yttrium-90 radioembolization of unresectable hepatocellular carcinoma - a single center experience. OncoTargets Ther 2017; 10: 4773-4785
51 Floridi C, Pesapane F, Angileri SA. et al. Yttrium-90 radioembolization treatment for unresectable hepatocellular carcinoma: a single-centre prognostic factors analysis. Med Oncol 2017; 34 (10) 174
52 Gramenzi A, Golfieri R, Mosconi C. et al; BLOG (Bologna Liver Oncology Group). Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver Int 2015; 35 (03) 1036-1047
53 Wahl DR, Stenmark MH, Tao Y. et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol 2016; 34 (05) 452-459
54 Paik EK, Kim M-S, Jang WI. et al. Benefits of stereotactic ablative radiotherapy combined with incomplete transcatheter arterial chemoembolization in hepatocellular carcinoma. Radiat Oncol 2016; 11 (01) 22
55 Que J, Kuo H-T, Lin L-C. et al. Clinical outcomes and prognostic factors of Cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma. BMC Cancer 2016; 16: 451
56 Park S, Jung J, Cho B. et al. Clinical outcomes of stereotactic body radiation therapy for small hepatocellular carcinoma. J Gastroenterol Hepatol 2020; 35 (11) 1953-1959
57 Shen P-C, Chang W-C, Lo C-H. et al. Comparison of stereotactic body radiation therapy and transarterial chemoembolization for unresectable medium-sized hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2019; 105 (02) 307-318
58 Yao E, Chen J, Zhao X. et al. Efficacy of stereotactic body radiotherapy for recurrent or residual hepatocellular carcinoma after transcatheter arterial chemoembolization. BioMed Res Int 2018; 2018: 5481909
59 Hasan S, Thai N, Uemura T. et al. Hepatocellular carcinoma with child Pugh-A cirrhosis treated with stereotactic body radiotherapy. World J Gastrointest Surg 2017; 9 (12) 256-263
60 Jang WI, Kim M-S, Bae SH. et al. High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. Radiat Oncol 2013; 8 (01) 250
61 Kwon JH, Bae SH, Kim JY. et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer 2010; 10: 475
62 Cárdenes HR, Price TR, Perkins SM. et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol 2010; 12 (03) 218-225
63 Kim JW, Kim DY, Han K-H, Seong J. Phase I/II trial of helical IMRT-based stereotactic body radiotherapy for hepatocellular carcinoma. Dig Liver Dis 2019; 51 (03) 445-451
64 Rajyaguru DJ, Borgert AJ, Smith AL. et al. Radiofrequency ablation versus stereotactic body radiotherapy for localized hepatocellular carcinoma in nonsurgically managed patients: analysis of the National Cancer Database. J Clin Oncol 2018; 36 (06) 600-608
65 Kim N, Kim HJ, Won JY. et al. Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma. Radiother Oncol 2019; 131: 81-87
66 Moore A, Cohen-Naftaly M, Tobar A. et al. Stereotactic body radiation therapy (SBRT) for definitive treatment and as a bridge to liver transplantation in early stage inoperable hepatocellular carcinoma. Radiat Oncol 2017; 12 (01) 163
67 Baumann BC, Wei J, Plastaras JP. et al. Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma: high rates of local control with low toxicity. Am J Clin Oncol 2018; 41 (11) 1118-1124
68 Huertas A, Baumann A-S, Saunier-Kubs F. et al. Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother Oncol 2015; 115 (02) 211-216
69 Sapir E, Tao Y, Schipper MJ. et al. Stereotactic body radiation therapy as an alternative to transarterial chemoembolization for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2018; 100 (01) 122-130
70 Yoon SM, Lim Y-S, Park MJ. et al. Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One 2013; 8 (11) e79854
71 Zhang T, Sun J, He W. et al. Stereotactic body radiation therapy as an effective and safe treatment for small hepatocellular carcinoma. BMC Cancer 2018; 18 (01) 451
72 Lazarev S, Hardy-Abeloos C, Factor O, Rosenzweig K, Buckstein M. Stereotactic body radiation therapy for centrally located hepatocellular carcinoma: outcomes and toxicities. J Cancer Res Clin Oncol 2018; 144 (10) 2077-2083
73 Wigg AJ, Narayana SK, Le H. et al. Stereotactic body radiation therapy for early hepatocellular carcinoma: a retrospective analysis of the South Australian experience. ANZ J Surg 2019; 89 (09) 1138-1143
74 Bibault J-E, Dewas S, Vautravers-Dewas C. et al. Stereotactic body radiation therapy for hepatocellular carcinoma: prognostic factors of local control, overall survival, and toxicity. PLoS One 2013; 8 (10) e77472
75 Kang J-K, Kim M-S, Cho CK. et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012; 118 (21) 5424-5431
76 Huang W-Y, Jen Y-M, Lee M-S. et al. Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012; 84 (02) 355-361
77 Su T-S, Liang P, Zhou Y. et al. Stereotactic body radiation therapy vs. transarterial chemoembolization in inoperable Barcelona Clinic Liver Cancer Stage a hepatocellular carcinoma: a retrospective, propensity-matched analysis. Front Oncol 2020; 10: 347
78 Sanuki N, Takeda A, Oku Y. et al. Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients. Acta Oncol 2014; 53 (03) 399-404
79 Scorsetti M, Comito T, Cozzi L. et al. The challenge of inoperable hepatocellular carcinoma (HCC): results of a single-institutional experience on stereotactic body radiation therapy (SBRT). J Cancer Res Clin Oncol 2015; 141 (07) 1301-1309
80 Tamura S, Okamura Y, Sugiura T. et al. A comparison of the outcomes between surgical resection and proton beam therapy for single primary hepatocellular carcinoma. Surg Today 2020; 50 (04) 369-378
81 Fukumitsu N, Sugahara S, Nakayama H. et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2009; 74 (03) 831-836
82 Oshiro Y, Mizumoto M, Okumura T. et al. Analysis of repeated proton beam therapy for patients with hepatocellular carcinoma. Radiother Oncol 2017; 123 (02) 240-245
83 Kimura K, Nakamura T, Ono T. et al. Clinical results of proton beam therapy for hepatocellular carcinoma over 5 cm. Hepatol Res 2017; 47 (13) 1368-1374
84 Kim TH, Park J-W, Kim BH. et al. Does risk-adapted proton beam therapy have a role as a complementary or alternative therapeutic option for hepatocellular carcinoma?. Cancers (Basel) 2019; 11 (02) E230
85 Kawashima M, Kohno R, Nakachi K. et al. Dose-volume histogram analysis of the safety of proton beam therapy for unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011; 79 (05) 1479-1486
86 Lee SU, Park J-W, Kim TH. et al. Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Strahlenther Onkol 2014; 190 (09) 806-814
87 Bush DA, Hillebrand DJ, Slater JM, Slater JD. High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial. Gastroenterology 2004; 127 (05) (Suppl. 01) S189-S193
88 Fukuda K, Okumura T, Abei M. et al. Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma. Cancer Sci 2017; 108 (03) 497-503
89 Kim TH, Park J-W, Kim BH. et al. Optimal time of tumour response evaluation and effectiveness of hypofractionated proton beam therapy for inoperable or recurrent hepatocellular carcinoma. Oncotarget 2017; 9 (03) 4034-4043
90 Kawashima M, Furuse J, Nishio T. et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005; 23 (09) 1839-1846
91 Hata M, Tokuuye K, Sugahara S. et al. Proton beam therapy for aged patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2007; 69 (03) 805-812
92 Nakayama H, Sugahara S, Tokita M. et al. Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer 2009; 115 (23) 5499-5506
93 Sekino Y, Okumura T, Fukumitsu N. et al. Proton beam therapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus. J Cancer Res Clin Oncol 2020; 146 (03) 711-720
94 Hata M, Tokuuye K, Sugahara S. et al. Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis. Strahlenther Onkol 2006; 182 (12) 713-720
95 Hata M, Tokuuye K, Sugahara S. et al. Proton beam therapy for hepatocellular carcinoma with limited treatment options. Cancer 2006; 107 (03) 591-598
96 Mizumoto M, Okumura T, Hashimoto T. et al. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int J Radiat Oncol Biol Phys 2011; 81 (04) 1039-1045
97 Chiba T, Tokuuye K, Matsuzaki Y. et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res 2005; 11 (10) 3799-3805
98 Sugahara S, Oshiro Y, Nakayama H. et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2010; 76 (02) 460-466
99 Chadha AS, Gunther JR, Hsieh C-E. et al. Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma. Radiother Oncol 2019; 133: 54-61
100 Bush DA, Smith JC, Slater JD. et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys 2016; 95 (01) 477-482
101 Hashimoto T, Tokuuye K, Fukumitsu N. et al. Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006; 65 (01) 196-202
102 Dai C-Y, Lin C-Y, Tsai P-C. et al. Impact of tumor size on the prognosis of hepatocellular carcinoma in patients who underwent liver resection. J Chin Med Assoc 2018; 81 (02) 155-163
103 Shinkawa H, Tanaka S, Takemura S, Ishihara T, Yamamoto K, Kubo S. Tumor size drives the prognosis after hepatic resection of solitary hepatocellular carcinoma without vascular invasion. J Gastrointest Surg 2020; 24 (05) 1040-1048