Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: Diverse global viewpoints

Table 1 Categorization of evidences and recommendations of the clinical guidelines¹

Oxford system level of evidences2
1A	Systematic review of randomized clinical trials
1B	Individual RCTs with narrow confidence intervals
1C	All or none studies
2A	Systematic reviews of cohort studies
2B	Individual cohort study including low-quality RCTs
2C	Outcomes research; ecological studies
3A	Systematic review of case-control studies
3B	Individual case-control studies
4	Case series and poor-quality cohort and case-control studies
5	Expert opinion without explicit critical appraisal or descriptive epidemiology
GRADE system3
Quality of evidence criteria
High	(1) Further research is unlikely to change confidence in the estimate of the clinical effect.
Moderate	(2) Further research may change confidence in the estimate of the clinical effect.
Low	(3) Further research is very likely to impact confidence on the estimate of clinical effect.
Strength of recommendation criteria
Strong	(1) Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost.
Weak	(2) Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost, or resource consumption.
NCCN categories of evidence and consensuses4
Category 1	Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

¹Most clinical guidelines used their simplified adaptation of Oxford and GRADE system; above are selected examples.

²Data from clinical guidelines by Canadian Association for the Study of the Liver.

³Data from clinical guidelines by Korean Liver Cancer Study Group.

⁴Data from the NCCN formal website (Available from: https://www.nccn.org/professionals/physician_gls/categories_of_consensus.aspx). RCT: Randomized controlled trials; NCCN: National Comprehensive Cancer Network.

Table 2 Key information of major clinical guidelines

Affiliation	Country	Publication, year	Staging system	Evidence stratification	(Possible) RT indication for HCC	Radiation oncologist panelists	Practical contents of EBRT	Quote	Level of Recom-mendation
EASL	Multinational (Europe)	J Hepatol, 2018	BCLC	GRADE	Palliating PVT	No	None	Many series or some trials have reported efficacy and tolerability of EBRT, but no well-conducted prospective trial to consider EBRT as proven option	C2 (under investigation, no proven role for treating HCC)
					Combined use with TACE
					SBRT bridging LT
NCCN	United States	Own publication	Child-Pugh score, UNOS criteria	Own system	For unresectable HCC	Yes	Limited information on dose/fracti-onations of SBRT	Case series and single-arm studies demonstrate safety and efficacy of radiation therapy in selected cases	2A (LRT for unresectable HCC)
					Alternative to other LRT (e.g., TACE or RFA)
APASL	Multinational (Asia)	Liver cancer, 2015	Own system considering Child-Pugh score, resectability, macrovas-cular invasion, number and size of tumors	GRADE	For unresectable HCC	No	None	Even though strong evidence is lacking, RT may be one of the promising treatment options for HCC	None (HCC) C2 (bone metastasis)
					SBRT or proton therapy as alternatives to other LRT
					Charged particle RT for PVT
AASLD	United States	Hepatol, 2018	AJCC staging, Milan criteria	GRADE	For unresectable HCC	No	None	The results to date are encouraging but inadequate to make a recommen-dation	C1 (for inoperable HCCs)
					Combined use with TACE
CASL	Canada	Can J Gastroenterol Hepatol, 2015	BCLC	OXFORD	SBRT palliating PVT and bridging LT	Yes	None	Phase I and II trials have shown efficacy in achieving disease control; again, there has not been any direct comparison between radiotherapy and any other form of treatment	Evidence level 5
National Health & Family Planning Commission	China	Liver Cancer, 2018	Own system considering Child-Pugh score, extrahepatic metastases, tumor number and size, vessel invasion	OXFORD	Palliating vessel invasion or extrahepatic metastases bridging LT postoperative RT for close margin	Yes	Dose and fractionations, normal organ constraints, targeting, respiratory gating methods		Evidence level 3 for all indications
KLCSG	South Korea	Gut Liver, 2019	Modified UICC system	GRADE	Combined use with TACE palliating PVT palliating bone, brain, lung, lymphatic metastases	Yes	Dose and fractionations, normal organ constraints	EBRT for the treatment of HCC is commonly used for lesions that are surgically unresectable and not amenable to other local modalities	B2 (combined use with TACE, for PVT); B1 (palliating metastases)
NCC Singapore	Singapore	Liver Cancer, 2016	Own system using Child-Pugh score, Milan criteria, tumor size, vessel invasion	OXFORD	Alternative for cases neither suitable for LT or RFA (early HCC) cases with vascular invasion	Yes	None		Evidence level 1B (alternative for LT or RFA); 2A (vascular invasion)
LAASL	Multinational (Latin America)	Ann Hepatol, 2014	BCLC	Modified OXFORD and GRADE	Palliation of symptoms, mass effect, bone metastasis	No	None	Primary symptoms should be treated with less invasive alternatives… radiotherapy may be used on a case-by-case basis	1C (symptomatic palliation)
INASL	India	J Clin Exp Hepatol, 2014	BCLC	OXFORD	For some unresectable HCCs	No	None	EBRT is a promising tool for some unresectable HCC. EBRT alone or in combination with other modalities cannot be recom-mended outside of clinical trials	Evidence level 2B (for some unresectable HCCs), 5 (definitive use)
ESLC	Egypt	Own publication, 2011	BCLC, CLIP	None	Bone metastasis	N/A	None	Addition of EBRT is amenable in case of bone metastasis together with sorafenib	N/A

EBRT: External beam radiotherapy; EASL: European Association for the Study of the Liver; BCLC: Barcelona Clinic Liver Cancer; PVT: Portal vein thrombosis; TACE: Transarterial chemoembolization; SBRT: Stereotactic body radiotherapy; LT: Liver transplantation; NCCN: National Comprehensive Cancer Network; UNOS: United Network for Organ Sharing; HCC: Hepatocellular carcinoma; LRT: Locoregional treatment; RFA: Radiofrequency ablation; APASL: Asia-Pacific Association for the Study of the Liver; RT: Radiotherapy; AASLD: American Association for the Study of Liver Disease; AJCC: American Joint Committee on Cancer; CASL: Canadian Association for the Study of the Liver; KLCSG: Korea Liver Cancer Study Group; NCC: National Cancer Center; LAASL: Latin America Association for the Study of the Liver; INASL: Indian National Association for the Study of the Liver; ESLC: Egyptian Study of Liver Cancer; CLIP: Cancer of Liver Italian Program.