Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally (1-3). Liver transplantation (LT) and liver resection (LR) are first line options for curative treatment of HCC (4-6). LT treats both the tumour and the surrounding cirrhotic microenvironment (7,8). It is associated with excellent long-term survival outcomes (9-11). Unfortunately, the availability of LT is hampered by the severe shortage of liver allografts (12). In contrast, LR is widely available, eliminates the need for an allograft but has a higher recurrence rate compared to LT (13).

Major society guidelines recommend LR when the hepatic function is preserved and sufficient remnant liver volume is maintained (4-6). By contrast, LT can be performed in the setting of hepatic decompensation and is recommended for patients with HCC within the Milan criteria, defined as 1 tumour up to 5 cm, or up to 3 tumours not exceeding 3 cm in the absence of macrovascular invasion (14,15).

No randomized controlled trial has been conducted to compare survival outcomes between patients receiving LT and LR for HCC. Previous analyses have been limited to results from observational studies (13,16). A previous meta-analysis reported similar overall survival (OS) between LT and LR among patients meeting the Milan criteria, however, there were limited data available at the point of analysis (13). In addition, survival outcomes between LR and LT may have changed over time with the widespread availability of safe and efficacious antiviral therapies for both hepatitis B virus (HBV) and hepatitis C virus (HCV) (17,18). Furthermore, it is unclear how survival outcomes vary by region, surveillance strategy and disease burden.

Therefore, through a systematic review and meta-analytic approach, we aimed to compare the OS and disease-free survival (DFS) of LR versus LT for treatment of patients with HCC within the Milan criteria. Our secondary aims were to compare the survival outcomes between LT and LR by region, time period, surveillance strategy and the presence of uninodular disease. We present the following article in accordance with the PRISMA reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-350/rc).

Methods

Search strategy

This review was registered with PROSPERO (CRD42021255085). With reference to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (19), a search was conducted on Medline and Embase databases for articles relating to LT and LR for the treatment of HCC from inception to 8 March 2021. The search strategy used was for ‘liver transplantation’, ‘liver resection’, and ‘hepatocellular carcinoma’ and the related terms in titles and abstracts. The full search strategy is included in Appendix 1. The references of included articles were also screened manually for a comprehensive search.

Study selection

Three authors (JHK, YO, WHL) independently screened abstracts to check the eligibility for inclusion, with disputes being resolved through consensus from a fourth independent author (DJHT). Retrospective and prospective cohort studies, cross-sectional studies and randomized controlled trials were considered for inclusion. Systematic reviews, meta-analyses, and editorials were excluded. Only English language articles were considered for inclusion. Studies were included if they (I) involved patients undergoing either LT or LR for HCC, (II) compared the survival outcomes, including OS and/or DFS, of LT and LR and (III) only included patients with tumours within the Milan criteria. Paediatric patients were excluded from the analysis.

Data extraction

Relevant data from included articles were extracted by a pair of independent authors (JHK and YO) into a structured proforma. The primary outcome of interest was the OS and DFS following LT or LR. OS was defined as the date of LT or LR to the date of death or last follow-up. DFS was defined as the time from LT or LR to the time of cancer recurrence or last follow-up. We extracted adjusted hazard ratio (HR) where possible. Study characteristics including author, year of study end-date, country, region, income level, and patient demographics [including but not limited to sample size, age, gender, MELD score, Child-Pugh score, presence of microvascular invasion, presence of cirrhosis, alpha-fetoprotein (AFP) level, type of surveillance strategy, indication for transplant, presence of poorly differentiated tumour histology, number of tumour nodules, length of follow-up, and tumour size] were also extracted. Income levels were defined according to the definitions set by the World Bank (20). Tumour grade was evaluated via the Edmondson-Steiner classification.

Surveillance strategy was classified into enhanced and non-enhanced groups, with enhanced surveillance defined as computed tomography (CT) or magnetic resonance imaging (MRI), at 3 to 4 monthly intervals in the first 2 years after surgery, then imaging at least 6 monthly afterwards. Non-enhanced surveillance was defined as the use of CT or MRI less frequently than every 3 to 4 months within the first and second year postoperatively, imaging less frequently than 6 monthly from the third postoperative year onward, or the use of ultrasound rather than CT or MRI in the first two postoperative years.

Statistical analysis and quality assessment

All analysis was conducted in R Studio (Version 4.0.3) using the meta package. A conventional pairwise meta-analysis was done in HR using the DerSimonian and Laird random effects model to assess the comparative survival between LR and LT for HCC in terms of OS and DFS. Statistical heterogeneity was assessed via I² and Cochran Q test values, where an I² value of 25%, 50% and 75% represented low, moderate, and high degree of heterogeneity respectively (21,22). A Cochran Q test with P value of ≤0.10 was considered significant for heterogeneity. However, random effects models were used in all analysis regardless of heterogeneity as recent evidence suggests that it provides more robust outcome measures compared to the alternative fixed effects models (23). When sufficient studies were available, the effect of risk factors on the dependant variable, HR for OS and DFS between LR and LT, was determined via meta-regression. This was done via univariate meta-regression using a mixed model with a logit transformation on independent variables including microinvasion, cirrhosis, Child-Pugh class, aetiology and poorly differentiated tumour histology. Statistical significance was considered for outcomes with a P value ≤0.05. Subgroup analysis was considered for differing survival outcomes between LT and LR by type of postoperative surveillance strategy, region, income level, and time period (study end-date before and after year of 2010). Additionally, sensitivity analysis was conducted for studies that conducted intention-to-treat (ITT) analysis, which was defined as analysis of all patients who were listed for LT, including those who did not receive LT due to dropout from the waiting list from death or progression of HCC. Sensitivity analysis was also conducted for studies involving living donor liver transplantation (LDLT) patients only. Quality assessment of included articles was done with the Newcastle-Ottawa Scale quality assessment (NOS). The NOS rates the risk of bias of cohort studies on the premises of appropriateness of sample frame, sampling method, ascertainment of exposure, demonstration that outcome of interest was not present at start of study, comparability of cohorts, methods for assessment of outcomes, duration of follow-up and adequacy of follow-up (24). Publication bias was assessed by visual inspection of the respective funnel plots (25).

Results

Study selection and study characteristics

A total of 2,278 articles were included in the initial search after removal of duplicates, of which 138 were selected for full text review; 35 articles met the final inclusion criteria (Figure 1), with 8 studies from China (26-33), 7 from the United States (34-40), 5 from South Korea (41-45), 2 each from France (46,47), Germany (48,49), Japan (50,51) and Spain (52,53), 1 each from Canada (54), Italy (55), Hong Kong (56), Israel (57), Taiwan (58), Turkey (59), and 1 multicentre study (60). Tables S1,S2 contain the summary of the key characteristics and quality assessment for included articles. A total of 18,095 patients with tumours within the Milan criteria were included in our analysis, with 8,204 and 9,891 patients undergoing LT and LR respectively. The majority of articles were retrospective studies (n=34), except for 1 prospective study; 11 articles provided survival data for uninodular HCC (26,30-32,34,43,45,46,53,56,60); 20 articles had a study end-date before 2010 (33,35-37,40,42,43,45,47,49-56,60-62). Additionally, 14 studies used enhanced surveillance strategies for HCC surveillance after surgery (26,28,30,33-35,40,43,44,56-58,61,62). All included studies were of high quality by NOS, with 10 studies having an NOS score of 9, and 25 studies having an NOS score of 8.

Figure 1 PRISMA flow diagram for included articles. LT, liver transplantation; LR, liver resection; HCC, hepatocellular carcinoma; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analyses.

Patient and tumour characteristics

A summary of the baseline demographics and tumour characteristics in the LT and LR groups is presented in Table 1. There was no significant difference in patient demographics or tumour characteristics between LT and LR, except for the presence of cirrhosis [LT: 95.51%; 95% confidence interval (CI): 94.52–96.32 vs. LR: 87.19%; 95% CI: 85.97–88.31; P<0.001]. Mean age was 53.74 (95% CI: 51.59–55.90) years in the LT group, compared to 57.05 (95% CI: 54.47–59.63) years in the LR group (P=0.054). In both LT and LR groups, the most common etiology of liver disease was HBV infection (LT: 39.45%; 95% CI: 16.42–68 vs. LR 47.67%; 95% CI: 27.57–68.56; P=0.658), followed by HCV (LT: 33.56%; 95% CI: 18.37–53.15 vs. LR: 19.79%; 95% CI: 11.10–32.76; P=0.184. Alcoholic liver disease was the next most common etiology (LT: 13.52%; 95% CI: 6.21–26.95 vs. LR: 14.83%; 95% CI: 7.83–26.28; P=0.851), followed by non-alcoholic steatohepatitis (NASH) (LT: 5.60%; 95% CI: 3.13–9.80 vs. LR: 9.22%; 95% CI: 5.59–14.85; P=0.1923).

With regards to tumour characteristics, 11.77% (95% CI: 8.39–16.26) of tumours in the LT group had poorly differentiated histology, compared to 14.84% (95% CI: 8.90–23.71) in patients that underwent LR (P=0.447). The proportion of patients with microvascular invasion (LT: 15.23%; 95% CI: 9.04–24.53 vs. LR: 19.83%; 95% CI: 12.63–29.75; P=0.434) and uninodular HCC (LT: 89.67%; 95% CI: 88.25–90.94 vs. LR: 91.15%; 95% CI: 90.09–92.11; P=0.080) were also similar between patients that underwent LT and LR. Mean size of the largest lesion was 2.74 (95% CI: 2.40–3.08) cm in patients that had undergone LT, compared to 3.24 (95% CI: 2.79–3.68) cm in the LR group (P=0.084).

Among LT recipients, 78.07% (95% CI: 75.88–80.11%) of patients underwent LDLT, while 19.89% (95% CI: 17.93–22.01%) underwent deceased donor liver transplantation (DDLT). However, in Asian transplant centres, LDLT was the dominant mode of LT (96.97%; 95% CI: 92.38–99.97%). Comparatively, in non-Asian transplant centres, there was a similar proportion of patients that underwent LDLT (46.06%; 95% CI: 41.91–50.26%) and DDLT (48.44%; 95% CI: 44.27–52.64%).

OS

Overall and by time period

A summary of the results is found in Table 2. From pooled analysis of 33 studies including 14,513 patients, patients that underwent LR had poorer OS compared to LT (HR =1.44; 95% CI: 1.14–1.81; P<0.01; Figure 2). When results were stratified by date of study, LR was associated with significantly poorer OS compared to LT for studies completed before 2010 (HR =1.50, 95% CI: 1.19–1.91; P<0.01). However, among studies that were completed in 2010 and after, there was no significant difference in OS (HR =1.39; 95% CI: 0.92–2.08; P=0.12). There was a high degree of heterogeneity (I² =92%; t² =0.3649; P<0.01). There was no evidence of publication bias based on funnel plot (Figure S1).

Figure 2 Forest plot for OS among patients who underwent LR versus LT for HCC. HR, hazard ratio; CI, confidence interval; OS, overall survival; LR, liver resection; LT, liver transplantation; HCC, hepatocellular carcinoma.

Uninodular HCC

Among patients with uninodular disease (11 studies, 6,021 patients), there was no significant difference in pooled OS between LR and LT (HR =1.40, 95% CI: 0.91–2.17; P=0.13).

Region and income

In patients undergoing treatment in centres from Europe (7 studies, 1,438 patients) and North America (7 studies, 9,822 patients), LR was associated with poorer OS when compared with LT (HR =1.90; 95% CI: 1.35–2.69; P<0.01 and HR =1.50; 95% CI: 1.10–2.04; P<0.01 respectively) (Table 2). However, there was no significant difference in pooled OS between LR and LT among studies conducted in Asia (16 studies, 7,067 patients HR =1.26; 95% CI: 0.85–1.85; P=0.25) and the Middle East (2 studies, 147 patients HR =1.07; 95% CI: 0.28–4.13; P=0.92). In terms of income level, LR was associated with poorer OS among patients from high income countries (HR =1.55; 95% CI: 1.28–1.87; P<0.01). In patients from middle income countries, there was no significant difference in OS (HR =1.30; 95% CI: 0.77–2.21; P=0.33).

LDLT

When analysis was limited to LDLT-only studies (8 studies, 936 patients), there was no significant difference in OS between LT and LR groups (HR =1.38; 95% CI: 0.75–2.55; P=0.30). In LDLT-only studies conducted in Asian transplant centres (7 studies, 722 patients), OS also did not differ significantly (HR =1.16; 95% CI: 0.71–1.89; P=0.565).

Postoperative surveillance strategy

In patients following an enhanced surveillance strategy, there was no significant difference in pooled OS between LR and LT (13 studies, 3,193 patients, HR =1.15; 95% CI: 0.87–1.51; P=0.33, Figure 3). By contrast, among studies that did not utilize enhanced postoperative surveillance (4 studies, 720 patients), LR was associated with poorer OS versus LT (HR =1.95; 95% CI: 1.24–3.07; P<0.01).

Figure 3 Forest plot for OS among patients who underwent LR versus LT, by surveillance strategy. HR, hazard ratio; CI, confidence interval; OS, overall survival; LR, liver resection; LT, liver transplantation.

DFS

Overall, and by time period

In total 25 studies (9,735 patients) provided data for analysis of DFS. Patients undergoing LR had poorer DFS compared to LT (HR =2.71; 95% CI: 2.23–3.28; P<0.01, Figure 4). When results were stratified by date of study completion, patients undergoing LT had improved DFS among both studies completed before (HR =2.24; 95% CI: 1.55–3.24; P<0.01) and after 2010 (HR =3.05; 95% CI: 2.45–3.79; P<0.01). There was a moderate degree of heterogeneity (I² =64%; t² =0.1262, P<0.01). There was no evidence of publication bias based on the funnel plot (Figure S2).

Figure 4 Forest plot for DFS among patients who underwent LR versus LT for HCC. HR, hazard ratio; CI, confidence interval; DFS, disease-free survival; LR, liver resection; LT, liver transplantation; HCC, hepatocellular carcinoma.

Uninodular HCC

Among patients with uninodular disease only (10 studies, 2,797 patients), LR was associated with poorer DFS compared with LT (HR =2.95; 95% CI: 2.30–3.79; P<0.01).

By region and income

Among studies from Asia (14 studies, 3,883 patients HR =2.61; 95% CI: 2.00–3.40; P<0.01), Europe (5 studies, 973 patients HR =3.03; 95% CI: 2.01–4.59; P<0.01), and North America (5 studies, 5,111 patients HR =3.08; 95% CI: 2.18–4.34; P<0.01), DFS was improved in patients that underwent LT compared to LR. In terms of income, LT was associated with significantly improved DFS compared to LR in both high (12 studies, 7,124 patients HR =2.71; 95% CI: 2.12–3.48; P<0.01) and middle-income countries (8 studies, 2,611 patients HR =2.76; 95% CI: 2.20–3.45; P<0.01).

LDLT

A sensitivity analysis was conducted for LDLT-only studies (7 studies, 722 patients). LT was associated with improved DFS compared to LR (HR =3.60; 95% CI: 2.77–4.69; P<0.01). Additionally, when studies were further stratified by region, LDLT-only studies from Asian transplant centres (5 studies, 690 patients) continued to report improved DFS in patients that had underwent LT compared to LR (HR =3.16; 95% CI: 2.30–4.34; P<0.001).

Meta-regression of factors associated with survival and DFS

Meta-regression of study-level demographic, clinical, and biochemical characteristics for potentially relevant factors with sufficient data revealed that NASH was associated with increased HR for DFS between LR and LT. This suggests that in patients with NASH, LT was associated with relatively improved DFS compared to LR (β =8.17; 95% CI: 3.99–12.35; P<0.01) (Table 3).

Sensitivity analyses for ITT studies

Analysis for OS among ITT studies (12 studies, 2,798 patients) showed a similar result to the main analysis, with a poorer OS (HR =1.31; 95% CI: 1.09–1.57; P<0.01) (Figure S3) among LR versus LT patients. Analysis for DFS among ITT studies (7 studies, 1,937 patients) showed that DFS remained poorer among LR versus LT patients (HR =2.17; 95% CI: 1.28–3.66; P<0.01) (Figure S4).

Discussion

In this meta-analysis of 35 studies and 18,421 HCC patients within the Milan criteria, we determined that patients who underwent LR had a poorer OS versus those who underwent LT (HR =1.44; 95% CI: 1.14–1.81), with similar findings among ITT studies. In addition, patients who underwent LR had almost threefold risk of HCC recurrence (HR =2.71; 95% CI: 2.23–3.28) compared with LT patients. These findings emphasize that LT remains the ideal treatment option for HCC by removing both the tumour and the surrounding diseased liver, thus addressing the field change effect and lowering the risk of recurrence (63).

However, among patients with uninodular lesions within the Milan criteria, there was no significant difference in OS between LR and LT (HR =1.40; 95% CI: 0.91–2.17), although the risk of recurrence remained around threefold (HR =2.95; 95% CI: 2.30–3.79). For such patients, LT is the ideal long-term curative treatment. However, considering graft shortages and the need for long term post-transplant immunosuppression, LR is a reasonable alternative. Our study provides useful data for care providers who are counselling patients with a single HCC lesion, especially in light of the increasing availability of LDLT as a treatment option (64).

LR was associated with poorer OS when compared to LT in North America and Europe, but not in Asia. This may be related to the lower proportion of cirrhosis among HBV-related HCC patients in Asia (3,8,65). LT among non-Asian countries are predominantly DDLTs, while LT among Asian countries are predominantly LDLTs. Among patients who underwent DDLT, the time spent on the waitlist helps to select for patients with better tumour biology, unlike LDLT, where waiting time is minimized (66). Smaller graft volume grafts used in LDLT may reduce OS in patients that underwent LT in Asian centres (67,68). Furthermore, strong surveillance programs in Asia, along with the use of additional biomarkers such as protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP-L3) may allow for earlier detection of HCC recurrence after LR and improved survival (6,69). These factors could have accounted for the lack of difference in OS between LT and LR among Asian as well as LDLT only studies. In addition, antiviral therapy for hepatitis B is well established and effective in reducing mortality after hepatectomy, which may also explain why survival after LR is comparable to that of LT in Asia, where HBV is the dominant cause of HCC (17,70-72). However, compliance to HBV antiviral therapy is poor, and urgent efforts are required to improve compliance and linkage to care for patients with HBV-related HCC (73). By contrast, HCV is a major cause of HCC in North America and Europe, and while direct antiviral therapy (DAA) is safe and effective in prolonging survival, DAAs have only recently become widely available. Its effect on survival after LR may only be seen in future studies (18).

Over time, it appeared that OS after LR was significantly poorer compared with LT among studies concluded prior to 2010 (HR =1.50; 95% CI: 1.19–1.91) but not after (HR =1.39; 95% CI: 0.92–2.08). This may be related to better surveillance and medical care resulting in recurrent disease detected earlier. Among studies that used enhanced surveillance, there was no significant difference in OS between LT and LR patients. This suggests that when comprehensive post-operative surveillance is performed, LR may result in a similar OS to LT through early detection of HCC recurrence allowing for earlier treatment. A study of 734 HCC patients that underwent resection found that lack of tumour surveillance was an independent predictor of mortality (74). Among hepatology guidelines, there is a lack of recommendations for surveillance after resection (5,6,15), however the National Comprehensive Cancer Network guidelines suggest that imaging be obtained every 3 to 6 months for the first 2 years after surgery, then 6–12 monthly thereafter for up to 5 years (75). Of note, adherence to HCC surveillance in the real world remain poor in general, and further efforts are urgently required to improve compliance (76-78). Additional studies are required to evaluate the optimal surveillance interval after curative surgery.

We found that OS after LR was poorer when compared to LT in high income countries, but not among middle income countries. We speculate that better medical care in high income countries may have resulted in disproportionately better survival outcomes after LT versus LR by maximising the benefit of LT and reducing post-LT complications. By contrast, a lower standard of post-transplant care may result in comparable survival with patients who underwent LR, however more data are required to validate these findings.

NASH-related HCC was found to be associated with increased HR for DFS between LR and LT, suggesting that LT was associated with relatively better DFS in patients with NASH. This is contrary to available data which suggests that NASH-related HCC has a similar prognosis after curative treatment to other disease aetiologies (79). This may be related to the limitation of using study-level data, rather than individual patient data. In addition, only a modest number of studies (n=5) had sufficient data for analysis of DFS in NASH, hence this result should be interpreted with caution.

In context with current literature

In contrast with a previous meta-analysis by Menahem and colleagues which reported no difference in the odds ratio for OS between LR and LT, we found that OS was significantly better for LT versus LR (13). Menahem and colleagues utilized odds ratio instead of HR to analyse survival outcomes (13), which is a less robust measure of time-dependent analysis that does not account for censoring of data (80). By contrast, we used HR to compare OS which allows for more accurate time-dependent analysis and performed additional analyses by region, time period, income, and the use of enhanced surveillance. In addition, we were able to provide pooled data for uninodular lesions within Milan which was not available in the prior study by Menahem et al. (13). Despite our findings emphasizing the survival advantage of LT versus LR, we recognize that many patients lack access to LT, especially in countries with low organ donation rates. In addition, even in countries where donor organs are more readily available, patients may still opt for LR over LT due to avoid the need for long-term immunosuppression. In these situations, should there be HCC recurrence after LR, salvage LT may still be a possible treatment option.

Strengths and limitations

This large meta-analysis provides a thorough and updated comparison of survival outcomes following LT and LR. However, there are several limitations to this study. Firstly, there are inherent selection biases in retrospective studies. While we have limited our included studies to patients within the Milan criteria, other features such as age are not strictly comparable in different studies. Proportion of cirrhosis was also significantly lower in the LR group, which could have partially confounded our findings. Furthermore, given that only retrospective studies were available for inclusion, this has led to a higher level of heterogeneity. In addition, there were limited studies available for the meta-regression of some baseline characteristics on survival outcomes, which reduces the statistical power for the analysis of risk factors. Finally, there was paucity of data from Africa and South America, which highlights the need for more studies from these regions.

Conclusions

In summary, we found that mortality was nearly 50% higher among patients with HCC treated with LR versus LT. Patients who underwent LR had a threefold higher risk of recurrent disease compared with LT recipients. However, survival was similar between patients with uninodular disease who underwent LR and LT. Survival after LR and LT was also similar in Asia, where LDLT predominates, but not in North America and Europe. In addition, survival was similar among LR and LT patients who underwent enhanced surveillance after surgery but was poorer among LR patients who underwent usual surveillance. Greater efforts are required to improve adherence to surveillance for HCC recurrence, especially after LR.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-350/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-350/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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