Patients with hepatocellular carcinoma and portal vein tumour thrombosis after successful downstaging may be candidates for liver transplantation: A meta-analysis

Are patients with hepatocellular carcinoma and portal vein tumour thrombosis candidates for liver transplantation?Journal of HepatologyVol. 78Issue 6PreviewIn this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting – in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. Full-Text PDF Reply to: "Patients with hepatocellular carcinoma and portal vein tumour thrombosis after successful downstaging may be candidates for liver transplantation: A meta-analysis"Journal of HepatologyVol. 80Issue 5PreviewWe thank Liu et al.1 for their additional meta-analysis in favour of the benefit of successful downstaging approaches to facilitate liver transplantation with acceptable outcomes in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). Their results should however be interpreted with caution since their meta-analysis considers only pooled survival data coming from retrospective studies missing matched control groups. While a few case series of highly selective patients with HCC-PVTT showed that successful downstaging according to pre-defined protocols enabled liver transplantation with overall 5-year survival rates of around 60%, there is a high level of heterogeneity among these studies. Full-Text PDF In their recent review article, Soin et al. debated whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT) are candidates for liver transplantation (LT). They reported significant long-term survival benefits from LT in patients with HCC and PVTT after successful downstaging. However, the authors concluded that the current quality of evidence for LT in patients with HCC and PVTT is low and their survival rates are still below accepted thresholds for LT.1Soin A. Lesurtel M. Bhangui P. et al.Are patients with hepatocellular carcinoma and portal vein tumour thrombosis candidates for liver transplantation?.J Hepatol. 2023; 78: 1124-1129Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Therefore, we conducted this meta-analysis to investigate the prognosis of patients with HCC and PVTT after LT. This meta-analysis was reported according to the criteria of Meta-Analysis of Observational Studies in Epidemiology (MOOSE).2Stroup D.F. Berlin J.A. Morton S.C. et al.Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.Jama. 2000; 283: 2008-2012Crossref PubMed Scopus (16936) Google Scholar A comprehensive search was performed in PubMed, Web of Science, EMBASE, and Cochrane Library from January 01 2003 until June 30 2023 and the language of publication is limited to English. The following keywords were used: "Hepatocellular Carcinoma" OR "HCC" OR "liver cancer" AND "liver transplantation" OR "LT" OR "liver transplant" AND "Portal Vein Tumor Thrombosis" OR "PVTT" OR "macrovascular invasion". Two reviewers searched the literature independently and extracted the data. Any disagreements were resolved by consulting the third author. Articles reporting the 5-year survival rates for patients with HCC and PVTT following LT were included in this research. Letters, editorials, comments, case reports, duplications, and case series of fewer than 5 patients were excluded. If studies come from the same center or contain data from the same database, only the most recent publications or the largest cohorts are included in the data analysis. The Cochran's Q test and I2 analyses were used to assess the statistical heterogeneity. The combined effect and 95% CI were estimated using a random effects model.3Greenland S. Quantitative methods in the review of epidemiologic literature.Epidemiologic Rev. 1987; 9: 1-30Crossref PubMed Scopus (1468) Google Scholar We evaluated publication bias by using Begg's test4Begg C.B. Mazumdar M. Operating characteristics of a rank correlation test for publication bias.Biometrics. 1994; 50: 1088-1101Crossref PubMed Scopus (13185) Google Scholar and Egger's test.5Egger M. Davey Smith G. Schneider M. et al.Bias in meta-analysis detected by a simple, graphical test.BMJ (Clinical research ed). 1997; 315: 629-634Crossref PubMed Scopus (39219) Google Scholar Sensitivity analyses were used to assess the impact of individual studies on the overall results. Subgroup analysis was performed for patients who were successfully downstaged and those who were not (or not successfully) downstaged. All statistical analyses were performed using Stata 13.1. A total of 14 studies including data on 686 patients with HCC and PVTT following LT were included in this meta-analysis. The results showed that pooled survival was 49% (95% CI 39-58%; I2 78.4% Fig. 1A) at 5 years for all patients with HCC and PVTT following LT. Six studies included 84 patients with HCC and PVTT who were successfully downstaged before LT; the pooled survival at 5 years was 63% (95% CI 53-73%; I2 0% Fig. 1B). In patients who were not (or were not successfully) downstaged, pooled survival at 5 years was 41% (95% CI 29-53%; I2 86% Fig. 1C). As shown in Fig. 1D-F, sensitivity analysis indicated that each study could be deleted once without significantly affecting the overall results. There was no publication bias detected by Begg's test (p = 0.125) or Egger's test (p = 0.848). PVTT was often considered as a contraindication for LT owing to the poor associated prognosis.6Clavien P.A. Lesurtel M. Bossuyt P.M. et al.Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.Lancet Oncol. 2012; 13: e11-e22Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar,7Zavaglia C. De Carlis L. Alberti A.B. et al.Predictors of long-term survival after liver transplantation for hepatocellular carcinoma.Am J Gastroenterol. 2005; 100: 2708-2716Crossref PubMed Scopus (228) Google Scholar This is consistent with our meta-analysis showing that the 5-year survival rate for patients who were not (or were not successfully) downstaged was 41%. However, our study shows that the 5-year survival rate for patients who were successfully downstaged before LT can reach a remarkable 63%, which meets some of the reported criteria and far exceeds survival in untreated patients or those receiving palliative care.8Cheng S. Chen M. Cai J. et al.Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus (2018 Edition).Liver Cancer. 2020; 9: 28-40Crossref PubMed Scopus (83) Google Scholar, 9Lerut J. Foguenne M. Lai Q. Hepatocellular cancer selection systems and liver transplantation: from the tower of babel to an ideal comprehensive score.Updates Surg. 2021; 73: 1599-1614Crossref PubMed Scopus (19) Google Scholar, 10Xu X. Lu D. Ling Q. et al.Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.Gut. 2016; 65: 1035-1041Crossref PubMed Scopus (155) Google Scholar The meta-analysis has some limitations, including the fact that most of the studies included were retrospective, and only one was prospective. Moreover, the downstaging protocols, the timing of LT, and postoperative adjuvant therapy in the included studies are different, which may have some impact on our analysis. In conclusion, this meta-analysis indicates that patients with HCC and PVTT may be candidates for LT after successful downstaging. However, more prospective and well-designed studies are needed to determine the standard protocol for successful downstaging, the timing of LT and postoperative adjuvant therapy, and to verify our findings. This work was supported by Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022049D) and Research Unit Project of Chinese Academy of Medical Sciences (2019-I2M-5-030). No potential conflicts of interest were reported by all authors. Please refer to the accompanying ICMJE disclosure forms for further details. The study was conceptualized by LZ and SZ, and literature search and data extraction were conducted by JL and JQ. The manuscript was drafted by JL and ZY, and all authors approved the final manuscript. Data supporting the findings of this study are included in this paper and can be obtained by contacting the corresponding author. 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