Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma

Table 1 Proposed evidences and recommendations from international guidelines

Guidelines	Hepatic resection	Radiofrequency ablation
EASL	Resection is the first-line treatment option for patients with solitary tumors and very well-preserved liver function, defined as normal bilirubin with either hepatic venous pressure gradient ≤ 10 mmHg or platelet count ≥ 100000 (evidence 2A; recommendation 1B)	Local ablation with radiofrequency or percutaneous ethanol injection is considered the standard of care for patients with BCLC 0-A tumors not suitable for surgery (evidence 2A; recommendation 1B)
EORTC[9]	Additional indications for patients with multifocal tumors meeting Milan criteria ( ≤ 3 nodules ≤ 3 cm) or with mild portal hypertension not suitable for liver transplantation require prospective comparisons with loco-regional treatments. (evidence 3A; recommendation 2C)	In tumors < 2 cm, BCLC 0, Ethanol injection and radio-frequency ablation achieve complete responses in more than 90% of cases with good long-term outcome [evidence 1(i)A; recommendation 1C]
AASLD[10]	Patients who have a single lesion can be offered surgical resection if they are non-cirrhotic or have cirrhosis but still have well preserved liver function, normal bilirubin and hepatic vein pressure gradient < 10 mmHg (recommendation 2)	Local ablation is safe and effective therapy for patients who cannot undergo resection, or as a bridge to transplantation (recommendation 2); Alcohol injection and radiofrequency are equally effective for tumors < 2 cm. However, the necrotic effect of radiofrequency ablation is more predictable in all tumor sizes and its efficacy is clearly superior to that of alcohol injection in larger tumors (recommendation 1)
APASL[11]	Liver resection is a first-line curative treatment of solitary or multifocal HCC confined to the liver, anatomically resectable, and with satisfactory liver function reserve (evidence 2B, recommendation B)	Local ablation is an acceptable alternative to resection for small HCC (< 3 cm) in Child-Pugh A cirrhosis (evidence 2B, recommendation B); Local ablation is a first-line treatment of unresectable, small HCC with 3 or fewer nodules in Child-Pugh A or B cirrhosis (evidence 2B, recommendation B)

Strength of evidence according to study design: Level 1, Randomized controlled clinical trials or meta-analyses of randomized studies; Level 2, Non-randomized controlled clinical trials; Level 3, Case series. Strength of evidence according to end-points: A, Total mortality; B, Cause-specific mortality; C, Carefully assessed quality of life; D, Indirect surrogates. Grading of recommendation: 1, Strong recommendation warranted; 2, Weaker recommendation. Grading of recommendation: A, Further research is very unlikely to change out confidence in the estimate of effect; B, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; C, Further research is very likely to have an important impact on our confidence in the estimate of effect. BCLC: Barcelona Clinic Liver Cancer; HCC: Hepatocellular carcinoma; EASL: European Association for the Study of the Liver; EORTC: European Organisation For Research And Treatment Of Cancer; AASLD: American Association for the Study of Liver Diseases; APASL: Asian Pacific Association for the Study of the Liver.

Table 2 Summary of published articles that directly compared hepatic resection and radio-frequency ablation identified through literature search

Ref.	Study period	Type of study	NOS
Feng et al[35]	2005-2008	RCT	-
Peng et al[36]	2003-2008	Retrospective	7
Wang et al[37]	2002-2009	Retrospective	6
Ruzzenente et al[47]	1995-2009	Retrospective	8
Nishikawa et al[42]	2004-2010	Retrospective	7
Hung et al[38]	2002-2007	Retrospective	7
Takayama et al[39]	2000-2003	Retrospective	5
Huang et al[34]	2003-2005	RCT	-
Ueno et al[41]	2000-2005	Retrospective	7
Abu-Hilal et al[48]	1991-2003	Retrospective	8
Guglielmi et al[43]	1996-2006	Retrospective	7
Hiraoka et al[40]	2000-2007	Retrospective	7
Hasegawa et al[46]	2000-2003	Survey	6
Lupo et al[45]	1999-2006	Retrospective	8
Chen et al[33]	1999-2004	RCT	-
Ogihara et al[49]	1995-2003	Retrospective	7
Montorsi et al[50]	1997-2003	Retrospective	6
Hong et al[51]	1999-2001	Retrospective	6
Vivarelli et al[44]	1998-2002	Retrospective	5

The Newcastle-Ottawa Score (NOS) scale can range from 5 to 9. RCT: Randomized controlled trials.

Table 3 Characteristics of randomized controlled studies that compared hepatic resection vs radiofrequency ablation

Ref.	Liver function	Tumor features	Treatment	Study characteristics and main findings
Chen et al[33]	Child-Pugh class AICG-R15 < 30%PLT > 40000/mm3	Single < 5 cm	HR: 90RFA: 71	21% of patients randomized to RFA withdrew their consent. The 1-, 3-, and 4-year overall survival rates after RFA and surgery were 95.8%, 71.4%, 67.9% and 93.3%, 73.4%, 64.0%, respectively. The corresponding DFS rates were 85.9%, 64.1%, 46.4% and 86.6%, 69%, 51.6%, respectively. Statistically, there was no difference. The 5-year rates were not reported
		Single tumor ≤ 3 cm	HR: 42RFA: 37	Authors stated that patient survival and DFS did not change in tumors < 3 cm but survival rates and P-values were not provided (only Kaplan-Meier curves were reported)
		Single 3.1-5.0 cm	HR: 48RFA: 34	Authors stated that patient survival and DFS did not change in tumors between 3.1 and 5.0 cm but survival rates and P-values were not provided (only Kaplan-Meier curves were reported)
Huang et al[34]	Child-Pugh class A/BICG-R15 < 20%PLT > 50000/mm3	Single ≤ 5 cm or up to 3 nodules < 3 cm	HR: 115RFA: 115	Despite randomization, RFA patients had higher prevalence of nodules ≤ 3 cm (P = 0.021). The 3- and 5-year survival rates for the RFA group and the HR group were 69.6%, 54.8% and 92.2%, 75.7%, respectively (P = 0.001). The corresponding RFS rates were 46.1%, 28.7% and 60.9%, 51.3%, respectively (P = 0.017)
		Single tumor ≤ 3 cm	HR: 45RFA: 57	The 3- and 5-year survival rates for the RFA group and the HR group were 77.2%, 61.4% and 95.6%, 82.2%, respectively (P = 0.030). Neither DFS nor RFS for this subgroup were provided
		Single 3.1-5.0 cm	HR: 44RFA: 27	The 3- and 5-year survival rates for the RFA group and the HR group were 66.7%, 51.5% and 95.5%, 72.3%, respectively (P = 0.046). Neither DFS nor RFS for this subgroup were provided
		Multifocal < 3 cm	HR: 26RFA: 31	The 3- and 5-year survival rates for the RFA group and the HR group were 58.1%, 45.2% and 80.8%, 69.2%, respectively (P = 0.042). Neither DFS nor RFS for this subgroup were provided
Feng et al[35]	Child-Pugh class A/BICG-R15 < 30%PLT > 50000/mm3	Up to 2 nodules < 4 cm	HR: 84RFA: 84	The 1- and 3-year survival rates for HR and RFA groups were 96.0%, 74.8% and 93.1%, 67.2%, respectively (P = 0.342). The corresponding RFS rates were 90.6%, 61.1% and 86.2%, 49.6%, respectively (P = 0.122). Results at 5-year not reported (or not reached). On the basis of this lack of evidence, the authors did not include treatment as a variable in multivariate analysis

Other inclusion criteria common to all randomized controlled trials (RCTs): no radiological evidence of invasion into the portal/hepatic vein branches, no extra-hepatic metastases, no previous treatment of hepatocellular carcinoma (HCC), patient should be suitable to be treated by surgical resection and radiofrequency ablation. HR: Hepatic resection; RFA: Radiofrequency ablation; DFS: Disease-free survival; PLT: Platelet.

Table 4 Characteristics of observational studies that compared hepatic resection vs radiofrequency ablation

Ref.	Liver function	Tumor features	Treatment	Study characteristics and main findings
Peng et al[36]	Child-Pugh class A	Single tumor ≤ 2 cm	HR: 74RFA: 71	RFA patients showed lower prothrombin activity (P = 0.001) and lower platelet count (P = 0.010). Other features were similar between the two groups
				The 3-, and 5-year survival rates were 87.7% and 71.9%, respectively, after RFA and 70.9% and 62.1% after HR (P = 0.048). The corresponding RFS rates were 65.2% and 59.8% with RFA and 56.1%, and 51.3% after HR (P = 0.548)
Wang et al[37]	Child-Pugh class A and B	BCLC early stage	HR: 208RFA: 254	Patient characteristics were considerably different between the two treatments. RFA patients were significantly older, anti-HCV+, in Child-Pugh class B, with lower platelet count, with smaller and multifocal tumors than HR patients (P = 0.001 in all cases)
				The 3- and 5-year survival rates were 87.8% and 77.2% for HR, and 73.5% and 57.4% for RFA (P = 0.001). The 3- and 5-year DFS rates were 59.9% and 50.8% for HR and 28.3% and 14.1% for RFA, respectively (P < 0.001)
		BCLC early stage after PS match	HR: 208RFA: 208	Patient characteristics were different between the two treatment arms. RFA patients were significantly older, anti-HCV+, in Child-Pugh class B, with lower platelet count, with smaller and multifocal tumors than HR patients (P = 0.001 in all cases). Patient and DFS rates not provided for this subgroup
		Single tumor < 2 cm	HR: 52RFA: 91	Patient characteristics were different between the two treatment arms. RFA patients were significantly older, anti-HCV+, with lower platelet count than HR patients (P < 0.050). No Child-Pugh stratification was provided
				The 3- and 5-year survival rates were 98% and 91.5% for HR, and 80.3% and 72% for RFA (P = 0.073). The 3- and 5-year DFS rates were 62.1% and 40.7% for HR and 39.8% and 29.3% for RFA, respectively (P = 0.006)
		Single tumor < 2 cm after PS match	HR: 52RFA: 52	Patient characteristics seem similar between the two treatments. The 3- and 5-year survival rates were 98% and 91.5% for HR, and 82.8% and 82.8% for RFA, respectively (P = 0.269). The 3- and 5-year DFS rates were 62.1% and 40.7% for HR and 46.8% and 38.0% for RFA (P = 0.031)
Ruzzenente et al[47]	Child-Pugh class A and B	Up to 3 tumors ≤ 6 cm after PS match	HR: 88RFA: 88	Patient characteristics seem similar between the two treatments. The 3- and 5-year survival rates were 68.7% and 59.3% for HR, and 50.1% and 27.7% for RFA (P = 0.012). The 3- and 5-year DFS rates were 50.4% and 27.1% for HR and 30.2% and 18.6% for RFA, respectively (P = 0.001)
	Child-Pugh class A and B	Single tumor < 5 cm	HR: 45RFA: 40	The 3- and 5-year survival rates were 66.1% and 54.5% for HR, and 63.7% and 43.8% for RFA (P = 0.633). The 3- and 5-year DFS rates were 42.4% and 22.6% for HR and 30.7% and 23.0% for RFA, respectively (P = 0.644). Patient and disease-free survival after HR were significantly superior to RFA, in patients with tumors ≥ 5 cm
				Further stratifications lead to very small groups (n < 10)
Nishikawa et al[42]	Child-Pugh class A and B	Single tumor ≤ 3 cm	HR: 78RFA: 92	RFA patients had smaller tumors (P = 0.001) and lower platelet count (P = 0.004) in comparison to HR patients
				The 5-year overall survival rates after RFA and HR were 63.1% and 74.6%, respectively (P = 0.259). The corresponding RFS rates were 18.0% and 26.0%, respectively (P = 0.324). In the multivariate analysis treatment was not an independent risk factor for overall and RFS
Hung et al[38]	Child-Pugh class A and B	Up to 3 tumors ≤ 5 cm	HR: 229RFA: 190	RFA patients were significantly older, anti-HCV+, with lower albumin and platelet count (P < 0.050) in comparison to HR patients
				The 3- and 5-year survival rates were 88.2% and 79.3% for HR, and 77.3% and 67.4% for RFA, respectively (P = 0.009). The 3- and 5-year RFS rates were 56.1% and 40.9% for HR and 29.0% and 20.5% for RFA (P = 0.001)
		Up to 3 tumors ≤ 5 cm after PS match	HR: 84RFA: 84	Patient characteristics seem similar between the two treatments
				Patient and DFS rates not provided but only reported in Kaplan-Meier graphs. For patient survival no difference was found (P = 0.519); RFS was significantly worse after RFA (P < 0.001)
		Single tumor < 2 cm	HR: 50RFA: 66	RFA patients were significantly older, anti-HCV+, with lower albumin and platelet count, higher bilirubin, AST and ICG-R15 and with smaller tumors (P = 0.001) in comparison to HR patients
				The 3- and 5-year survival rates were 91.1% and 84.6% for HR, and 86.5% and 77.8% for RFA, respectively (P = 0.358). The 3- and 5-year RFS rates were 42.6% and 21.8% for HR and 59.5% and 45.2% for RFA (P = 0.104)
Takayama et al[39]	Child-Pugh class A and B	Single tumor ≤ 2 cm	HR: 1235RFA: 1315	Data from the Liver Cancer Study Group of Japan database. Results were reported in the form of brief communication. RFA patients were significantly more frequently in Child-Pugh class B, had higher ICG-R15 and smaller tumor size (P = 0.001 in all cases) in comparison to HR patients
				The 1- and 2-year survival rates were 98% and 94% for HR, and 99% and 95% for RFA, respectively (P = 0.280). The 1- and 2-year DFS rates were 91% and 70% for HR and 84% and 58% for RFA, respectively (P = 0.001)
				Multivariate analysis on DFS confirmed alpha-fetoprotein, therapy and Child-Pugh class as independent factors
Ueno et al[41]	Child-Pugh class A and B	BCLC early stage	HR: 123RFA: 155	RFA patients were significantly more frequently in Liver Damage class B or C, had higher ICG-R15, MELD score and smaller tumor size (P = 0.001 in all cases) in comparison to HR patients
				The 3- and 5-year survival rates were 92% and 80% for HR, and 92% and 63% for RFA, respectively (P = 0.06). The 3- and 5-year DFS rates were 47% and 38% for HR and 36% and 20% for RFA (P = 0.02)
		Single tumor ≤ 3 cm	HR: 78RFA: 92	The 3- and 5-year survival rates were 95% and 95% for HR, and 90% and 60% for RFA, respectively (P = 0.01). The 3- and 5-year DFS rates were 56% and 44% for HR and 37% and 11% for RFA (P = 0.02)
		Single tumor 3.1-5.0 cm	HR: 32RFA: 9	The 3- and 5-year survival rates were 92% and 72% for HR, and 73% and 73% for RFA, respectively (P = 0.15). The 3- and 5-year DFS rates were 33% and 25% for HR and 14% and 14% for RFA (P = 0.12)
		2 or 3 nodules ≤ 3 cm	HR: 13RFA: 54	The 3- and 5-year survival rates were 67% and not reached for HR, and 93% and 63% for RFA, respectively (P = 0.002). The 3- and 5-year DFS rates were 29% and not reached for HR and 35% and 22% for RFA (P = 0.59)
Abu-Hilal et al[48]	Child-Pugh class A and B	Single tumor ≤ 5 cm	HR: 34	This was a matched analysis for age, sex, tumor size, and Child-Pugh grade
			RFA: 34	The 5-year survival was 56% for HR, and 57% for RFA (P = 0.302). The 5-year DFS was 28% for HR and 21% for RFA (P = 0.028)
Guglielmi et al[43]	Child-Pugh class A and B	Up to 3 tumors ≤ 6 cm	HR: 91RFA: 109	RFA patients were significantly older, belonged more frequently to Child-Pugh class B and more frequently had multinodular tumors (P = 0.010) in comparison to HR patients
				The 3- and 5-year survival rates were 64% and 48% for HR, and 42% and 20% for RFA, respectively (P = 0.010). The 3- and 5-year DFS rates were 56% and 27% for HR and 22% and 22% for RFA (P = 0.001)
				Superiority of HR was confined to patients in Child-Pugh class A. Further stratifications resulted in groups of patients not large enough (n < 10) to obtain realistic comparisons
				Type of treatment was significantly related to survival and DFS at multivariate analyses
	Child-Pugh class A	Single tumor ≤ 3 cm	HR: 20RFA: 11	The 3- and 5-year survival rates were 93% and 71% for HR, and 50% and not reached for RFA, respectively (P = 0.060)
	Child-Pugh class A	Single tumor > 3 cm	HR: 33RFA: 23	The 3- and 5-year survival rates were 64% and 55% for HR, and 63% and 45% for RFA, respectively (P = 0.700)
Hiraoka et al[40]	Child-Pugh class A and B	Single tumor ≤ 3 cm	HR: 59RFA: 105	RFA patients belonged more frequently to Child-Pugh class B (P = 0.011), more frequently had tumors < 2 cm (P = 0.001), and had worse ICG-R15 (P = 0.026) in comparison to HR patients
				The 3- and 5-year survival rates were 91.4% and 59.4% for HR, and 87.8% and 59.3% for RFA, respectively (P = NS). The 3- and 5-year DFS rates were 64.3% and 22.4% for HR and 58.7% and 24.6% for RFA (P = NS)
				No multivariate analysis provided
Hasegawa et al[46]	Child-Pugh class A and B	Up to 3 tumors ≤ 3 cm	HR: 2857RFA: 3022	Data were analyzed together with a population of 1306 patients submitted to percutaneous ethanol injection. RFA patients were significantly older, belonged more frequently to Child-Pugh class B, had lower serum albumin, higher bilirubin, worse ICG-R15 and more frequently had multinodular and smaller tumors (P < 0.001 in all cases) in comparison to HR patients
				Results were limited to 24 mo. The 1- and 2-year survival rates were 98.3% and 94.5% for HR, and 98.5% and 93.0% for RFA, respectively (P = 0.640)
				The 1- and 2-year recurrence rates were 17.0% and 35.5% for HR and 26.0% and 55.4% for RFA (P < 0.001)
				At multivariate analysis, type of treatment did not affect overall survival but affected recurrence rate
Lupo et al[45]	Child-Pugh class A and B	Single tumor 3-5 cm	HR: 42RFA: 60	The groups were similar in terms of median age, Child-Pugh score and tumor size
				The 3- and 5-year survival rates were 57% and 43% for HR, and 53% and 32% for RFA, respectively (P = 0.824). The 3- and 5-year DFS rates were 35% and 14% for HR and 18% and 0% for RFA (P = 0.283)
				No multivariate analyses were performed
Ogihara et al[49]	Child-Pugh class A and B	Single tumor without size limit	HR: 47RFA: 40	RFA patients were significantly older, belonged more frequently to Child-Pugh class B and had smaller tumors (P < 0.001 in all cases) in comparison to HR patients
				The 3- and 5-year survival rates were 65% and 31% for HR, and 58% and 39% for RFA, respectively (P = NS). DFS not provided. No multivariate analysis was provided
	Child-Pugh class A and B	Single tumor ≤ 5 cm	HR: 18RFA: 26	In these subgroups, RFA patients were still significantly older and belonged more frequently to Child-Pugh class B (P < 0.050) in comparison to HR patients
				The 3- and 5-year survival rates were 64% and 21% for HR, and 53% and 32% for RFA, respectively (P = NS). The 3- and 5-year DFS rates were 37% and 37% for HR and 31% and 23% for RFA (P = NS)
				Results did not change in single tumors > 5 cm
Montorsi et al[50]	Child-Pugh class A and B	Single tumor ≤ 5 cm	HR: 40RFA: 58	All RFA were performed with laparoscopic approach. RFA patients had significantly worse INR and higher AST (P < 0.050). A trend toward higher bilirubin, lower platelet count and higher ALT was also reported (P < 0.10)
				The 3- and 4-year survival rates were 73% and 61% for HR, and 61% and 42% for RFA, respectively (P = 0.139). The RFS rates were not reported and only plotted in a Kaplan-Meier curve reporting a P = 0.024. Five-year rates not reported. Multivariate analysis on survival did not include the primary exposure variable (HR vs RFA)
Hong et al[51]	Child-Pugh class A	Single tumor ≤ 4 cm	HR: 93RFA: 55	RFA patients were significantly older (P < 0.001) but the other characteristics reported were not statistically different between the two groups
				The 1- and 3-year survival rates were 97.9% and 83.9% for HR, and 100% and 72.7% for RFA, respectively (P = 0.24). The 1- and 3-year RFS rates were 75.9% and 54.7% for HR and 74.1% and 40.2% for RFA (P = 0.54). Five-year rates not reported. Results did not change when patients were stratified by AJCC or CLIP stages
				No multivariate analyses were performed
Vivarelli et al[44]	Child-Pugh class A and B	No inclusion criteria specified	HR: 79RFA: 79	RFA patients belonged more frequently to Child-Pugh class B and more frequently had multinodular tumors (P < 0.001 in both cases)
				The 1- and 3-year survival rates were 83% and 65% for HR, and 78% and 33% for RFA, respectively (P = 0.002). The 1- and 3-year DFS rates were 79% and 50% for HR and 60% and 20% for RFA (P = 0.001). Five-year rates not reported. No multivariate analyses were performed
	Child-Pugh class A and B	Single tumor ≤ 3 cm	HR: 21RFA: 22	The 1- and 3-year survival rates were 89% and 79% for HR, and 89% and 50% for RFA, respectively (P = NS). The 1- and 3-year DFS rates were 84% and 67% for HR and 70% and 34% for RFA (P = NS). Five-year rates not reported
	Child-Pugh class A and B	Single tumor > 3 cm	HR: 58RFA: 57	The 1- and 3-year survival rates were 81% and 59% for HR, and 74% and 24% for RFA, respectively (P = 0.007). The 1- and 3-year DFS rates were 77% and 43% for HR and 56% and 12% for RFA (P = 0.003). Five-year rates not reported. These differences were confirmed when the analyses were confined to Child-Pugh class A patients

HR: Hepatic resection; RFA: Radiofrequency ablation; RFS: Recurrence-free survival; DFS: disease-free survival; PS: Propensity score; AST: Aspartate aminotransferase; NS: Not significant; BCLC: Barcelona Clinic Liver Cancer; HCV: Hepatitis C virus; AJCC: American Joint Committee on Cancer; CLIP: Cancer of the Liver Italian Program; MELD: Model for end-stage liver disease.