Stereotactic body radiation therapy for early-stage hepatocellular carcinoma – a systematic review on outcome

Figures & data

Figure 1. PRISMA flowchart.

Table 1. PICO eligibility criteria.

PICO	Description
Patients	Patients with small HCC (biggest reported median diameter <5 cm), single or multiple lesions
Intervention	SBRT for small HCC
Comparisons	no intervention OR TA OR TACE OR others
Outcomes	Local control, overall survival, toxicity

Table 2. Characteristics of the included studies.

Author, year of publication, time of study, design	No of patients (no of lesions)	Median age (years) (range)	Male (%)	No of patients (%) ECOG 0 and 1	Tumor size (median, range)	BCLC 0 and A no of patients (%)	CPS class A number of patients (%)	Dose [Gy]/ number of fractions (median dose per fraction^1)	LC (%)	OS (%)	Freedom from liver progression (%)	Distant metastasis-free survival rate	Median follow up (months) (range)
Jeong Y [20], 2018, 2012–2013, retrospective	119 (139)	60 (36–90)	97 (81.5)	0–102 (85.7) 1–13 (10.9)	1.7	Modified UICC stage I 60 (50.4)	108 (90.8)	30–60/3–6 (15)	1 yr–99 3 yr–97	1 yr–99 3 yr–84	1 yr–62 3 yr–33	1 yr–95 3 yr–78	25.8 (3.2–36.8)
Baumann [21], 2018, 2012– 2016, retrospective	37 (43)	65 (44–88)	31 (84)	0–20 (54) 1–14 (38)	2.7 (1.1–5.6)	0–2 (5) A–10 (27)	A 26 (70)	50/5 (10)	1 yr–95^2	1 yr–87^3	1 yr–66^4	1 yr–95^5	14 (2–45)
Hasan [22], 2017, 2009 –2016, retrospective	40 (49)	NR	32 (82)	0–21 (55) 1–14 (37)	3.5 (1.5–8.9)	0–6 (15) A–10 (25)	NR	40–50/4–5 (9)	1 yr–92 2 yr–69	1 yr–92 2 yr–60	NR	NR^6	24 (4–64)
Moore [23], 2017, 2001–2016, retrospective	23 (23)	62.2 (43–83.9)	16 (70)	NR	2.5 (1.0–4.8)	A–23 (100)	13 (56.5)	30/5 48/4 54/3	NR	34.2 months (2.0–53.7)^7	1 yr–100^8	NR	12 (2–48.7)
Hanazawa [24], 2017, 2012–2015, retrospective	17 (17)	77 (63–85)	13 (76.5)	0–10 (58.8) 1–6 (35.3).	2.2	NR	9 (52.9)	45–50/5–10 (10)	1 yr–100	1 yr–82	1 yr–53	NR	16
Kim [13], 2016, 2012–2014, prospective	18 (22)	59.5 (42–83)	14 (77.8)	NR	1.95 (1.0–3.3)	NR	17 (94.4)	52/4 (13)	1 yr–78 2 yr–71	1 yr–94 2 yr–69	1 yr–61 2 yr–61^9	1 yr–89 2 yr–83	23 (11–38)
Takeda [14], 2016, 2007–2012, prospective	90 (90)	73 (48–85) 58	58 (64)	0–85 (94)	2.3 (1.0–4.0)	0–31 (34) A–45 (50)	61 (68)	35/5 40/5	3 yr–96	3 yr–67	3 yr–34	NR	41.7 (6.8–96.2)
Shiozawa [25], 2015, 2011–2014, retrospective	35 (35)	75.1 (8.1)	24 (68.5)	NR	2.86 ± 1.15	NR	28 (80)	60/3–5	1 yr–97	1 yr–95	1 yr–86	NR	12.6 (6.7–35.5)
Wahl [26], 2016, 2004–2012, retrospective	63 (83)	62 (35–85)	54 (85.7)	NR	2.2 (0–10)	NR	57 (69.7)	30–50/3–5	NR	1 yr–74 2 yr–46	1 yr–97 2 yr–84	NR	NR
Huertas [27], 2015, 2007–2013, retrospective	77 (97)	71 (44–91)	58 (75.3)	0–29 (37.7) 1–41 (53.2)	2.4 (0.7–6.3)	A–35 (45.5)	66 (85.7)	45/3	1 yr–99 2 yr–99	1 yr–82 2 yr–57	1 yr–69 2 yr–44	NR	12
Kimura [28], 2015, 2008–2013, retrospective	65 (74)	73 (49–90)	44 (67.6)	NR	1.6 (0. 5–5.4)	0–37 A–28	56 (86.1)	48/4 (12)	1 yr–100 2 yr–100	1 yr–92 2 yr–76	1 yr–64 2 yr–40	NR	26
Yoon [29], 2013, 2007–2009, retrospective	93 (103)	61 (42–86)	75 (80.6)	NR	2 (1–6)	NR	69 (74.2)	30–60/3–6	3 yr–76^10 93^11 100^12	1 yr–86 3 yr–54	1 yr–52 3 yr–32	1 yr–88 3 yr–72	25.6 (1.8–55.4)
Sanuki N [30], 2014, 2005–2012, retrospective	185 (185)	73 (40–86)	131	NR	2.7 (1–5)	TNM	158	40/5 35/5	1 yr–99 2 yr–93 3 yr–91	1 yr–95 2 yr–83 3 yr–70	3 yr–36	NR	31 (3–80) 23 (3–78)
Takeda, 2014 [31], 2005–2012, retrospective	63 (63)	74 (50–85)	36	NR	2.6 (1.0–5.0)	0–12 A–31	44 (69.8)	35/5 40 /5	1 yr–100 2 yr–95 3 yr–92	1 yr–100 2 yr–87 3 yr–73	1 yr–76 2 yr–55 3 yr–36	NR	31.1 (12–88.1)
Park JH [32], 2013, 2008–2011, retrospective	26 (28)	60 (42–88)	16 (61.5)	22 (84.6)	2.8 (1.1–5.7)	NR	19 (73)	40–50/10 (4–5)	2 yr–88	1 yr–89 2 yr–67	2 yr–37	2 yr–68	20.2 (7.5–36.8)
Choi [33], 2008, 2004–2005, retrospective	22 (23)	60 (44–78)	14 (63.6)	18 (81.8)	2.3 (3.6–5.7)	NR	19 (86.3)	30–39 /3	NR	1 yr–88	NR	NR	11.5 (2–18.5)

LC: local control; OS: overall survival.

¹If reported.

²For solitary lesion 1-year LC was 100%.

³For solitary lesion 1-year OS was 93%.

⁴For solitary lesions 76%.

⁵1-year distant metastasis free survival was 100% for solitary lesions.

⁶They reported 6 patients with distant metastasis.

⁷The authors reported only median survival in months.

⁸The authors did not report any intrahepatic recurrence in 54 months follow up.

⁹Progression free survival was reported: 1 year – 55.6%, 2 year – 49.4%.

¹⁰For lesions > 30 mm.

¹¹For lesions 21–30 mm.

¹²For lesions <20 mm.

Figure 2. Left panel: relationship between 1-year and 2-year LC and tumor diameter. Right panel: relationship between 1-year and 2-year OS and tumor diameter. Also compare with Supplement Figures. Note that y-axis is zoomed in to for better visualization (40–100%).

Figure 3. Left panel: relationship between BED10 and 1-year and 2-year. Right panel: relationship between BED10 and 1-year and 2-year. Note that y-axis is zoomed in to for better visualization (40–100%).

Table 3. Treatment-related toxicities.

Author	Hepatic toxicity number of patients (%)	Gastrointestinal toxicity number of patients (%)	Other toxicity number of patients (%)
Jeong, 2018	Elevated transaminases or bilirubin G1 ≥ 10 (8.4)	NR	NR
	Worsening of Child-Pugh score ≥2 with the elevation  transaminases or bilirubin G1–2 (1.7), G2–4 (3.4), G3–1 (1.7)
Baumann 2018	Liver capsular pain G3–1 (2.7)  Elevated transaminases G3–1 (2.7)  Ascites–2 (5.4)	Gastric bleeding G 3–1 (2.7)	NR
Hasan, 2017	Elevated transaminases G1–9 (22.5)  Elevated alkaline phosphatase G2–1 (2.5)	0	Fatigue G2–3 (7.5)
Moore, 2017	0	Abdominal discomfort G1–2 (8.7)	Weakness and fatigue G1–2 (8.7)
Hanazawa, 2017	Elevated transaminases (temporary) G3–1 (5.9)^1	duodenal ulcer G2–1 (5.9)	NR
Kim, 2016	Hyperbilirubinemia G2–1 (5.6)	0	Leukocytopenia G3–2 (11.1)  Thrombocytopenia G3–5 (27.8)  Hematologic events G1–1 (5.6), G2–6 (33.3) Radiation pneumonitis G2–1 (5.6)
Tekeda, 2016	Elevated transaminases G3–2 (2.2)  Worsening of Child-Pugh score ≥ 2 points G3–8 (8.9)	0	Thrombocytopenia  G3–5 (5.6)
Shiozawa, 2015	Ascites 4 (11.4)	0	0
Wahl, 2016	Chronic biliary toxicity G3–2 (3.2)  Worsening ascites–1 (1.6)	Gastrointestinal bleeding–1 (1.6)  Chronic luminal gastrointestinal toxicity G3–2 (3.2)	0
Huertas, 2015	Ascites G1–2 (2.6), G2–2 (2.6), G3–1 (1.3)  Chronic ascites–8 (10.4)	Anorexia G1–1 (1.3)  Nausea G1–2 (2.6)  Epigastric pain G1–3 (3.9)  Hematemesis G5–1 (1.3)  Chronic gastric ulcer G3–1(1.3), G4–1 (1.3)	Asthenia G1–1 (1.3), G2–1 (1.3)  Rib pain G1–1 (1.3)
Kimura, 2015	Elevated bilirubin–2 (3)  Elevated AST/ALT–2 (3)  Ascites–4 (6.2)		Thrombocytopenia-10 (15.4)
Yoon, 2013	Hepatic toxicity- 6 (6.5)   Elevation in the Child-Pugh score to > 2–9 (9.7)  Chronic biliary stricture–1 (1.1)	0	Rib fracture–2 (2.2)
Sanuki, 2014	Elevated transaminases–6 (3.2)  Chronic hepatic toxicity G5–2 (1.1)	0	Fatigue–9 (4.8)
Takeda, 2014	Elevated transaminases or bilirubin G3 -acute–10 (15.9), subacute–9 (14.3), chronic–13 (20.6)	0	Ascites–1 (1.6)
Park, 2013	Hepatic toxicity G3–1 (3.8)  Elevation in the Child–Pugh >2: 1 (3.8)	0	Rib fracture–1 (3.8)^2
Choi, 2008	Elevated transaminases G1–7 (32), G3–1 (4.5)  Elevated bilirubin G1–4 (18)  Hypoalbuminemia G1–3 (13.6)	Nausea G1–10 (45.5), G2–1 (4.5)	Leukocytopenia G1–5 (22.7)  Thrombocytopenia  G1–3 (13.6)

Shiba S, Abe T, Shibuya K, et al. Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. BMC Cancer. 2017;17:721.

 PubMed Web of Science ®Google Scholar

Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.

 PubMed Web of Science ®Google Scholar

Tirkes T, Hollar MA, Tann Dom,   et al. RECIST mRECIST Choi and PERSIST criteria for tumour assessment. 2013.

 Google Scholar

Park J, Yoon SM, Lim S, et al. Two-week schedule of hypofractionated radiotherapy as a local salvage treatment for small hepatocellular carcinoma. J Gastroenterol Hepatol. 2013;28:1638–1642.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Ohri N, Dawson L, Krishnan S, et al. Radiotherapy for hepatocellular carcinoma: new indications and directions for future study. J Natl Cancer Inst. 2016;108:djw133.

 PubMedGoogle Scholar

Kim J, Seong J, Lee I, et al. Phase I dose-escalation study of helical intensity-modulated radiotherapy-based stereotactic body radiotherapy for hepatocellular carcinoma. Oncotarget. 2016;7:40756–40766.

 PubMedGoogle Scholar

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.

 PubMed Web of Science ®Google Scholar

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;12:4–11.

 PubMed Web of Science ®Google Scholar

Jeong Y, Cho B, Park JH, et al. Stereotactic body radiation therapy using respiratory-gated volumetric-modulated arc therapy technique for small hepatocellular carcinoma. Liver Cancer. 2018;4:201.

 Google Scholar

Shiozawa K, Watanabe M, Ikehara T, et al. Comparison of percutaneous radiofrequency ablation and CyberKnife ® for initial solitary hepatocellular carcinoma: a pilot study. WJG. 2015;21:13490.

 PubMed Web of Science ®Google Scholar

Kimura T, Aikata H, Takahashi S, et al. Stereotactic body radiotherapy for patients with small hepatocellular carcinoma ineligible for resection or ablation therapies. Hepatol Res. 2015;45:378–386.

 PubMed Web of Science ®Google Scholar

Hasan S, Thai N, Uemura T, et al. Hepatocellular carcinoma with child Pugh-A Cirrhosis treated with stereotactic body radiotherapy. WJGS. 2017;9:256–263.

 Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Zeng ZC, Seong J, Yoon SM, et al. Consensus on stereotactic body radiation therapy for small-sized hepatocellular carcinoma at the 7th Asia-Pacific Primary Liver Cancer Expert Meeting. Liver Cancer. 2017;6:264–274.

 PubMed Web of Science ®Google Scholar

Garancini M, Nespoli S, Romano F, et al. Surgical management of hepatocellular carcinoma within and beyond BCLC indications in a middle volume center. J Visc Surg. 2018;155:275–282.

 PubMed Web of Science ®Google Scholar