The prognosis of ablative treatments and liver resection for early-stage hepatocellular carcinoma：a systematic review and Bayesian network meta

doi:10.21203/rs.3.rs-3407549/v1

Download PDF

Research Article

The prognosis of ablative treatments and liver resection for early-stage hepatocellular carcinoma：a systematic review and Bayesian network meta

https://doi.org/10.21203/rs.3.rs-3407549/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective

To compare overall survival (OS) rates and disease-free survival (DFS) rates following radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation (CA) and Liver resection (LR) for hepatocellular carcinoma (HCC).

Method

PubMed, SCI, and Cochrane databases were searched for literature until March 1st, 2023. The data obtained from the literature were netted using Stata 15.0 and R 4.2.3. The primary assessments of content were overall survival (OS) rates and disease-free survival (DFS) rates at 1 and 3 years. OS rates and DFS rates were reported as the hazard ratio (HR) with 95% confidence interval (95% CrI) to summarize the effect of each comparison.

Result

A total of 25 publications with 5247 patients were included, including 12 studies in mainland China and 13 in other regions. Overall outcomes: for one-year and three-year overall survival rates, there was no statistical difference between the groups compared; for one-year disease-free survival rates, the HR was 1.85 (95% CrI: 1.31–2.61) for LR compared with RFA; 1.76 (95% CrI: 1.22–2.54) for LR compared with MWA, with no statistical difference in the rest of the groups compared; for three-year disease-free survival rates, the HR was 1.92 (95% CrI: 1.38–2.66) for LR compared with RFA; 1.88 (95% CrI: 1.31–2.68) for LR compared with MWA, and the rest were not statistically significant.

Conclusion

For particularly early-stage hepatocellular carcinoma, ablative procedures have comparable therapeutic efficacy; LR is more effective in reducing tumor recurrence than interventional ablation.

Liver resection

Ablative treatments

Hepatocellular carcinoma

Primary liver cancer is the sixth most common cancer globally and the third leading cause of death, particularly by hepatocellular liver cancer (HCC) [1], mainly caused by viral hepatitis infection and chronic alcoholic/nonalcoholic liver disease in developing and developed settings, respectively [2]. However, early diagnosis and timely intervention can reduce mortality and increase life expectancy of HCC, where there are increasingly diverse treatments available, especially for early-stage HCC with BCLC (Barcelona Clinic Liver Cancer) grade 0 and BCLC stage A, including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation (CA) and liver resection (LR). Recently, ablation techniques have been significantly improved, where RFA is recommended over percutaneous anhydrous ethanol infusion (PEI) as the preferred modality for percutaneous treatment of HCC by the American Association for the Study of Liver Diseases (AASLD) [3]. Nevertheless, inconsistent findings were evident for the comparison of prognosis between LR and ablative treatments in early-stage HCC, especially small HCC < 2–3 cm. For example, the tumor recurrence rates were not different between LR and RFA for early-to-mid stage HCC suggested by a cohort study [4], but a higher rate of intrahepatic recurrence and a lower medium-to-long term disease-free survival rate in RFA than LR were found by a retrospective study [5].

Several meta-analyses have compared the prognosis of LR with a specific ablation treatment. A previous meta-analysis found that overall survival rate and disease-free survival rate were higher in LR group than in RFA group [6], whereas another meta-analysis suggested higher disease-free survival rate of LR than RFA but no difference for overall survival rate [7]. One meta-analysis compared LR with MWA, suggesting no difference of overall survival rate and disease-free survival rate between MWA and LR in the short term, but better overall survival rate for LR than MWA in the med-to-long term [8]. Apart from the inconsistent evidence above, there is a lack of evidence comparing the prognosis of liver hepatectomy, cryoablation, microwave and radiofrequency ablation simultaneously for early HCC, which may shed lights on the practice of HCC treatment. To address this gap, we conducted a net meta-analysis comparing the prognosis of LR and each ablation treatment in early and very early-stage hepatocellular carcinoma.

The network meta-analysis was reported according to the PRISMA-NMA extension statements for network meta-analysis [9]. The protocol was registered with PROSPER (registration number: CRD42023415742).

1. Search strategy

PubMed, web of science and Cochrane databases were searched for literature up to March 1st, 2023. Some relevant literature was supplemented by independent review. The search strategy for each source maining "radiofrequency ablation" "microwave ablation" "cryosurgery" "carcinoma, hepatocellular "and " Hepatectomy " were used as subject terms, and a combination of subject terms and free terms was used to search in groups of two or three, respectively. The type of study mainly searched with "randomized controlled trial" or "cohort study", and the language of search was limited to English. Search strategy for PubMed has been shown in the supplementary material, and transformed with different databases.

2. Selection criteria

Two reviewers (Min and Tong) independently screened the potential publication titles and abstracts and reviewed the full text of the eligible articles.

Inclusion criteria: (1) randomized controlled study or cohort study design; (2) the study should compare the surgical treatment of partial LR with the ablative treatments; (3) participants with very early/early stage hepatocellular carcinoma according to the BCLC classification, specifically a single node ≤ 2 cm as very early-stage HCC and a single node ≤ 5 cm or up to three nodes ≤ 3 cm as early stage HCC [3]; (4) publication language as English.

Exclusion criteria: (1) no definitive survival data; (2) duplicate publications of multiple abstracts and/or papers by the same author team; (3) studies of subjects with vascular invasion and intermediate to advanced HCC; (4) case reports, case series, narrative, systematic reviews, or commentaries.

3. Data extraction

Two researchers (Min and Tong) independently screened the literature, any discrepancies were resolved by discussion by the senior investigators (Li). Extracted data were entered directly into a pre-constructed table.

4. Study outcomes:

Hazard ratio (HR) by comparing overall survival rates/ disease-free survival (DFS) rates for different groups in the first and third years. The expressions of the calculated risk ratios for overall survival rates and disease-free survival rates were based on relevant statistical methods[10] .

5. Construction of network diagrams:

Stata 15.0 software was used to evaluate the treatment network by forming network diagrams in which circles represent interventions and the thickness of the line connecting the circles is proportional to the number of studies between interventions. Network diagrams of closed triangles were also evaluated.

6. Assessment of risk of bias:

The Cochrane revised tool (ROB 2.0) was used for the evaluation of the risk of bias in prospective cohort studies[11]. NOS scale was used to assess bias in retrospective cohort studies. The risk of publication bias was assessed using funnel plots.

7. Statistical analysis:

This study used Stata 15 and R 4.0.3 software for statistical analysis. A network relationship diagram was drawn by Stata 15 to represent the network relationships between the interventions. In this study, inconsistency model tests and Node-Splitting were used to assess overall network inconsistency and local inconsistency. Bayesian models were built using the ‘rjags’ package and the ‘gemtc’ R packages to perform a net meta-analysis of the outcome indicators of the four interventions. The Stata 15 software was also used to plot the probability ranking graph, and the funnel graph reflecting publication bias.

1.Study characteristics

A total of 1430 relevant papers were retrieved from PubMed, SCI and Cochrane databases after removing duplicates, and another 21 papers were obtained from other relevant references. After reading the titles and abstracts, 59 papers were initially selected to meet the criteria. After carefully reading the literature, 25 papers were selected and the basic information and underlying data were extracted and presented (Table 1), and the specific screening process has been shown (Fig. 1), which included 5 RCT studies and 20 retrospective cohort studies, all were two-arm studies. These studies were published from 2005 to 2020, including 4025 patients.

Table 1

Basic information
Author, year	Country Region	Participants, n	Mean age (years)	OS rates (%)		DFS rates (%)
				1 year	3 years	1 year	3 years
Ng,2017[4]	Hong Kong	RFA:109 LR:109	57.0 (23.0–78.0) 55.0 (31.0–82.0)	95.4 94.5	82.3 80.6	70.6 74.1	46.6 50.9
Lee,2018[5]	Korea	RFA:34 LR:29	56.1 ± 7.4 55.6 ± 7.9	100 96.6	97.1 96.6	- -	44.1 66.7
Chong,2020[12]	Hong Kong	RFA:46 MWA:47	64.5 (42.0–85.0) 63.0 (50.0–80.0)	93.5 97.9	72.7 67.1	58.7 51.1	22.7 24.1
Feng, 2012[20]	Chinese mainland	RFA:84 LR:84	51.0 (24.0–83.0) 47.0 (18.0–76.0)	96 93.1	74.8 67.2	90.6 86.2	61.1 49.6
Wang,2015[21]	Chinese mainland	RFA:180 CA:180	53.34 ± 8.91 53.87 ± 9.59	97 97	66 67	84 89	50 54
Ohmoto,2008[22]	Japan	RFA:34 MWA:49	67.0 (44.0–78.0) 64.0 (38.0–75.0)	100 89	70 49	63 52	26 15
Theodora,2016[23]	US	RFA:55 MWA:99	62.0 (23.0–88.0) 61.0 (44.0–82.0)	83.6 78.8	49.1 24	- -	- -
Lu, 2005[24]	Chinese mainland	RFA:53 MWA:49	54.5 ± 11.7 50.1 ± 13.7	71.7 81.6	37.6 50.5	37.2 45.9	15.5 26.9
Liu,2018[25]	Chinese mainland	RFA:436 MWA:126	56.0 (46.0–65.0) 54.0 (45.3–60.0)	96.4 99	80.7 94.6	60.4 78.9	22.8 46.9
Zhang, 2013[26]	Chinese mainland	RFA:47/31 MWA:36/41	54.0 ± 10.5 54.0 ± 9.5	93.6/87.1 100/85.4	66/61.3 80.6/36.6	68.1/74.2 72.2/53.3	34/54.8 41.7/26.8
Thomas,2015[27]	Germany	RFA:25 MWA:28	57.0 ± 4.2 60.0 ± 4.2	100 100	72 79	96.9 97.2	90.6 91.7
Ding, 2013[28]	Chinese mainland	RFA:85 MWA:113	58.64 ± 8.52 59.06 ± 11.68	98.7 98	82.7 77.6	80.3 75	39.5 32.1
Xu,2017[29]	Chinese mainland	RFA:159 MWA:301	54.0 ± 11.0 54.2 ± 11.0	98.7 99.3	86.8 90.4	89.9 94.4	67.3 71.8
Casaccia,2017[30]	Italy	RFA:22 LR:24	60.82 ± 7.25 63.58 ± 9.55	81.8 95.8	50 58.3	40.9 70.8	18.2 25
Chong,2018[31]	Hong Kong	RFA:59 LR:59	59.3 ± 11.0 57.7 ± 10.5	96.6 94.9	78.7 88.2	59.3 86.3	25.3 68
Lai,2013[32]	Hong Kong	RFA:31 LR:80	63.1 ± 12.8 60.8 ± 9.9	100 92	92 75	76 76	40 60
Roberto, 2009[33]	Italy	RFA:74 LR:78	68.0 ± 7.0 68.0 ± 8.0	88 93	66 85	- -	- -
Shi,2014[34]	Chinese mainland	MWA: 40/56 LR: 37/54	56.6 ± 9.2 54.5 ± 9.9	98/95 97/94	78/72 82/71	85/73 89/83	54/34 66/57
Sun,2020[35]	Chinese mainland	MWA: 51/64 LR: 41/73	57.5 ± 9.6 54.5 ± 10.4	97.4/90.9 100/93.5	76.9/65.5 83.3/74.2	82.1/68.4 88.6/83.6	51.1/41.1 72.7/58.8
Zheng,2020[36]	Chinese mainland	MWA:93 LR:300	58.0 (49.0–66.0) 57.0 (50.0–62.0)	90.1 95.5	82.9 86.1	66.3 71.8	46.1 44.3
Hu,2019[37]	Chinese mainland	MWA:64 CA:56	55.2 ± 7.2 54.9 ± 11.3	85.8 92	63.5 87.4	77.8 81.4	49 58.5
Zhang, et al[38]	Chinese mainland	RFA:67 LR:67	57.78 ± 10.97 57.51 ± 8.37	98.5 98.5	85 90	79.1 88.1	47 65.6
Cheng, et al[39]	Hong Kong	RFA:31 LR:99	65.48 ± 11.73 63.60 ± 9.86	96 97.9	79.2 96.2	60.6 91.2	37.9 66.7
Li, et al[40]	Taiwan	RFA:58 LR:58	61 (34–80) 61 (35–82)	91.4 98.2	77.2 88.8	91.2 93	62 71.7
Feng, et al[41]	Chinese mainland	MWA: 121 LR: 121	57.1 ± 9.7 57.0 ± 8.4	98.3 96.5	84.7 81.8	81.8 85.4	54.4 67.8

2. Assessment of network

A complete triangular relationship existed between RFA, MWA and CA, the same as RFA, MWA and LR (Fig. 2), allowing for computational consistency and inconsistency analysis. Survival and disease-free survival outcomes for LR, RFA, MWA and CA combined are represented in statistical tables and forest plots (Table 2, Fig. 3). SUCRA curve plots reflected the different treatment modalities with different outcome rankings (Fig. 4). The largest number of studies was between RFA and MWA. Only one study addressed all outcomes between MWA and CA, the same situation arose between RFA and CA, and there was no direct study evidence between LR and CA.

Table 2

League table demonstrating the hazard ratio along with 95% CrI for OS rates at 1 year and 3 years and hazard ratio along with 95% CrI for DFS rates at 1 year and 3 years for different treatment comparison
	Treatment	LR	RFA	MWA	CA
OS rates at 1 year	LR vs	NA	0.71(0.45,1.13)	0.81(0.49,1.35)	1.22(0.41,3.64)
	RFA vs	1.40(0.88,2.22)	NA	1.14(0.74,1.76)	1.71(0.60,4.87)
	MWA vs	1.23(0.74,2.04)	0.88(0.57,1.36)	NA	1.50(0.55,4.13)
	CA vs	0.82(0.27,2.44)	0.58(0.21,1.66)	0.67(0.24,1.83)	NA
DFS rates at 1 year	LR vs	NA	0.54(0.38,0.76)	0.57(0.39,0.82)	0.76(0.31,1.87)
	RFA vs	1.85(1.31,2.61)	NA	1.05(0.76,1.46)	1.41(0.60,3.33)
	MWA vs	1.76(1.22,2.54)	0.95(0.69,1.32)	NA	1.35(0.57,3.16)
	CA vs	1.31(0.53,3.21)	0.71(0.30,1.67)	0.74(0.32,1.74)	NA
OS rates at 3 year	LR vs	NA	0.79(0.53,1.17)	0.74(0.48,1.14)	1.52(0.53,4.34)
	RFA vs	1.27(0.86,1.89)	NA	0.95(0.65,1.38)	1.52(0.53,4.34)
	MWA vs	1.35(0.88,2.07)	1.06(0.73,1.54)	NA	2.04(0.75,5.58)
	CA vs	0.66(0.23,1.89)	0.52(0.19,1.41)	0.49(0.18,1.34)	NA
DFS rates at 3 year	LR vs	NA	0.52(0.38,0.72)	0.53(0.37,0.76)	0.59(0.25,1.40)
	RFA vs	1.92(1.38,2.66)	NA	1.02(0.74,1.42)	1.13(0.49,2.58)
	MWA vs	1.88(1.31,2.68)	0.98(0.70,1.36)	NA	1.11(0.48,2.53)
	CA vs	1.70(0.71,4.03)	0.89(0.39,2.02)	0.90(0.40,2.07)	NA

For one-year and three-year survival rates, HR values are all within the credible interval. In a conclusion, the one-year and three-year survival rates of the four treatment modalities were not statistically different between the groups.

For one-year disease-free survival, the HR was 1.85 (95% CrI: 1.31–2.61) for LR compared with RFA; 1.76 (95% CrI: 1.22–2.54) for LR compared with MWA. In a word, the one-year disease-free survival rate of LR was statistically higher than that of RFA and MWA, but there was no difference between the remaining groups compared.

For three-year disease-free survival, the HR was 1.92 (95% CrI: 1.38–2.66) for LR compared with RFA; 1.88 (95% CrI: 1.31–2.68) for LR compared with MW. As with one-year disease-free survival, LR had a higher disease-free survival rate than RFA and MWA at 3 years after the procedure, and there was no statistical difference in the three-year disease-free survival rates between LR and CA and the remaining three ablation modalities.

3. Rank probability of treatment regimen

The ranked probability ranking of the effect of all four treatment modalities has been reflected by the SUCRA graph (Fig. 4), for one-year survival, CA ranked first with the highest probability (0.621), followed by LR (0.316), then MWA and RFA; for one-year disease-free survival, LR ranked first (0.72), followed by CA (0.28), with both RFA and MWA ranking last; for three-year survival, again CA ranked first with the highest probability (0.773), followed by LR (0.206), then RFA (0.04) and MWA (0.01) with little difference; and for three-year disease-free survival, HR ranked first (0.882), followed by CA ( 0.118), with RFA and MWA ranking last both.

4. Consistency and inconsistency analysis

In order to develop the final model with all resulting parameters, the adaptation iterations were kept at 20,000, thus removing the initial simulation results of the MCMC analysis from the model. The number of simulation iterations was kept at 100,000. The sparsity factor was kept at 10 and the number of chains was kept at 4. For all four outcome parameters, the assessment of the adequacy of convergence of the Gelman Rubin diagnosis was below 1.05 (Fig. 5). The p value of inconsistency in Node-Splitting was not significant for all the outcomes in all the comparisons (Table 5).

5. Subgroup analysis

The subgroups of the study were divided into Chinese mainland and other regions according to the region where the study was conducted. Among the included literature, only Chinese mainland was analyzed for cryoablation efficacy, so the Chinese mainland subgroup included four different treatment modalities, while the other regions subgroup included only three treatment modalities such as partial hepatectomy, thermal radiofrequency ablation and microwave ablation.

In the subgroup from Chinese mainland, LR had an advantage in disease-free survival rates over MWA, but there was no statistical difference between other treatment modalities for both overall survival and disease-free survival. For LR compared with MWA in the one-year disease-free survival, the HR was 1.49 (95% CrI: 1.02–2.17); in the three-year disease-free survival, the HR was 1.63 (95% CrI: 1.04–2.56). In contrast, in the subgroups from regions other than Chinese mainland, there were no statistically significant differences between the three treatment modalities for one- and three-year overall survival rates. For the one-year disease-free survival, the HR was 2.33 (95% CrI: 1.34–4.06) for LR compared with RFA; 3.14 (95% CrI: 1.16–8.49) for LR compared with MWA (Table 3). For the three-year disease-free survival, the HR was 2.28 (95% CrI: 1.54–3.39); and for LR versus MWA, the HR was 2.74 (95% CrI: 1.26–5.59) (Table 4).

Table 3

League table of China mainland group
	Treatment	LR	RFA	MWA	CA
OS rates at 1 year	LR vs	NA	0.80(0.42,1.55)	0.95(0.56,1.64)	1.47(0.54,4.01)
	RFA vs	1.24(0.65,2.40)	NA	1.19(0.74,1.91)	1.83(0.72,4.65)
	MWA vs	1.05(0.61,1.80)	0.84(0.52,1.36)	NA	1.54(0.65,3.65)
	CA vs	0.68(0.25,1.86)	0.55(0.22,1.39)	0.65(0.27,1.54)	NA
DFS rates at 1 year	LR vs	NA	0.65(0.41,1.03)	0.67(0.46,0.98)	0.91(0.39,2.09)
	RFA vs	1.55(0.97,2.46)	NA	1.04(0.73,1.49)	1.41(0.65,3.04)
	MWA vs	1.49(1.02,2.17)	0.96(0.67,1.37)	NA	1.35(0.63,2.89)
	CA vs	1.10(0.48,2.54)	0.71(0.33,1.54)	0.74(0.35,1.59)	NA
OS rates at 3 year	LR vs	NA	0.84(0.48,1.47)	0.88(0.56,1.40)	1.69(0.63,4.55)
	RFA vs	1.19(0.68,2.08)	NA	1.05(0.67,1.65)	2.01(0.82,4.95)
	MWA vs	1.13(0.72,1.79)	0.95(0.61,1.49)	NA	1.92(0.78,4.73)
	CA vs	0.59(0.22,1.59)	0.50(0.20,1.22)	0.52(0.21,1.29)	NA
DFS rates at 3 year	LR vs	NA	0.63(0.36,1.09)	0.61(0.39,0.96)	0.69(0.26,1.84)
	RFA vs	1.59(0.92,2.75)	NA	0.97(0.63,1.51)	1.10(0.45,2.70)
	MWA vs	1.63(1.04,2.56)	1.03(0.66,1.60)	NA	1.13(0.46,2.77)
	CA vs	1.44(0.54,3.83)	0.91(0.37,2.22)	0.88(0.36,2.16)	NA

Table 4

League table of other regions group
	Treatment	LR	RFA	MWA
OS rates at 1 year	LR vs	NA	0.67(0.27,1.63)	0.50(0.10,2.40)
	RFA vs	1.50(0.61,3.67)	NA	0.75(0.20,2.82)
	MWA vs	1.99(0.42,9.52)	1.33(0.35,4.95)	NA
DFS rates at 1 year	LR vs	NA	0.43(0.25,0.75)	0.32(0.12,0.86)
	RFA vs	2.33(1.34,4.06)	NA	0.74(0.33,1.70)
	MWA vs	3.14(1.16,8.49)	1.35(0.59,3.08)	NA
OS rates at 3 year	LR vs	NA	0.75(0.41,1.36)	0.47(0.18,1.19)
	RFA vs	1.33(0.74,2.41)	NA	0.62(0.30,1.29)
	MWA vs	2.15(0.84,5.51)	1.61(0.77,3.35)	NA
DFS rates at 3 year	LR vs	NA	0.44(0.29,0.65)	0.37(0.17,0.80)
	RFA vs	2.28(1.54,3.39)	NA	0.83(0.43,1.63)
	MWA vs	2.74(1.26,5.95)	1.20(0.61,2.34)	NA

Table 5

Consistency inspection and Nodal analysis
Statistical approach	Inconsistent model	Nodel difference method
	p-value	Minimum p-value
one-year OS rates	0. 48	0.480
three-year DFS rates	0.36	0.537
three-year OS rates	0.39	0.188
three-year DFS rates	0.79	0.491

6. Risk assessment

For the included RCT studies, we used the ROB 2 tool to assess the risk of bias, and the results are shown below (Table 6); while for the non-RCT category, we used the NOS scale for scoring, and the final assessment scores were above 6 (Table 7), suggesting less bias. In addition, analysis of the data using Stata revealed a symmetrical funnel plot distribution (Fig. 6), suggesting a small and acceptable publication bias.

Table 6

Assessment of the RCTs included in meta-analysis
SI. no.	RoB 2 parameters	Ng, et al[4]	Lee, et al[5]	Chong, et al[12]	Feng, et al[20]	Wang, et al[21]
1	Randomization process	LR	LR	LR	LR	LR
2	Concealment of allocation	LR	LR	LR	SC	LR
3	Assignment to intervention	LR	LR	LR	LR	LR
4	Adhering to intervention	LR	LR	LR	LR	LR
5	Missing of outcome data	LR	LR	LR	LR	LR
6	Measurements of outcome	LR	LR	LR	LR	LR
7	Selection of reported results	SC	SC	LR	LR	LR
8	Overall bias	SC	SC	LR	SC	LR
LR low risk, RR high risk, SC some concern

Table 7

Assessment of the nRCTs included in meta-analysis
Study	Selection				Comparability	Exposure			Scores
	Representativeness (expressed cohort)	Selection (non-exposed cohort)	Ascertainment (exposure)	no outcome events before study	Control for important	Assessment of outcome events	Adequacy of follow-up	Completeness of follow-up	Scores
Ohmoto, et al[22]	1	1	1	0	2	1	1	1	8
Theodora,et al[23]	1	1	1	0	1	1	1	1	7
Lu, et al[24]	1	1	1	0	1	1	1	1	7
Liu, et al[25]	1	1	1	0	1	1	1	1	7
Zhang, et al[26]	1	1	1	0	1	1	1	1	7
Thomas, et al[27]	1	1	1	0	2	1	1	1	8
Ding, et al[28]	1	1	1	0	2	1	1	1	8
Xu, et al[29]	1	1	1	0	2	1	1	1	8
Casaccia,et al[30]	1	1	1	0	2	1	1	1	8
Chong, et al[31]	1	1	1	0	2	1	1	1	8
Lai, et al[32]	1	1	1	0	2	1	1	1	8
Roberto, et al[33]	1	1	1	0	1	1	1	1	7
Shi, et al[34]	1	1	1	0	2	1	1	1	8
Sun, et al[35]	1	1	1	0	1	1	1	1	7
Zheng, et al[36]	1	1	1	0	2	1	1	1	8
Hu, et al[37]	1	1	1	0	1	1	1	1	7
Zhang, et al[38]	1	1	1	0	2	1	1	1	8
Cheng, et al[39]	1	1	1	0	2	1	1	1	8
Li, et al[40]	1	1	1	0	2	1	1	1	8
Feng, et al[41]	1	1	1	0	2	1	1	1	8

This network meta-analysis compared the prognosis of 3 common ablative treatment modalities (RFA, MWA, CA) with conventional liver resection (LR) for early-stage hepatocellular carcinoma. The results showed that in the one-year disease-free survival rates and three-year disease-free survival rates, LR had significant advantages over RFA and MWA. There was no statistically significant difference in overall survival rates at one-year and three-year among the four treatment modalities, and no significant difference in overall survival rates or disease-free survival rates among CA compared with other treatment modalities. Unlike the previous net meta-analysis, we introduced liver resection, a traditional treatment modality, and included the most recent studies for comparison.

We did not find a significant difference overall survival between RFA and LR, indicating that RFA showed an excellent early to mid-term prognosis in the treatment of hepatocellular carcinoma and avoided the postoperative trauma and medical costs associated with LR. The results of LR compared with MWA were similar to those of RFA. There was no statistically significant difference in prognostic outcomes between MWA and RFA, and the two were almost identical in overall survival rates and disease-free survival rates in the latest RCT study [12]. Because of the heat sink effect, RFA has limitations for paravalvular lesions, mainly because blood flow takes away the high energy of radio frequency [13]. Some studies have shown that [14] MWA can better deal with tumors located in the paravalvular area and cope with larger tumors. Therefore, theoretically, MWA could be an alternative to RFA for early-stage hepatocellular carcinoma, but the data in this study did not suggest a significant difference between the two.

However, in terms of disease-free survival rates, LR showed an advantage over RFA and MWA, which implies that there may be local tumor progression after ablation, which is mainly related to the tumor site, ablation radius, whether repeated punctures and the presence of satellite lesions and microvascular invasion [14]. In addition to the heat sink effect, when adjacent to blood vessels, most operators may prefer a more conservative and safe scope of ablation in this case, so the probability of recurrence increases. On the contrary, when the tumor is located far away from the intrahepatic vessels under the liver envelope, treatment with ablation is not entirely suitable. Some studies [15] have shown that when ablating tumors are located under the pericardium, the high-energy vapor generated during ablation may spread tumor fragments to the needle tract or even to the abdominal cavity, resulting in tumor recurrence after ablation. When the tumor size is > 2–3 cm, the high-energy coverage area of RFA may be insufficient, and the postoperative recurrence rate is elevated [16], which is also related to the subjective of the operator's judgment on whether the high-energy coverage is achieved. Therefore, for patients with early-stage hepatocellular carcinoma who can tolerate surgery or whose tumors are in the above-mentioned high-risk locations, we recommend traditional liver resection to reduce the possibility of recurrence.

Cryoablation is a relatively new technology due to its ability to ablation visualization and induces an immune response to suppress tumor cells [13, 17, 18]. However, it is not widely used in treating hepatocellular carcinoma, and fewer studies have been conducted worldwide, mostly confined to China. There are no clinical studies directly comparing cryoablation with hepatectomy, so we indirectly compared the efficacy of both utilizing a network meta-analysis. The present findings showed no statistical difference in overall survival rates and disease-free survival rates between cryoablation and other treatments. This result cannot be ruled out due to fewer CA-related studies. Therefore, there were no CA-related studies in the non-Mainland China group in our subgroup analysis, which is one of the limitations of this article.

The results of subgroup analysis based on country region showed that within the non-Mainland China group, LR had a significant advantage in disease-free survival rates over RFA and MWA, consistent with our overall findings. In contrast, within the mainland China group, LR had an advantage in disease-free survival rates over MWA, but not significantly different from RFA. We consider that it may be related to the epidemiological characteristics of hepatocellular carcinoma in mainland China. The first successful RFA for hepatocellular carcinoma was reported by Rossi [19] in 1995, and then it rapidly developed into the mainstream first-line treatment for hepatocellular carcinoma. The clinical application of RFA for hepatocellular carcinoma in mainland China is relatively 10 years late. Still, the prognosis of RFA treatment in China is better due to the large number of patients with hepatocellular carcinoma, reference to foreign radio frequency experience, and avoidance of relevant risk factors. The studies included in this meta-analysis showed that the mean one-year overall survival rates after RFA treatment in mainland China was as high as 96.40%, and the mean one-year disease-free survival rate was as high as 87.84%.

In clinical practice, tumor size is the main influencing factor for surgical or ablative treatment choice. Most studies have also investigated the correlation between tumor size and prognosis. In all the studies we included, the subjects were very early or early-stage HCC under BCLC classification, defined as a single node ≤ 5 cm or a maximum of three nodes ≤ 3 cm. In the original study data, only the average size of all patients' tumors was available, which did not reflect the relationship between tumor size and the number of tumors scientifically, so no relevant subgroup analysis was performed. Further investigation is warranted for the choice of treatment modalities for single or multiple hepatocellular carcinomas to fill this gap.

By systematically comparing the prognostic indicators of four modalities for early and very early-stage HCC, LR had a significant advantage over RFA and MWA for the disease-free survival rate, particularly in non-mainland China region, but not in the studies from mainland China. Percutaneous ablation therapy has a higher local recurrence risk compared with surgical treatment of early and very early-stage hepatocellular carcinoma, which may contribute to the clinical management of early-stage hepatocellular carcinoma.

Author Contributions:

(I) Conception and design: Yiyang Min, Kuinan Tong, Huajun Lin;

(II) Administrative support: Dong Wang, Wei Guo, Shun Li, Zhongtao Zhang;

(III) Provision of study materials or patients: None;

(IV) Collection and assembly of data: Yiyang Min, Kuinan Tong;

(V) Data analysis and interpretation: Yiyang Min, Kuinan Tong;

(VI) Manuscript writing: Yiyang Min, Kuinan Tong, Shun Li;

(VII) Final approval of manuscript: All authors.

Data availability

All data in this article can be offered to the public.

Compliance with Ethical Standards

Funding: No funding was received to assist with the preparation of this manuscript.

Conflict of Interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors

Zhang, C. H., Cheng, Y., Zhang, S., et al, 2022. Changing epidemiology of hepatocellular carcinoma in Asia. Liver international : official journal of the International Association for the Study of the Liver, 42(9), 2029–2041. https://doi.org/10.1111/liv.15251
Yang, J. D., Hainaut, P., Gores, G. J., et al, 2019. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nature reviews. Gastroenterology & hepatology, 16(10), 589–604. https://doi.org/10.1038/s41575-019-0186-y
Heimbach, J. K., Kulik, L. M., Finn, R. S., et al, 2018. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology (Baltimore, Md.), 67(1), 358–380. https://doi.org/10.1002/hep.29086
Ng, K. K. C., Chok, K. S. H., Chan, A. C. Y., et al, 2017. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma. The British journal of surgery, 104(13), 1775–1784. https://doi.org/10.1002/bjs.10677
Lee, H. W., Lee, J. M., Yoon, J. H., et al, 2018. A prospective randomized study comparing radiofrequency ablation and hepatic resection for hepatocellular carcinoma. Annals of surgical treatment and research, 94(2), 74–82. https://doi.org/10.4174/astr.2018.94.2.74.
Feng, Q., Chi, Y., Liu, Y., et al, 2015. Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies. Journal of cancer research and clinical oncology, 141(1), 1–9. https://doi.org/10.1007/s00432-014-1708-1
Yuan, B. H., Zhu, Y. K., Zou, X. M., et al, 2022. Repeat hepatic resection versus percutaneous ablation for the treatment of recurrent hepatocellular carcinoma: meta-analysis. BJS open, 6(2), zrac036. https://doi.org/10.1093/bjsopen/zrac036
Yang, G., Xiong, Y., Sun, J., et al, 2020. The efficacy of microwave ablation versus liver resection in the treatment of hepatocellular carcinoma and liver metastases: A systematic review and meta-analysis. International journal of surgery (London, England), 77, 85–93. https://doi.org/10.1016/j.ijsu.2020.03.006
Hutton, B., Salanti, G., Caldwell, D. M., et al, 2015. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Annals of internal medicine, 162(11), 777–784. https://doi.org/10.7326/M14-2385
Woods, B. S., Hawkins, N., Scott, D. A., 2010. Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC medical research methodology, 10, 54. https://doi.org/10.1186/1471-2288-10-54
Higgins, J. P., Altman, D. G., Gøtzsche, P. C., et al, 2011. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.), 343, d5928. https://doi.org/10.1136/bmj.d5928
Chong, C. C. N., Lee, K. F., Cheung, S. Y. S., et al, 2020. Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial). HPB : the official journal of the International Hepato Pancreato Biliary Association, 22(8), 1121–1127. https://doi.org/10.1016/j.hpb.2020.01.008
Nault, J. C., Sutter, O., Nahon, P., et al, 2018. Percutaneous treatment of hepatocellular carcinoma: State of the art and innovations. Journal of hepatology, 68(4), 783–797. https://doi.org/10.1016/j.jhep.2017.10.004
Huang, S., Yu, J., Liang, P., Yu, X., et al, 2014. Percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: a long-term follow-up. European journal of radiology, 83(3), 552–558. https://doi.org/10.1016/j.ejrad.2013.12.015
Zhong-Yi, Z., Wei, Y., Kun, Y., et al, 2017. Needle track seeding after percutaneous radiofrequency ablation of hepatocellular carcinoma: 14-year experience at a single centre. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 33(4), 454–458. https://doi.org/10.1080/02656736.2017.1278630
Mazzaferro, V., Lencioni, R., Majno, P., 2014. Early hepatocellular carcinoma on the procrustean bed of ablation, resection, and transplantation. Seminars in liver disease, 34(4), 415–426. https://doi.org/10.1055/s-0034-1394365
Hu K. Q., 2014. Advances in clinical application of cryoablation therapy for hepatocellular carcinoma and metastatic liver tumor. Journal of clinical gastroenterology, 48(10), 830–836. https://doi.org/10.1097/MCG.0000000000000201
Mahnken, A. H., König, A. M., & Figiel, J. H., 2018). Current Technique and Application of Percutaneous Cryotherapy. Aktuelle Technik und Anwendung der perkutanen Kryotherapie. RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin, 190(9), 836–846. https://doi.org/10.1055/a-0598-5134
Rossi, S., Di Stasi, M., Buscarini, E., et al, 1995. Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma. The cancer journal from Scientific American, 1(1), 73–81.
Feng, K., Yan, J., Li, X., et al, 2012. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. Journal of hepatology, 57(4), 794–802. https://doi.org/10.1016/j.jhep.2012.05.007
Wang, C., Wang, H., Yang, W., et al, 2015. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology (Baltimore, Md.), 61(5), 1579–1590. https://doi.org/10.1002/hep.27548
Ohmoto, K., Yoshioka, N., Tomiyama, Y., et al, 2009. Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas. Journal of gastroenterology and hepatology, 24(2), 223–227. https://doi.org/10.1111/j.1440-1746.2008.05596.x
Potretzke, T. A., Ziemlewicz, T. J., Hinshaw, J. L., et al, 2016. Microwave versus Radiofrequency Ablation Treatment for Hepatocellular Carcinoma: A Comparison of Efficacy at a Single Center. Journal of vascular and interventional radiology : JVIR, 27(5), 631–638. https://doi.org/10.1016/j.jvir.2016.01.136
Lu, M. D., Xu, H. X., Xie, X. Y., et al, 2005. Percutaneous microwave and radiofrequency ablation for hepatocellular carcinoma: a retrospective comparative study. Journal of gastroenterology, 40(11), 1054–1060. https://doi.org/10.1007/s00535-005-1671-3
Liu, W., Zheng, Y., He, W., et al, 2018. Microwave vs radiofrequency ablation for hepatocellular carcinoma within the Milan criteria: a propensity score analysis. Alimentary pharmacology & therapeutics, 48(6), 671–681. https://doi.org/10.1111/apt.14929
Zhang, L., Wang, N., Shen, Q., et al, 2013. Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma. PloS one, 8(10), e76119. https://doi.org/10.1371/journal.pone.0076119
Vogl, T. J., Farshid, P., Naguib, N. N., et al, 2015. Ablation therapy of hepatocellular carcinoma: a comparative study between radiofrequency and microwave ablation. Abdominal imaging, 40(6), 1829–1837. https://doi.org/10.1007/s00261-015-0355-6
Ding, J., Jing, X., Liu, J., et al, 2013. Comparison of two different thermal techniques for the treatment of hepatocellular carcinoma. European journal of radiology, 82(9), 1379–1384. https://doi.org/10.1016/j.ejrad.2013.04.025
Xu, Y., Shen, Q., Wang, N., et al, 2017. Microwave ablation is as effective as radiofrequency ablation for very-early-stage hepatocellular carcinoma. Chinese journal of cancer, 36(1), 14. https://doi.org/10.1186/s40880-017-0183-x
Casaccia, M., Santori, G., Bottino, G., et al, 2017. Laparoscopic resection vs laparoscopic radiofrequency ablation for the treatment of small hepatocellular carcinomas: A single-center analysis. World journal of gastroenterology, 23(4), 653–660. https://doi.org/10.3748/wjg.v23.i4.653
Chong, C. C., Lee, K. F., Chu, C. M., et al, 2020. Laparoscopic Hepatectomy (with or without Robotic Assistance) versus Radiofrequency Ablation as a Minimally Invasive Treatment for Very Early-Stage or Early-Stage Hepatocellular Carcinoma. Digestive surgery, 37(1), 65–71. https://doi.org/10.1159/000497112
Lai, E. C., Tang, C. N., 2013. Radiofrequency ablation versus hepatic resection for hepatocellular carcinoma within the Milan criteria--a comparative study. International journal of surgery (London, England), 11(1), 77–80. https://doi.org/10.1016/j.ijsu.2012.11.019
Santambrogio, R., Opocher, E., Zuin, M., et al, 2009. Surgical resection versus laparoscopic radiofrequency ablation in patients with hepatocellular carcinoma and Child-Pugh class a liver cirrhosis. Annals of surgical oncology, 16(12), 3289–3298. https://doi.org/10.1245/s10434-009-0678-z
Shi, J., Sun, Q., Wang, Y., et al, 2014. Comparison of microwave ablation and surgical resection for treatment of hepatocellular carcinomas conforming to Milan criteria. Journal of gastroenterology and hepatology, 29(7), 1500–1507. https://doi.org/10.1111/jgh.12572
Sun, Q., Shi, J., Ren, C., et al, 2020. Survival analysis following microwave ablation or surgical resection in patients with hepatocellular carcinoma conforming to the Milan criteria. Oncology letters, 19(6), 4066–4076. https://doi.org/10.3892/ol.2020.11529
Zheng, H., Xu, C., Wang, X., et al, 2020. Microwave ablation shows similar survival outcomes compared with surgical resection for hepatocellular carcinoma between 3 and 5 cm. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 37(1), 1345–1353. https://doi.org/10.1080/02656736.2020.1849825
Hu, J., Chen, S., Wang, X., et al, 2019. Image-Guided Percutaneous ‎Microwave Ablation Versus Cryoablation For Hepatocellular Carcinoma In High-Risk Locations: Intermediate-Term Results. Cancer management and research, 11, 9801–9811. https://doi.org/10.2147/CMAR.S227961
Zhang, C., Gao, R., Guo, S., et al, 2022. Anatomic resection versus radiofrequency ablation with an ablative margin ≥ 1.0 cm for solitary small hepatocellular carcinoma measuring ≤ 3 cm: Comparison of long-term outcomes using propensity score matching analysis. European journal of radiology, 155, 110498. https://doi.org/10.1016/j.ejrad.2022.110498
Cheng, K. C., Ho, K. M., 2022. Pure laparoscopic liver resection versus percutaneous radiofrequency ablation for small hepatocellular carcinoma: a propensity score and multivariate analysis. Translational cancer research, 11(1), 43–51. https://doi.org/10.21037/tcr-21-1045
Li, Y. C., Chen, P. H., Yeh, J. H., et al, 2021. Clinical outcomes of surgical resection versus radiofrequency ablation in very-early-stage hepatocellular carcinoma: a propensity score matching analysis. BMC gastroenterology, 21(1), 418. https://doi.org/10.1186/s12876-021-01995-z
Feng, H., Yang, C., Xu, F., et al, 2022. Therapeutic efficacy of microwave coagulation versus liver resection for hepatocellular carcinoma within the Milan criteria: A propensity score matching analysis. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 48(2), 418–424. https://doi.org/10.1016/j.ejso.2021.08.035

No competing interests reported.

SupplementaryMaterial.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

The prognosis of ablative treatments and liver resection for early-stage hepatocellular carcinoma：a systematic review and Bayesian network meta

Status:

Version 1

Abstract

Objective

Method

Result

Conclusion

Figures

Introduction

Material and method

Result

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1