Background: Stereotactic body radiation therapy (SBRT) is an advanced technique of external beam radiation therapy that delivers large ablative doses of radiation. In the past decade, many cancer centers have adopted SBRT as one mode of radically treating small-sized hepatocellular carcinoma (HCC), based on encouraging clinical outcomes. SBRT thus seems reasonable as first-line treatment of inoperable HCC confined to the liver. However, most of the clinical studies to date have been retrospective in nature, with key issues still under investigation. Summary: The above-mentioned publications were subjected to scrutiny, fueling discussions at the 7th Asia-Pacific Primary Liver Cancer Expert (APPLE 2016) Meeting on various clinical variables, such as indications for SBRT, therapeutic outcomes, treatment-related toxicities, doses prescribed, and specific techniques. The consensus reached should be of interest to all professionals active in the treatment of HCC, especially radiation oncologists. Key Messages: SBRT is a safe and effective therapeutic option for patients with small-sized HCC, offering substantial local control, improved overall survival, and low toxicity.

Keywords:
Hepatocellular carcinoma, Stereotactic body radiation therapy, Survival, Radiation-induced liver disease
1.
Benedict SH, Yenice KM, Followill D, et al: Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys 2010;37:4078-4101.
2.
Han KH, Kudo M, Ye SL, et al: Asian consensus workshop report: expert consensus guideline for the management of intermediate and advanced hepatocellular carcinoma in Asia. Oncology 2011;81(suppl 1):158-164.
3.
Yau T, Tang VY, Yao TJ, et al: Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691-1700.e3.
4.
Yoon SM, Lim YS, Park MJ, et al: Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One 2013;8:e79854.
5.
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;53:399-404.
6.
Su TS, Liang P, Lu HZ, et al: Stereotactic body radiation therapy for small primary or recurrent hepatocellular carcinoma in 132 Chinese patients. J Surg Oncol 2016;113:181-187.
7.
Wahl DR, Stenmark MH, Tao Y, et al: Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol 2016;34:452-459.
8.
Huang WY, Jen YM, Lee MS, et al: Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012;84:355-361.
9.
Korean Liver Cancer Study Group (KLCSG); National Cancer Center, Korea (NCC): 2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015;9:267-317.
10.
de Lope CR, Tremosini S, Forner A, et al: Management of HCC. J Hepatol 2012;56(suppl 1):S75-S87.
11.
Katz AW, Chawla S, Qu ZH, et al: Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol Biol Phys 2012;83:895-900.
12.
O'Connor JK, Trotter J, Davis GL, et al: Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl 2012;18:949-954.
13.
Jang WI, Kim MS, 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;8:250.
14.
Bibault JE, 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:e77472.
15.
Sawrie SM, Fiveash JB, Caudell JJ: Stereotactic body radiation therapy for liver metastases and primary hepatocellular carcinoma: normal tissue tolerances and toxicity. Cancer Control 2010;17:111-119.
16.
Huertas A, Baumann AS, Saunier-Kubs F, et al: Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother Oncol 2015;115:211-216.
17.
Jacob R, Turley F, Redden DT, et al: Adjuvant stereotactic body radiotherapy following transarterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of ≥3 cm. HPB (Oxford) 2015;17:140-149.
18.
Honda Y, Kimura T, Aikata H, et al: Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma. J Gastroenterol Hepatol 2013;28:530-536.
19.
Paik EK, Kim MS, Jang WI, et al: Benefits of stereotactic ablative radiotherapy combined with incomplete transcatheter arterial chemoembolization in hepatocellular carcinoma. Radiat Oncol 2016;11:22.
20.
Brade AM, Ng S, Brierley J, et al: Phase 1 trial of sorafenib and stereotactic body radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2016;94:580-587.
21.
ICRU: Prescribing, recording and reporting photon beam therapy (supplement to ICRU Report No. 50). ICRU Report No. 62, 1999.
22.
Wang MH, Ji Y, Zeng ZC, et al: Impact factors for microinvasion in patients with hepatocellular carcinoma: possible application to the definition of clinical tumor volume. Int J Radiat Oncol Biol Phys 2010;76:467-476.
23.
Hansen AT, Petersen JB, Høyer M: Internal movement, set-up accuracy and margins for stereotactic body radiotherapy using a stereotactic body frame. Acta Oncol 2006;45:948-952.
24.
Case RB, Sonke JJ, Moseley DJ, et al: Inter- and intrafraction variability in liver position in non-breath-hold stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2009;75:302-308.
25.
Eccles C, Brock KK, Bissonnette JP, et al: Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy. Int J Radiat Oncol Biol Phys 2006;64:751-759.
26.
Heinzerling JH, Anderson JF, Papiez L, et al: Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver. Int J Radiat Oncol Biol Phys 2008;70:1571-1578.
27.
Hu Y, Zhou YK, Zeng ZC, et al: 4D-CT scans reveal reduced magnitude of respiratory liver motion achieved by different abdominal compression plate positions in patients with intrahepatic tumors undergoing helical tomotherapy. Med Phys 2016;43:4335.
28.
Eccles CL, Dawson LA, Moseley JL, et al: Interfraction liver shape variability and impact on GTV position during liver stereotactic radiotherapy using abdominal compression. Int J Radiat Oncol Biol Phys 2011;80:938-946.
29.
Brock KK: Imaging and image-guided radiation therapy in liver cancer. Semin Radiat Oncol 2011;21:247-255.
30.
Sothmann T, Blanck O, Poels K, et al: Real time tracking in liver SBRT: comparison of CyberKnife and Vero by planning structure-based γ-evaluation and dose-area-histograms. Phys Med Biol 2016;61:1677-1691.
31.
Wunderink W, Méndez Romero A, Seppenwoolde Y, et al: Potentials and limitations of guiding liver stereotactic body radiation therapy set-up on liver-implanted fiducial markers. Int J Radiat Oncol Biol Phys 2010;77:1573-1583.
32.
Heinz C, Gerum S, Freislederer P, et al: Feasibility study on image guided patient positioning for stereotactic body radiation therapy of liver malignancies guided by liver motion. Radiat Oncol 2016;11:88.
33.
Kitamura K, Shirato H, Shimizu S, et al: Registration accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-tracking radiation therapy (RTRT). Radiother Oncol 2002;62:275-281.
34.
Wang PM, Hsu WC, Chung NN, et al: Feasibility of stereotactic body radiation therapy with volumetric modulated arc therapy and high intensity photon beams for hepatocellular carcinoma patients. Radiat Oncol 2014;9:18.
35.
Liu R, Buatti JM, Howes TL, et al: Optimal number of beams for stereotactic body radiotherapy of lung and liver lesions. Int J Radiat Oncol Biol Phys 2006;66:906-912.
36.
Paddick I, Lippitz B: A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 2006;105(suppl):194-201.
37.
Price TR, Perkins SM, Sandrasegaran K, et al: Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer 2012;118:3191-3198.
38.
Sanuki N, Takeda A, Mizuno T, et al: Tumor response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis. AJR Am J Roentgenol 2013;201:W812-W820.
39.
Sanuki-Fujimoto N, Takeda A, Ohashi T, et al: CT evaluations of focal liver reactions following stereotactic body radiotherapy for small hepatocellular carcinoma with cirrhosis: relationship between imaging appearance and baseline liver function. Br J Radiol 2010;83:1063-1071.
40.
Kimura T, Takahashi S, Takahashi I, et al: The time course of dynamic computed tomographic appearance of radiation injury to the cirrhotic liver following stereotactic body radiation therapy for hepatocellular carcinoma. PLoS One 2015;10:e0125231.
41.
Park MJ, Kim SY, Yoon SM, et al: Stereotactic body radiotherapy-induced arterial hypervascularity of non-tumorous hepatic parenchyma in patients with hepatocellular carcinoma: potential pitfalls in tumor response evaluation on multiphase computed tomography. PLoS One 2014;9:e90327.
42.
Sanuki N, Takeda A, Oku Y, et al: Threshold doses for focal liver reaction after stereotactic ablative body radiation therapy for small hepatocellular carcinoma depend on liver function: evaluation on magnetic resonance imaging with Gd-EOB-DTPA. Int J Radiat Oncol Biol Phys 2014;88:306-311.
43.
Takeda A, Oku Y, Sanuki N, et al: Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma. Radiother Oncol 2012;104:374-378.
44.
Jung J, Yoon SM, Cho B, et al: Hepatic reaction dose for parenchymal changes on Gd-EOB-DTPA-enhanced magnetic resonance images after stereotactic body radiation therapy for hepatocellular carcinoma. J Med Imaging Radiat Oncol 2016;60:96-101.
45.
Yamashita H, Onishi H, Matsumoto Y, et al: Local effect of stereotactic body radiotherapy for primary and metastatic liver tumors in 130 Japanese patients. Radiat Oncol 2014;9:112.
46.
Lo CH, Huang WY, Lee MS, et al: Stereotactic ablative radiotherapy for unresectable hepatocellular carcinoma patients who failed or were unsuitable for transarterial chemoembolization. Eur J Gastroenterol Hepatol 2014;26:345-352.
47.
Takeda A, Sanuki N, Eriguchi T, et al: Stereotactic ablative body radiotherapy for previously untreated solitary hepatocellular carcinoma. J Gastroenterol Hepatol 2014;29:372-379.
48.
Park JH, Yoon SM, Lim YS, et al: Two-week schedule of hypofractionated radiotherapy as a local salvage treatment for small hepatocellular carcinoma. J Gastroenterol Hepatol 2013;28:1638-1642.
49.
Bujold A, Massey CA, Kim JJ, et al: Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013;31:1631-1639.
50.
Ibarra RA, Rojas D, Snyder L, et al: Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta Oncol 2012;51:575-583.
51.
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.
52.
Huang J, Yan L, Cheng Z, et al: A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010;252:903-912.
53.
Feng K, Yan J, Li X, et al: A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol 2012;57:794-802.
54.
Guro H, Cho JY, Han HS, et al: Current status of laparoscopic liver resection for hepatocellular carcinoma. Clin Mol Hepatol 2016;22:212-218.
55.
Lee DH, Lee JM, Lee JY, et al: Radiofrequency ablation of hepatocellular carcinoma as first-line treatment: long-term results and prognostic factors in 162 patients with cirrhosis. Radiology 2014;270:900-909.
56.
Culleton S, Jiang H, Haddad CR, et al: Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma. Radiother Oncol 2014;111:412-417.
57.
Jung J, Yoon SM, Kim SY, et al: Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma: clinical and dose-volumetric parameters. Radiat Oncol 2013;8:249.
58.
Andolino DL, Johnson CS, Maluccio M, et al: Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011:81:e447-e453.
59.
Mazzaferro V, Bhoori S, Sposito C, et al: Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17(suppl 2):S44-S57.
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