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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id>
<journal-title>Frontiers in Oncology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Oncol.</abbrev-journal-title>
<issn pub-type="epub">2234-943X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fonc.2024.1366607</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Oncology</subject>
<subj-group>
<subject>Systematic Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Liver transplantation vs liver resection in HCC: promoting extensive collaborative research through a survival meta-analysis of meta-analyses</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Martinino</surname>
<given-names>Alessandro</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1010613"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bucaro</surname>
<given-names>Angela</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2261025"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cardella</surname>
<given-names>Francesca</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1393852"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wazir</surname>
<given-names>Ishaan</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Frongillo</surname>
<given-names>Francesco</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1694159"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ardito</surname>
<given-names>Francesco</given-names>
</name>
<xref ref-type="aff" rid="aff5">
<sup>5</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Giovinazzo</surname>
<given-names>Francesco</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/544991"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of Surgery, Duke University</institution>, <addr-line>Durham, NC</addr-line>, <country>United States</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS</institution>, <addr-line>Rome</addr-line>, <country>Italy</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Surgical Oncology of Gastrointestinal Tract Unit, Vanvitelli University</institution>, <addr-line>Naples</addr-line>, <country>Italy</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Vardhaman Mahavir Medical College &amp; Safdarjung Hospital</institution>, <addr-line>New Delhi</addr-line>, <country>India</country>
</aff>
<aff id="aff5">
<sup>5</sup>
<institution>Hepatobilairy and General Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS</institution>, <addr-line>Rome</addr-line>, <country>Italy</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Giorgio Treglia, Ente Ospedaliero Cantonale (EOC), Switzerland</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Pierluigi Romano, University Hospital of Padua, Italy</p>
<p>Sjaak Pouwels, Elisabeth Tweesteden Hospital (ETZ), Netherlands</p>
<p>Gianluca Rompianesi, University of Naples Federico II, Italy</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Francesco Giovinazzo, <email xlink:href="mailto:giovinazzo_francesco@live.com">giovinazzo_francesco@live.com</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>18</day>
<month>03</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>14</volume>
<elocation-id>1366607</elocation-id>
<history>
<date date-type="received">
<day>06</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>02</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Martinino, Bucaro, Cardella, Wazir, Frongillo, Ardito and Giovinazzo</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Martinino, Bucaro, Cardella, Wazir, Frongillo, Ardito and Giovinazzo</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>HCC is a major global health concern, necessitating effective treatment strategies. This study conducts a meta-analysis of meta-analyses comparing liver resection (LR) and liver transplantation (LT) for HCC.</p>
</sec>
<sec>
<title>Methods</title>
<p>The systematic review included meta-analyses comparing liver resection vs. liver transplantation in HCC, following PRISMA guidelines. Primary outcomes included 5-year overall survival (OS) and disease-free survival (DFS). AMSTAR-2 assessed study quality. Citation matrix and hierarchical clustering validated the consistency of the included studies.</p>
</sec>
<sec>
<title>Results</title>
<p>A search identified 10 meta-analyses for inclusion. The median Pearson correlation coefficient for citations was 0.59 (IQR 0.41-0.65). LT showed better 5-year survival and disease-free survival in all HCC (OR): 0.79; 95% CI: 0.67-0.93, I^2:57% and OR: 0.44; 95% CI: 0.25-0.75, I^2:96%). Five-year survival in early HCC and ITT was 0.63 (95% CI: 0.50-0.78, I^2:0%) and 0.60 (95% CI: 0.39-0.92, I^2:0%). Salvage LT vs. Primary LT did not differ between 5-year survival and disease-free survival (OR: 0.62; 95% CI: 0.33-1.15, I^2:0% and 0.93; 95% CI: 0.82-1.04, I^2:0%).</p>
</sec>
<sec>
<title>Conclusion</title>
<p>Overall, the study underscores the superior survival outcomes associated with LT over LR in HCC treatment, supported by comprehensive meta-analysis and clustering analysis. There was no difference in survival or recurrence rate between salvage LT and primary LT. Therefore, considering the organ shortage, HCC can be resected and transplanted in case of recurrence.</p>
</sec>
</abstract>
<kwd-group>
<kwd>liver transplantation</kwd>
<kwd>liver resection</kwd>
<kwd>hepatocellular carcinoma</kwd>
<kwd>survival</kwd>
<kwd>meta-analysis</kwd>
</kwd-group>
<counts>
<fig-count count="7"/>
<table-count count="4"/>
<equation-count count="0"/>
<ref-count count="132"/>
<page-count count="13"/>
<word-count count="3638"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Surgical Oncology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>Hepatocellular carcinoma (HCC), with 782000 cases diagnosed and 746 000 deaths in 2012 and an age-adjusted worldwide incidence of 10&#xb7;1 cases per 100 000 person-years (<xref ref-type="bibr" rid="B1">1</xref>), is the sixth most common cancer and the third-leading cause of cancer-related mortality in the world (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>).</p>
<p>HCC usually develops in the setting of chronic liver diseases, such as cirrhosis, infections like hepatitis B or C, non-alcoholic fatty liver disease, or alcohol-related liver disease (<xref ref-type="bibr" rid="B1">1</xref>&#x2013;<xref ref-type="bibr" rid="B3">3</xref>). Most HCCs (80%) occur in sub-Saharan Africa and eastern Asia, where the main risk factors are chronic hepatitis B and aflatoxin B1 exposure. Instead, in the USA, Europe, and Japan, hepatitis C is the leading risk factor, together with excessive alcohol intake (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>).</p>
<p>The management of HCC depends on several factors, including the size and number of tumours, the underlying liver function, and the patient&#x2019;s overall health status (<xref ref-type="bibr" rid="B6">6</xref>, <xref ref-type="bibr" rid="B7">7</xref>). Liver resection (LR) and transplantation (LT) are the most effective curative treatments for HCC, with promising outcomes in survival and disease-free survival (DFS) (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B8">8</xref>&#x2013;<xref ref-type="bibr" rid="B10">10</xref>). In patients without clinically significant portal hypertension (CSPH), compensated liver function, and early HCC stages, LR achieves 70% 5-year survival in HCC. However, the survival rate decreases by 50% when those adverse factors are present (<xref ref-type="bibr" rid="B1">1</xref>). On the other hand, 5-year survival in HCC after LT is more than 70% with a recurrence rate of less than 10&#x2013;15% (<xref ref-type="bibr" rid="B1">1</xref>) (<xref ref-type="bibr" rid="B11">11</xref>). However, the choice of the two treatments is also limited by the availability of donor organs. Therefore, choosing between LT and LR for HCC in several cases is still controversial (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B10">10</xref>).</p>
<p>As robust evidence is missing with contrasting results, the objective of the present study was to perform a survival meta-analysis of meta-analyses to compare LT and LR in HCC. The primary outcomes were 5-year overall and disease-free survival after the two different types of treatment.</p>
</sec>
<sec id="s2">
<title>Methods</title>
<p>The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.</p>
<p>A computerised search of PubMed, Scopus and Cochrane Library was carried out. Reference lists of all obtained and relevant articles were screened manually and cross-referenced to identify any additional studies. Articles published from the time of inception to June 2023 were included. An advanced search was performed using the following terms: [(transplant) OR (transplantation)] AND (hepatocellular) OR (HCC) OR (liver cancer).</p>
<sec id="s2_1">
<title>Outcomes of interest</title>
<p>The primary outcomes were 5-year graft overall (OS) and disease-free survival (DFS) in liver resection vs. liver transplantation in all HCCs. The secondary outcomes were OS and DSF in early HCC, Intention to treat, and salvage liver transplantation for HCC.</p>
</sec>
<sec id="s2_2">
<title>Inclusion criteria</title>
<p>The systematic review included meta-analyses comparing liver resection vs. liver transplantation in HCC and reporting the primary and secondary outcomes. Abstracts, letters, comments, editorials and expert opinions, unpublished articles and abstracts, reviews without original data, and case reports were excluded from the analysis. Studies were included only when reporting the number or the rate of events (deaths or recurrences). Two reviewers (AM and IW) independently screened the titles and abstracts of all retrieved articles. The full texts of articles that could fulfil the inclusion criteria were obtained and checked for eligibility.</p>
</sec>
<sec id="s2_3">
<title>Internal validity (methodological quality)</title>
<p>The internal validity of the meta-analyses was assessed by the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) method. AMSTAR is a standardised and reliable method for assessing the quality of systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. FG and FC completed the AMSTAR proforma for all included reviews, and discrepancies were discussed to reach a consensus. Studies were, finally, classified on the level of quality through the online tool calculator (<xref ref-type="bibr" rid="B12">12</xref>).</p>
</sec>
<sec id="s2_4">
<title>Cytation matrix and dendrogram analysis</title>
<p>A sample citation matrix was created by measuring the primary overlap of every included study (<xref ref-type="supplementary-material" rid="SM1">
<bold>Supplementary Table&#xa0;1</bold>
</xref>), and the Pearson correlation coefficient (r) was calculated. r was visualised through a heatmap. A hierarchical cluster analysis of the r was visualised through a dendrogram clusterisation and a silhouette analysis used to identify the number of clusters (<xref ref-type="bibr" rid="B13">13</xref>).</p>
</sec>
<sec id="s2_5">
<title>Data analysis</title>
<p>The results of the meta-analyses were combined using a summary meta-analysis model for odds ratios (OR) and hazard ratio (HR) with 95% confidence intervals.</p>
<p>The fixed-effect method was used to combine the results without statistically significant heterogeneity. The random-effect method was used when heterogeneity was confirmed (p &#x2264;0&#xb7;10). Potential publication bias was investigated by funnel plot. Egger&#x2019;s and Begger&#x2019;s tests were used to assess funnel plot asymmetry and biases [12], and Makaskill&#x2019;s test was used to quantify the bias (14). P&#xa0;&lt;0&#xb7;05 (two-tailed) was considered to indicate statistical significance [13]. Trim-and-fill method was used to adjust for the publication biases.</p>
<p>The meta-analysis of meta-analyses and hierarchical analysis was performed using the R software suite (v3.4.0, <ext-link ext-link-type="uri" xlink:href="https://www.R-project.org">https://www.R-project.org</ext-link>). Statistical heterogeneity between metanalysis was evaluated by &#x3c7;2 and I2, with significance set at p &#x2264;0,10 (<xref ref-type="bibr" rid="B14">14</xref>&#x2013;<xref ref-type="bibr" rid="B16">16</xref>).</p>
</sec>
</sec>
<sec id="s3" sec-type="results">
<title>Results</title>
<sec id="s3_1">
<title>Literature search</title>
<p>The PRISMA flow diagram reports the number of studies screened, assessed, and excluded (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). 19 full-text articles were assessed for eligibility, and 10 meta-analyses comparing an overall 105 studies were included in the umbrella review (<xref ref-type="bibr" rid="B11">11</xref>, <xref ref-type="bibr" rid="B17">17</xref>&#x2013;<xref ref-type="bibr" rid="B25">25</xref>). The characteristics of the included meta-analyses are shown in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>PRISMA flow diagram.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g001.tif"/>
</fig>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Included studies.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="center">Authors</th>
<th valign="top" align="center">Journal</th>
<th valign="top" align="center">Publication Year</th>
<th valign="top" align="center">Range of Years of Included Studies</th>
<th valign="top" align="center">No. of Primary Studies</th>
<th valign="top" align="center">No. of Retrospective Study</th>
<th valign="top" align="center">Finding Direction</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="center">Dhir et&#xa0;al. (<xref ref-type="bibr" rid="B17">17</xref>)</td>
<td valign="top" align="center">HPB</td>
<td valign="top" align="center">2012</td>
<td valign="top" align="center">1990-2011</td>
<td valign="top" align="center">10</td>
<td valign="top" align="center">10</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Rahman et&#xa0;al. (<xref ref-type="bibr" rid="B11">11</xref>)</td>
<td valign="top" align="center">J Gastrointest Surg</td>
<td valign="top" align="center">2012</td>
<td valign="top" align="center">2000-2012</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Li et&#xa0;al. (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="top" align="center">World J Gastroenterol</td>
<td valign="top" align="center">2012</td>
<td valign="top" align="center">1996-2011</td>
<td valign="top" align="center">11</td>
<td valign="top" align="center">11</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Zheng et&#xa0;al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="top" align="center">Transplantation</td>
<td valign="top" align="center">2014</td>
<td valign="top" align="center">Inception to 8 March 2013</td>
<td valign="top" align="center">62</td>
<td valign="top" align="center">not specified</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Proneth et&#xa0;al. (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="top" align="center">Ann Surg Oncol</td>
<td valign="top" align="center">2014</td>
<td valign="top" align="center">1990-2013</td>
<td valign="top" align="center">7</td>
<td valign="top" align="center">7</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Xu et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="top" align="center">Hepatobiliary Pancreat Dis Int</td>
<td valign="top" align="center">2014</td>
<td valign="top" align="center">1990-2012</td>
<td valign="top" align="center">17</td>
<td valign="top" align="center">17</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Menahem et&#xa0;al. (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="top" align="center">Liver Transplantation</td>
<td valign="top" align="center">2017</td>
<td valign="top" align="center">Inception to 8 March 2015</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">9</td>
<td valign="top" align="center">No differences</td>
</tr>
<tr>
<td valign="top" align="center">Schoenberg et&#xa0;al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="top" align="center">Medicine</td>
<td valign="top" align="center">2017</td>
<td valign="top" align="center">1990-2016</td>
<td valign="top" align="center">54</td>
<td valign="top" align="center">54</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Li et&#xa0;al. (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="top" align="center">Clinical Transplantation</td>
<td valign="top" align="center">2017</td>
<td valign="top" align="center">Inception to 8 March 2017</td>
<td valign="top" align="center">6</td>
<td valign="top" align="center">6</td>
<td valign="top" align="center">LT</td>
</tr>
<tr>
<td valign="top" align="center">Koh et&#xa0;al. (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="top" align="center">Hepatobiliary Surg Nutr</td>
<td valign="top" align="center">2022</td>
<td valign="top" align="center">Inception to 8 March 2021</td>
<td valign="top" align="center">35</td>
<td valign="top" align="center">34</td>
<td valign="top" align="center">LT</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3_2">
<title>Quality assessment</title>
<p>Authors of five of the eight meta-analyses cited the previously published meta-analyses, and only one study had no prior studies available to cite (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>). Every included study used Medline/PubMed as part of the literature search, and nine studies also used Embase (<xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref>). There was variation in the utilisation of other databases, but every study (excluding two) used at least two electronic databases. According to the AMSTAR quality assessment, four studies rated low quality and six critically low quality (<xref ref-type="table" rid="T4">
<bold>Table&#xa0;4</bold>
</xref>). The median Pearson correlation coefficient was 0.59 (IQR 0.41-0.65) for all the included studies (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>). Hierarchical clustering of the r identified 3 clusters after silhouette analysis (Cluster Sizes and Average Silhouette Widths: Cluster 1 (26 data points): Average Silhouette Width of 0.443; Cluster 2 (62 data points): Average Silhouette Width of 0.724; Cluster 3 (12 data points): Average Silhouette Width of 0.909); (Median: 0.7341 IQR: 0.5543- 0.8369; Mean: 0.6731 Range 0.1244-0.9534. (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2B</bold>
</xref>).</p>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Number of meta-analyses.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="bottom" align="center">Authors</th>
<th valign="bottom" align="center">Publication Year</th>
<th valign="bottom" align="center">Date of Last Literature Search (mo/yr)</th>
<th valign="top" align="center">No. of Meta-Analyses Possible to Cite</th>
<th valign="top" align="center">No. of Meta-Analyses Cited</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="bottom" align="center">Hong-Yu Li (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">01/04/2010</td>
<td valign="bottom" align="center">1</td>
<td valign="bottom" align="center">0</td>
</tr>
<tr>
<td valign="bottom" align="center">Mashaal Dhir (<xref ref-type="bibr" rid="B17">17</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">31/03/2011</td>
<td valign="bottom" align="center">0</td>
<td valign="bottom" align="center">0</td>
</tr>
<tr>
<td valign="bottom" align="center">Atiq Rahman (<xref ref-type="bibr" rid="B11">11</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">01/03/2012</td>
<td valign="bottom" align="center">2</td>
<td valign="bottom" align="center">0</td>
</tr>
<tr>
<td valign="bottom" align="center">Zheng Zheng (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">01/04/2012</td>
<td valign="bottom" align="center">4</td>
<td valign="bottom" align="center">0</td>
</tr>
<tr>
<td valign="bottom" align="center">Xin-Sen Xu (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">01/07/2012</td>
<td valign="bottom" align="center">5</td>
<td valign="bottom" align="center">1</td>
</tr>
<tr>
<td valign="bottom" align="center">Andrea Proneth (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">01/09/2013</td>
<td valign="bottom" align="center">6</td>
<td valign="bottom" align="center">1</td>
</tr>
<tr>
<td valign="bottom" align="center">Benjamin Menahem (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="bottom" align="center">2017</td>
<td valign="bottom" align="center">01/12/2016</td>
<td valign="bottom" align="center">7</td>
<td valign="bottom" align="center">0</td>
</tr>
<tr>
<td valign="bottom" align="center">Markus B. Schoenberg (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="bottom" align="center">2017</td>
<td valign="bottom" align="center">01/03/2017</td>
<td valign="bottom" align="center">8</td>
<td valign="bottom" align="center">3</td>
</tr>
<tr>
<td valign="bottom" align="center">Wei Li (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="bottom" align="center">2018</td>
<td valign="bottom" align="center">01/06/2017</td>
<td valign="bottom" align="center">9</td>
<td valign="bottom" align="center">1</td>
</tr>
<tr>
<td valign="bottom" align="center">Jin Hean Koh (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="bottom" align="center">2022</td>
<td valign="bottom" align="center">01/03/2021</td>
<td valign="bottom" align="center">11</td>
<td valign="bottom" align="center">1</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Search methodology.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="center">Authors</th>
<th valign="middle" align="center">Year of Publication</th>
<th valign="middle" align="center">Medline/PubMed</th>
<th valign="middle" align="center">Embase</th>
<th valign="middle" align="center">Cochrane Library</th>
<th valign="middle" align="center">Other</th>
<th valign="middle" align="center">Language Limitations</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="bottom" align="center">Mashaal Dhir (<xref ref-type="bibr" rid="B17">17</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Atiq Rahman (<xref ref-type="bibr" rid="B11">11</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">no</td>
</tr>
<tr>
<td valign="bottom" align="center">Hong-Yu Li (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="bottom" align="center">2012</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Zheng Zheng (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">nr</td>
</tr>
<tr>
<td valign="bottom" align="center">Andrea Proneth (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Xin-Sen Xu (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="bottom" align="center">2014</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Benjamin Menahem (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="bottom" align="center">2017</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Markus B. Schoenberg (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="bottom" align="center">2017</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
<tr>
<td valign="bottom" align="center">Wei Li (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="bottom" align="center">2017</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">nr</td>
</tr>
<tr>
<td valign="bottom" align="center">Jin Hean Koh (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="bottom" align="center">2022</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">yes</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">no</td>
<td valign="bottom" align="center">Only English</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T4" position="float">
<label>Table&#xa0;4</label>
<caption>
<p>Amstar 2 evaluation.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Domains</th>
<th valign="top" align="left">Items-Authors</th>
<th valign="top" align="left">Hong-yu (<xref ref-type="bibr" rid="B19">19</xref>)</th>
<th valign="top" align="left">Kostakis (<xref ref-type="bibr" rid="B26">26</xref>)</th>
<th valign="top" align="left">Koh (<xref ref-type="bibr" rid="B18">18</xref>)</th>
<th valign="top" align="left">Zheng Zheng (<xref ref-type="bibr" rid="B25">25</xref>)</th>
<th valign="top" align="left">Xin-sen Xu (<xref ref-type="bibr" rid="B24">24</xref>)</th>
<th valign="top" align="left">Schoenberg (<xref ref-type="bibr" rid="B23">23</xref>)</th>
<th valign="top" align="left">Proneth (<xref ref-type="bibr" rid="B22">22</xref>)</th>
<th valign="top" align="left">Rahaman (<xref ref-type="bibr" rid="B11">11</xref>)</th>
<th valign="top" align="left">Dhir (<xref ref-type="bibr" rid="B17">17</xref>)</th>
<th valign="top" align="left">Menahem (<xref ref-type="bibr" rid="B21">21</xref>)</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">1. Did the research questions and inclusion criteria for the review include the components of PICO?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">3. Did the review authors explain their selection of the study designs for inclusion in the review?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">4. Did the review authors use a comprehensive literature search strategy?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">Partial yes</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">5. Did the review authors perform study selection in duplicate?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">6. Did the review authors perform data extraction induplicate?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">7. Did the review authors provide a list of excluded studies and justify the exclusions?</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">Partial Yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">8. Did the review authors describe the included studies in adequate detail?</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included<break/>in the review?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">Partial yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">10. Did the review authors report on the sources of funding for the studies included in the review?</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">11. If meta-analysis was performed did the review authors use appropriate methods for statistical<break/>combination of results?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual<break/>studies on the results of the meta-analysis or other evidence synthesis?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">13. Did the review authors account for RoB in individual studies when interpreting/discussing the results<break/>of the review?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left">
<bold>Critical</bold>
</td>
<td valign="top" align="left">15. If they performed quantitative synthesis did the review authors carry out an adequate investigation<break/>of publication bias (small study bias) and discuss its likely impact on the results of the review?</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">no</td>
<td valign="middle" align="left">yes</td>
<td valign="middle" align="left">yes</td>
</tr>
<tr>
<td valign="top" align="left"/>
<td valign="top" align="left">
<bold>Overall AMSTAR 2 Rating</bold>
</td>
<td valign="top" align="left">Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
<td valign="top" align="left">Low quality</td>
<td valign="top" align="left">Low quality</td>
<td valign="top" align="left">Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
<td valign="top" align="left">Critially<break/>Low quality</td>
</tr>
</tbody>
</table>
</table-wrap>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>
<bold>(A)</bold> Cluster Dendrogram. <bold>(B)</bold> Silhouette Plot of Cluster Assignments.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g002.tif"/>
</fig>
</sec>
<sec id="s3_3">
<title>Primary outcome</title>
<sec id="s3_3_1">
<title>5 years overall survival</title>
<p>LT showed better 5-year survival in all HCC (Odd Ratio (OR): 0.79; 95% CI: 0.67-0.93, I^2:57%), (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3A</bold>
</xref>), Egger&#x2019;s test showed a significant funnel plot asymmetry (t = -2.62, df = 5, p = 0.0468). Begg&#x2019;s test did not find funnel plot asymmetry (z = -1.05, p = 0.2931) (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3B</bold>
</xref>). After the 5-year survival Trim-and-fill method, both Egger&#x2019;s and Begg&#x2019;s tests did not show evidence of publication bias (t&#xa0;= -0.07, df = 9, p-value = 0.9437 and z = -0.08, p-value = 0.9372, respectively) (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3C</bold>
</xref>).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>
<bold>(A)</bold> 5-year overall survival in all HCC. <bold>(B)</bold> Funnel plot. <bold>(C)</bold> Funnel plot after Trim-and-fill.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g003.tif"/>
</fig>
</sec>
<sec id="s3_3_2">
<title>5 years disease survival</title>
<p>DFS favoured LT for all HCC (OR: 0.44; 95% CI: 0.25-0.75, I^2:96%) (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4A</bold>
</xref>). The Egger&#x2019;s test (t = 0.02, df = 3, p-value = 0.9879) and Begg&#x2019;s test (z = -0.68, p-value = 0.4969) did not indicate significant publication bias in the original analysis (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4B</bold>
</xref>). After applying the Trim-and-fill method, the Egger&#x2019;s test (t = 0.02, df = 3, p-value = 0.9879) and Begg&#x2019;s test (z = -0.76, p-value = 0.4485) still did not show significant evidence of publication bias (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4C</bold>
</xref>).</p>
<fig id="f4" position="float">
<label>Figure&#xa0;4</label>
<caption>
<p>
<bold>(A)</bold> 5-year disease-free survival in all HCC. <bold>(B)</bold> Funnel plot. <bold>(C)</bold> Funnel plot after Trim-and-fill.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g004.tif"/>
</fig>
</sec>
</sec>
<sec id="s3_4">
<title>HR Overall and disease-free survival</title>
<p>Two studies reported the HR for overall and disease-free survival favouring LT over liver resection (1.30, 95% CI: 1.10-1.55, I^2: 24% and 2.46, 95% CI: 2.03-2.99, I^2: 47%) (<xref ref-type="fig" rid="f5">
<bold>Figures&#xa0;5A, B</bold>
</xref>).</p>
<fig id="f5" position="float">
<label>Figure&#xa0;5</label>
<caption>
<p>
<bold>(A)</bold> HR overall survival. <bold>(B)</bold> HR disease free survival.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g005.tif"/>
</fig>
</sec>
<sec id="s3_5">
<title>Secondary outcomes</title>
<p>Five-year survival in early HCC and ITT was 0.63 (95% CI: 0.50-0.78, I^2:0%), (<xref ref-type="fig" rid="f6">
<bold>Figure&#xa0;6A</bold>
</xref>) and 0.60 (95% CI: 0.39-0.92, I^2:0%), respectively (<xref ref-type="fig" rid="f6">
<bold>Figure&#xa0;6B</bold>
</xref>). Salvage LT vs. Primary LT did not differ between 5-year survival and DFS (OR: 0.62; 95% CI: 0.33-1.15, I^2:0% and 0.93; 95% CI: 0.82-1.04, I^2:0%) (<xref ref-type="fig" rid="f7">
<bold>Figures&#xa0;7A, B</bold>
</xref>).</p>
<fig id="f6" position="float">
<label>Figure&#xa0;6</label>
<caption>
<p>
<bold>(A)</bold> Five-year survival in early HCC. <bold>(B)</bold> Five-year survival in ITT.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g006.tif"/>
</fig>
<fig id="f7" position="float">
<label>Figure&#xa0;7</label>
<caption>
<p>
<bold>(A)</bold> Salvage vs primary (overall). <bold>(B)</bold> Salvage vs primary (disease free).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1366607-g007.tif"/>
</fig>
</sec>
</sec>
<sec id="s4" sec-type="discussion">
<title>Discussion</title>
<p>Comparing the outcomes of LT and LR in HCC is crucial because it can inform the decision-making process for selecting the most appropriate treatment option for individual patients (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B11">11</xref>, <xref ref-type="bibr" rid="B21">21</xref>). By identifying the best treatment between LT and LR, healthcare providers improve the patient&#x2019;s overall survival and quality of life. Furthermore, there is a shortage of donor organs worldwide, so optimising organ allocation is central to HCC. In some cases, LR may be a viable alternative to LT as a definitive treatment, especially for patients with early-stage HCC and those with limited underlying liver disease or bridge therapy in case of cancer recurrences (<xref ref-type="bibr" rid="B10">10</xref>, <xref ref-type="bibr" rid="B27">27</xref>&#x2013;<xref ref-type="bibr" rid="B29">29</xref>). The study included a large cohort of patients, which is a relatively large sample size and may increase the reliability of the findings.</p>
<p>Furthermore, the study conducted a systematic review and meta-analysis of multiple meta-analyses, which may provide a more comprehensive picture of the topic. Also, the study conducted subgroup analyses for different types of HCC and liver transplantation, which may help identify specific factors that influence outcomes.</p>
<p>LT showed better OS and DFS than LR for HCC. However, survival after retransplantation for cancer recurrences was equal to primary LT for HCC. The finding agreed with the included meta-analyses, independently from the correlation matrix and the cluster analysis.</p>
<p>The results of the meta-analysis provide valuable insights into the comparative effectiveness of liver transplantation (LT) and liver resection for hepatocellular carcinoma (HCC) in terms of 5-year overall survival, disease-free survival, and hazard ratio (HR) for overall survival. These findings align with the evolving body of research in the field, which examines the optimal treatment approaches for HCC patients.</p>
<p>While the meta-analysis indicates funnel plot asymmetry through Egger&#x2019;s test, this could suggest the presence of publication bias that may skew the results. Using the Trim-and-fill method to address publication bias enhances the reliability of the findings. The favourable disease-free survival outcomes favouring LT over liver resection for all HCC cases align with previous research suggesting that LT can lead to more extended periods without recurrence (<xref ref-type="bibr" rid="B30">30</xref>, <xref ref-type="bibr" rid="B31">31</xref>). The absence of significant publication bias in the initial analysis and after using the Trim-and-fill method adds confidence to these findings.</p>
<p>Furthermore, the HR analysis suggests that LT may be associated with better overall survival than liver resection, as the HR favours LT. The I^2 value of 24% suggests moderate heterogeneity, indicating relatively consistent results among the studies included.</p>
<p>The quality assessment of the included studies reveals that there was at least a critical flaw in the meta-analysis methodology. Many of the studies under consideration did not adequately address the potential risks of bias in their analyses, nor did they thoroughly discuss how these biases might influence the outcomes reported in the review. This oversight raises concerns about the robustness and reliability of the findings presented in these studies (<xref ref-type="bibr" rid="B32">32</xref>). Biases, whether related to study design, data collection, or reporting, can introduce systematic errors that may distort the overall conclusions of a meta-analysis. Failing to acknowledge and address these biases can undermine the validity and credibility of the study&#x2019;s results. It is essential for future research to comprehensively evaluate and report on the potential biases and their potential impact to ensure the accuracy and reliability of the meta-analytic findings.</p>
<p>There was some heterogeneity in the data, particularly in the DFS analysis, possibly due to differences in study design and patient populations. Therefore, despite the present findings, individual patient factors and clinical considerations should still be considered when determining the most appropriate treatment approach for HCC (<xref ref-type="bibr" rid="B31">31</xref>).</p>
<p>The correlation analysis of the present study indicates a moderate association level between the variables, while hierarchical clustering identified three distinct clusters based on the correlation coefficients. The integration of hierarchical clustering analysis to validate the consistency of findings adds further strength to the results. The silhouette analysis suggests these clusters are well-defined, with different data points forming cohesive groups. The three clusters showed good separation and assignment of data points to clusters, confirming a consistent agreement among the meta-analyses about the advantage of LT over LR, independently from the included studies.</p>
<p>Several potential sources of bias in this study should be considered. While the results and conclusions of the study may provide valuable insights into the overall management of HCC, it is essential to consider the heterogeneity of the patient population and the specific clinical contexts when interpreting the findings for different subgroups of patients. A limitation of the present study was the difficulties in drawing the same conclusions for patients with HCC within or outside Milan criteria, undergoing a first or a salvage transplantation. Similarly, whether the manuscript included three meta-analyses, reporting outcomes in ITT patients, the lack of robust data may result in a positive outcome for the LT group and in a disadvantage in the LR group. Another potential source of bias is measurement bias, as the determination of survival and disease-free survival may be affected by factors such as follow-up time, surveillance protocols, and the definition of recurrence. Finally, there may be publication bias, as studies with negative or null findings may be less likely to be published or included in systematic reviews and meta-analyses (<xref ref-type="bibr" rid="B33">33</xref>, <xref ref-type="bibr" rid="B34">34</xref>).</p>
<p>By systematically analysing the citation matrix, the authors identified clusters of meta-analysis indicating potential overlap or duplication. However, the association was moderate, and the primary outcomes results consistent. The integration of hierarchical clustering analysis to validate the consistency of findings added further strength to the results. The silhouette analysis suggested these clusters were well-defined, with different data points forming cohesive groups. The three clusters showed good separation and assignment of data points to clusters, confirming a consistent agreement among the meta-analyses about the advantage of LT over LR, independently from the included studies.</p>
<p>Future research could explore the impact of patient-specific characteristics on treatment effectiveness, investigate new biomarkers for patient selection, develop individualised treatment algorithms, and assess novel therapies in combination with surgical interventions to improve outcomes.</p>
<p>In conclusion, the study&#x2019;s findings consistently suggest that LT offers better 5-year and disease-free survival rates than LR for HCC. These results hold significance for clinical practice, as they provide insights into the most effective treatment approach for HCC patients. The study underscores the importance of addressing biases and limitations in meta-analyses and highlights potential areas for future research to enhance HCC treatment strategies.</p>
</sec>
<sec id="s5" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="supplementary-material" rid="SM1">
<bold>Supplementary Material</bold>
</xref>. Further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>AM: Conceptualization, Formal analysis, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. AB:&#xa0;Writing&#xa0;&#x2013; original draft, Writing &#x2013; review &amp; editing. FC: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. IW:&#xa0;Writing&#xa0;&#x2013; original draft, Writing &#x2013; review &amp; editing. FF: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. FA:&#xa0;Writing&#xa0;&#x2013; original draft, Writing &#x2013; review &amp; editing. FG: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.</p>
</sec>
</body>
<back>
<sec id="s7" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<sec id="s8" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s9" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s10" sec-type="supplementary-material">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fonc.2024.1366607/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fonc.2024.1366607/full#supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="Image_1.pdf" id="SM1" mimetype="application/pdf"/>
<supplementary-material xlink:href="Table_1.docx" id="ST1" mimetype="application/vnd.openxmlformats-officedocument.wordprocessingml.document"/>
</sec>
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