Leaflet manual of external beam radiation therapy for hepatocellular carcinoma: a review of the indications, evidences, and clinical trials

Figures & data

Figure 1 Numbers of published studies on radiotherapy for hepatocellular carcinoma over time. The counts were based on a search of the Scopus electronic database in March 2018 that was limited to original article. The search keywords included “hepatocellular carcinoma” AND “radiotherapy”.

Table 1 Current indications for use of EBRT for HCC and representative reference studies

Author	Treatment	Candidates	Study type	Number of patients/study	Treatment outcomes			Toxicity ≥ G3	Category of indication	Clinical experience	Evidence of literature
					Tumor response	Median OS	OS rates
Rim et al^Citation28	3DCRT	HCC with PVT	MA	1,903 22 studies	RR 51.3% (95% CI: 45.7–57.0)	mOS 11.6 mo.	1-year OS 43.5% (95% CI: 37.6–50.2)	Less than <10% in most of studies	EBRT to HCC with PVT	Abundant	Low to moderate
Rim et al^Citation31	EBRT	HCC with IVCT and/or RA	MA	164 8 studies	RR 59.2% (95% CI: 39.0–76.7)	mOS 13.2 mo.	1-year OS 53.6% (95% CI: 45.7–61.3)	2 cases among 164 (1.2%, 1 ER and 1 PE)	EBRT to HCC with IVCT and/or RA	Scarce, but currently no better option than EBRT	Low
Huo and Eslick^Citation35	Combined RT with TACE (TACE & RT vs TACE alone)	Unresectable HCC	MA	2,577 25 studies (11 RCTs)	Favors TACE and RT (complete response: OR 2.73, 95% CI: 1.95–3.81)	22.7 mo. (TACE & RT) 13.5 mo. (TACE alone)	Favors TACE plus RT (1-year OS, OR 1.36, 95% CI: 1.19–1.54; 2-year OS, OR 1.55, 95% CI: 1.31–1.85)	GU/DU higher in combined group (OR 12.80, 95% CI: 1.6–104.3)	Combined RT with TACE for unresectable HCC	Abundant	High
Yoon^Citation48	Combined RT with TACE (TACE & RT vs sorafenib)	HCC with major vascular invasion	RCT	90	Favors TACE and RT RR, 28.9% vs 4.7% (p<0.001)	Favors TACE plus RT 6-month PFS 65.8% vs 13.7% (p<0.001)
Lee et al^Citation37	Combined RT with HAIC	Unresectable HCC	RS	243		16.7% underwent curative resection after RT 5-year OS 49.6%			Combined RT with HAIC for unresectable HAIC	Scarce	Scarce
Byun et al^Citation38	Combined RT with HAIC	BCLC-C HCC	RS	637 (VI 73%, multiple tumors 35.3%)		Overall mOS: 15 mo. (>60 Gy vs <60 Gy, mOS 39 vs 14 mo. (p=0.001)		No GI toxicity ≥ G3
Bujold et al^Citation42	SBRT	Unsuitable for OP, TACE, RFA, PEI	PS	102 (PVT 55%, median TD 7.2 cm)	RR 54%, 1-year LC 87% (95% CI: 78–93)	mOS 17 mo.		23.5% of liver related toxicity	SBRT for HCC unsuitable for conventional local Tx	Moderate to abundant	Low to moderate
Lasley et al^Citation43	SBRT	HCC	PS	CPC-A: 33 CPC-B: 46	2-year LC: 91% (CPC-A) 82% (CPC-B)	mOS: 48 mo. (CPC-A) 17 mo. (CPC-B)	2-year OS: 72% (CPC-A) 33% (CPC-B)	Liver toxicity: 11% (CPC-A) 38% (CPC-B)
Scorsetti et al^Citation44	SBRT	Unresectable HCC	PS	43 (CPC-B 47%)	1-year LC: 85.8%	mOS: 18 mo.		Liver toxicity in 7 patients (16%); 5 of 7 was CPC-B
Qi et al^Citation46	SBRT	HCC	MA	1,473 30 cohorts	1-year LC: 87% (95% CI: 71–87)		1-year OS: 80% (95% CI: 71–87)	Acute: hepatic 4.9% (95% CI: 3.0–8.1), BM 4.9% (3.4–7.2), overall 9.6% (6.0–15.1) late: 6.4% (4.0–10.1)
Rim et al^Citation28	SBRT	HCC with PVT	MA	208 (7 cohorts)	RR 70.7% (95% CI: 63.7–76.8) LC 86.9% (95% CI: 81.0–91.2)	mOS: 14 mo. (range: 11–19)	1-year OS: 48.5% (95% CI: 39.4–57.8)	Less than <10% in most of studies

Abbreviations: 3DCRT, 3-dimensional conformal radiotherapy; BCLC, Barcelona Clinic of Liver Cancer; BM, bone marrow; CI, confidence interval; CPC, Child-Pugh Class; DU, duodenal ulcer; EBRT, external beam radiation therapy; ER, esophageal rupture; G3, grade 3; GI, gastrointestinal; GU, gastric ulcer; HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; IVCT, inferior vena cava thrombosis; LC, local control; MA, meta-analysis; mOS, median overall survival; OP, operation; OR, odds ratio; OS, overall survival; PE, pulmonary embolism; PEI, percutaneous ethanol injection; PFS, progression-free survival; PS, prospective study; PVT, portal vein thrombosis; RA, right atrium; RCTs, randomized controlled trials; RFA, radiofrequency ablation; RR, response rate; RS, retrospective study; RT, radiotherapy; SBRT, stereotactic body radiotherapy; TACE, transarterial chemoembolization; TD, tumor diameter; Tx, treatment; VI, vascular invasion.

Table 2 Ongoing randomized controlled trials of EBRT for HCC

Trial number	Country of primary facility	Control arm	EBRT arm	Target disease	Current status
NCT1901692	Korea	Sorafenib	TACE and EBRT	HCC with major vascular invasion	Completed
NCT2724475	China	Laser	3DCRT	Intermediate and advanced HCC	Completed
NCT2470533	Belgium	TACE	SBRT	HCC (BCLC A-B)	Recruiting
NCT2125396	China	TACE	EBRT	Postoperative HCC	Recruiting
NCT3338647	India	TACE	SBRT	Advanced HCC	Recruiting
NCT857805	USA	TACE	Proton	HCC not exceeding San Francisco criteria	Recruiting
NCT2182687	USA	TACE	SBRT	HCC within Milan criteria (bridging therapy)	Recruiting
NCT2323360	Italy	re-TACE	SBRT	Incomplete TACE of unresectable HCC	Recruiting
NCT3326375	Korea	re-TACE	SBRT	Incomplete TACE of HCC	Recruiting
NCT2921139	Taiwan	re-TACE	SBRT	HCC with incomplete response of TACE	Recruiting
NCT1141478	USA	Sorafenib	Sorafenib and proton RT	HCC exceeding San Francisco criteria	Recruiting
NCT1730937	USA	Sorafenib	Sorafenib and SBRT	Advanced, recurrent HCC	Recruiting
NCT1963429	Korea	RFA	Proton	Recurrent or residual small HCC	Recruiting
NCT2640924	Taiwan	RFA	Proton	Medium or large HCC	Recruiting
NCT3172559	Canada	None	SBRT	HCC ineligible to TACE	Recruiting
NCT2511522	Canada	Supportive care	Palliative EBRT	HCC or liver metastases	Recruiting
NCT3168152	USA	Microwave ablation	SBRT	Localized HCC	Recruiting
NCT2239900	USA	Ipilimumab	SBRT	Advanced solid tumors (liver and lung)	Recruiting
NCT557024	China	RFA	RFA and RT	HCC performed prior RFA	Unknown

Abbreviations: BCLC, Barcelona Clinic of Liver Cancer; EBRT, external beam radiation therapy; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; 3DCRT, 3-dimensional conformal radiotherapy; SBRT, stereotactic body radiotherapy; RFA, radiofrequency ablation; RT, radiotherapy.

Table S1 Search keywords and numbers of published studies relevant to the indications for external beam radiation therapy (EBRT) for hepatocellular carcinoma (HCC). Publication counts are based on a search limited to original articles in the Scopus database performed in March 2018

Category of indication	Search keywords	Number of published clinical articles	Year with ≥5 studies published annually
EBRT to HCC with portal vein thrombosis (PVT)	(radiotherapy OR “radiation therapy”) AND (“hepatocellular carcinoma” OR HCC) AND (“portal vein thrombosis” OR PVT OR PVTT)	217	2007
EBRT to HCC with inferior vena cava thrombosis and/or right atrium	(radiotherapy OR “radiation therapy” OR EBRT) AND (“hepatocellular carcinoma” OR HCC) AND (“inferior vena cava” OR IVCT OR IVCTT)	41	None
Combined radiotherapy (RT) with transarterial chemoembolization (TACE) for unresectable HCC	(radiotherapy OR “radiation therapy” OR EBRT) AND (“hepatocellular carcinoma” OR HCC) AND (“transarterial chemoembolization” OR TACE)	315	2004
Combined RT with hepatic arterial infusion chemotherapy (HAIC) for unresectable HCC	(radiotherapy OR “radiation therapy” OR EBRT) AND (“hepatocellular carcinoma” OR HCC) AND (“hepatic arterial infusion chemotherapy” OR HAIC)	31	2017
Stereotactic body radiotherapy (SBRT) for HCC unsuitable for conventional local treatment	(“stereotactic body radiotherapy” OR SBRT) AND (“hepatocellular carcinoma” OR HCC)	164	2012

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