Surgical resection versus liver transplant for patients with hepatocellular carcinoma

  • Review
  • Intervention

Authors


Abstract

Background

Hepatocellular carcinoma is a major worldwide health problem, involving more than half a million new patients yearly, with a different incidence in different parts of the world. Hepatocellular carcinoma develops in about 80% of cirrhotic patients, and cirrhosis is considered the strongest predisposing factor for it. Surgical resection and liver transplantation are conventional treatment modalities that can offer long-term survival for patients with hepatocellular carcinoma.

Objectives

To assess the benefits and harms of surgical resection compared with those of liver transplantation in patients with hepatocellular carcinoma.

Search methods

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI-EXPANDED) at ISI Web of Science (last search February 2013). We also searched the abstracts from annual meetings of the American Society of Clinical Oncology, the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL), provided through The Cochrane Hepato-Biliary Group until February 2013.

Selection criteria

Randomised clinical trials comparing surgical resection and hepatic transplantation.

Data collection and analysis

The search strategies were run and two authors individually evaluated whether the retrieved studies fulfilled the inclusion criteria.

Main results

No randomised clinical trials comparing surgical resection and liver transplantation as the major methods of treating hepatocellular carcinoma were found.

Authors' conclusions

There are no randomised clinical trials comparing surgical resection and liver transplantation for hepatocellular carcinoma treatment.

Résumé scientifique

Résection chirurgicale versus greffe du foie pour les patients présentant un carcinome hépatocellulaire

Contexte

Le carcinome hépatocellulaire est un problème de santé majeur dans le monde ; il concerne plus d'un demi-million de nouveaux patients chaque année et a une incidence différente selon les zones géographiques. Le carcinome hépatocellulaire se développe chez environ 80 % des patients cirrhotiques et la cirrhose est considérée comme le plus important facteur de prédisposition. La résection chirurgicale et la greffe de foie sont les modalités de traitement conventionnelles qui peuvent offrir une survie à long terme aux patients atteints d'un carcinome hépatocellulaire.

Objectifs

Évaluer les bénéfices et les préjudices de la résection chirurgicale comparés à ceux de la greffe de foie chez des patients atteints d'un carcinome hépatocellulaire.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre des essais contrôlés du groupe Cochrane sur les affections hépato-biliaires, le registre Cochrane des essais contrôlés (CENTRAL) dans The Cochrane Library, MEDLINE, EMBASE et Science Citation Index Expanded (SCI-EXPANDED) sur ISI Web of Science (date de la dernière recherche : février 2013). Nous avons également effectué des recherches dans les résumés des rencontres annuelles de l'American Society of Clinical Oncology, de l'American Association for the Study of Liver Diseases (AASLD) et de la European Association for the Study of the Liver (EASL), fournis par le groupe Cochrane sur les affections hépato-biliaires jusqu'à février 2013.

Critères de sélection

Les essais cliniques randomisés comparant la résection chirurgicale et la greffe hépatique.

Recueil et analyse des données

Les stratégies de recherche ont été mises en œuvre et deux auteurs ont évalué individuellement si les études obtenues répondaient aux critères d'inclusion.

Résultats principaux

Aucun essai clinique randomisé comparant la résection chirurgicale et la greffe de foie comme principales méthodes de traitement du carcinome hépatocellulaire n'a été trouvé.

Conclusions des auteurs

Il n'existe aucun essai clinique randomisé comparant la résection chirurgicale et la greffe de foie pour le traitement du carcinome hépatocellulaire.

Plain language summary

Surgical resection versus liver transplantation for hepatocellular carcinoma

The two main treatments for hepatocellular carcinoma are liver transplantation and liver resection. To compare these two methods with each other, we searched literature databases until February 2013 for randomised clinical trials comparing hepatic resection versus liver transplantation as the methods of managing hepatocellular carcinoma. None of the identified studies met our inclusion criteria. There were no randomised clinical trials found that could be included for analysis in this review. No randomised clinical trials could support or refute surgical resection compared with liver transplantation for patients with hepatocellular carcinoma.

Résumé simplifié

Résection chirurgicale versus greffe du foie dans les cas de carcinome hépatocellulaire

Les deux principaux traitements contre le carcinome hépatocellulaire sont la greffe de foie et la résection hépatique. Pour comparer ces deux méthodes l'une à l'autre, nous avons recherché dans des bases de données de littérature jusqu'à février 2013 des essais cliniques randomisés comparant la résection hépatique versus la greffe de foie comme méthodes de prise en charge du carcinome hépatocellulaire. Aucune des études identifiées ne répondait à nos critères d'inclusion. Aucun des essais cliniques randomisés trouvés n'a pu être inclus dans l'analyse de cette revue. Aucun essai clinique n'a pu soutenir ou déconseiller l'utilisation de la résection chirurgicale comparée à la greffe de foie pour les patients atteints d'un carcinome hépatocellulaire.

Notes de traduction

Traduit par: French Cochrane Centre 7th August, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Hepatocellular carcinoma is a major worldwide health problem, involving more than half a million new patients yearly (Llovet 2005). The incidence ranges from less than 10 patients per 100,000 persons in North America and Western Europe to 50 to 150 patients per 100,000 persons in parts of Africa and Asia where hepatocellular carcinoma is responsible for a large number of cancer deaths (Blum 2005). However, a rise in the incidence of and mortality from hepatocellular carcinoma, most likely reflecting the increased prevalence of hepatitis C virus (HCV) infection, has recently been observed in most industrialised countries (Taylor-Robinson 1997; Deuffic 1998; El-Serag 2007).

Hepatocellular carcinoma has a significantly higher incidence in cirrhotic patients, and cirrhosis has been recognised as the strongest predisposing factor (Collier 1998; Llovet 2003; Sherman 2005). Hepatitis B virus (HBV) infection is the main risk factor in Asia and Africa, where chronic carriers have a 100-fold relative risk for developing hepatocellular carcinoma compared to non-carriers (Bosch 2004). In China, the lifetime risk of hepatocellular carcinoma in patients with chronic hepatitis B approaches 40% (Carr 2012). In Western countries, however, hepatitis C virus (HCV) infection and alcoholism are the main risk factors, together with other causes of cirrhosis such as primary or secondary haemochromatosis, 1-antitrypsin deficiency, Wilson's disease, and primary biliary cirrhosis (Badvie 2000; Llovet 2003; Bosch 2004; Bruix 2006).

Until the development of ultrasound, most of the hepatocellular carcinoma patients were diagnosed at a symptomatic stage when the tumour was already advanced, and hence treatment was unfeasible (Clark 2005; Bruix 2006). In advanced hepatocellular carcinoma, life expectancy after diagnosis was short and most patients died within the first year of follow-up. Median survival times have been reported as under 13 months, for example, 0.9 months to 12.8 months for patients receiving no specific treatment and three months to six months after the onset of symptoms (Paraskevopoulos 1994; Wallner 1994; Llovet 2003; Bruix 2006). Nowadays, however, ultrasound allows early hepatocellular carcinoma detection and dynamic imaging techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI), permit an accurate assessment of tumour burden (Bruix 2005; Lencioni 2005).

Surgical resection and liver transplantation are conventional treatment modalities that can offer long-term survival for patients with hepatocellular carcinoma (Mazzaferro 1996; Grazi 2001; Liu 2004; Llovet 2005; McCormack 2005). Liver resection is the most common treatment (Ribero 2006) as transplantation is limited by a shortage of donor organs (Llovet 1999; Kim 2006) and the associated risks of life-time immunosuppression (Botha 2007; Mazariegos 2007). The ultimate goal of hepatic resection of hepatocellular carcinoma is to prolong overall survival and to improve quality of life by eradicating the malignancy while preserving hepatic function (Bain 1997; Song 2004; Sotiropoulos 2006). Percutaneous local ablative therapies are alternative treatment options for hepatocellular carcinoma that have been studied in some trials and have been shown to have comparable results to surgery, specially for those patients with early hepatocellular carcinoma (Livraghi 1995; Ohnishi 1996; Lencioni 1997; Ohnishi 1998; Lencioni 2003).

Resectability of hepatocellular carcinoma depends on many factors, such as hepatic distribution of the tumour, vascular invasion, liver function, size of residual liver, and expertise of the surgical team (Bain 1997; Song 2004; Llovet 2005). Although there are no strict criteria, patients with solitary lesions (less than 5 cm in diameter) confined to one liver lobe without vascular invasion and with well-preserved hepatic function are the best candidates for surgical resection (Song 2004; Botha 2007). In contrast with some previous studies in which only 10% to 20% of tumours were resectable at the time of diagnosis (Nagorney 1989; Paquet 1991), it has been shown that resection of hepatocellular carcinoma is currently possible in 60% of patients in Asia, and 25% to 40% of patients in Western countries (Llovet 2005; McCormack 2005). It has been shown that 20% to 25% of the surgical population with hepatocellular carcinoma are both transplantable and resectable (Adam 2003), which makes the decision in selecting the first-line treatment for hepatocellular carcinoma more difficult (Bhoori 2007).

Over the last two decades, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative management (Song 2004; Llovet 2005). The operative mortality proportion for hepatectomy has decreased from the 10% to 20% level seen in the 1980s to less than 5% today (Poon 2004; Song 2004). In non-cirrhotic hepatocellular carcinoma patients, surgical resection is associated with a five-year survival of 40% to 50% (Fong 1999; Marin 2003; Popescu 2005; Capussotti 2006) and as high as 68% in one study (Nagasue 1986). In cirrhotic hepatocellular carcinoma patients, operative mortality is higher than in non-cirrhotic patients (10% compared to 4%) and of those who survive the surgery a five-year survival of 25% to 37% has been reported (Farmer 1994; Fong 1999; Grazi 2001; Yeh 2002; Poon 2004). Generally, resection yields better results (five-year survival of 60% to 70%) in patients with early hepatocellular carcinoma who present with single tumours and excellent liver functional reserve (Bruix 1996; Takayama 1998; Llovet 1999; Takayama 2000; Okuda 2002). Recent improvements in screening of hepatocellular carcinoma, leading to detection of the tumour at early stages when it is more likely to be operable (Llovet 2005), alongside advances in surgical techniques, such as treatment of large tumours, that is more than 10 cm in diameter (Verhoef 2004; Capussotti 2006), have added value to liver resection as a treatment option.

As a treatment option for hepatocellular carcinoma, liver transplantation is hypothetically superior to resection because it permits radical resection of the primary tumour, treatment of the underlying liver disease, treatment of the portal hypertension, and reduces the risk of developing new hepatocellular carcinomas and progression to end-stage liver failure. For many patients it is not possible to perform resection because of the tumour size, anatomical location of the tumour, or poor liver function, and liver transplantation is the only surgical option (Bartlett 2008). However, liver transplantation has its own drawbacks, such as a long waiting time due to the scarcity of organs and the risks of immunosuppression.

The first popular proposed guideline for selecting the patients to undergo liver transplantation was the Milan criteria guideline (single hepatocellular carcinoma ≤ 5 cm or up to three nodules ≤ 3 cm in diameter; no extrahepatic manifestations; and no vascular incision) (Bismuth 1993; Mazzaferro 1996). This guideline has become the gold standard in many centres for selecting patients for liver transplantation. The Milan criteria showed four-year overall and disease-free survival rates of 85% and 92%, respectively (Mazzaferro 1996). These outcomes for early hepatocellular carcinoma have been confirmed in many other studies, with reported five-year overall survival rates of 58% to 74% (Llovet 1999; Figueras 2001). Despite the acceptable results of the Milan criteria, some practitioners believe that they are too restrictive and more patients may benefit from liver transplantation. By analysing the outcomes of 70 patients with hepatocellular carcinoma undergoing liver transplantation, Yao 2001 found that patients with a single lesion ≤ 6.5 cm, two to three nodules with the largest ≤ 4.5 cm, or a total tumour diameter ≤ 8 cm had a 75% five-year survival and proposed the University of California at San Francisco (UCSF) criteria. Patients surpassing the UCSF criteria, however, had a one-year survival rate of 50% following liver transplantation (Yao 2001). A study analysing 1206 patients who underwent liver transplantation found that patients with two to four tumours ≤ 5 cm or a solitary hepatocellular carcinoma ≤ 6 cm had tumour-free survival similar to those that were within the Milan criteria (Onaca 2007). Although the results for the expanded criteria seem promising, a retrospective study found that patients meeting the Milan criteria pre-transplant had a five-year survival rate of 60% compared to 45% for those exceeding the Milan criteria but meeting the UCSF criteria (Decaens 2006).

Another option for treating patients with hepatocellular carcinoma is salvage transplant. In this method liver resection is performed initially and a liver transplant is reserved for patients whose liver function deteriorates or who develop more intrahepatic tumours (Bartlett 2008). This method is practical, particularly considering the discrepancy between the demand and number of available organs for transplant. The reported outcomes of salvage transplant are different in different studies. While some studies have shown higher morbidity, mortality, and tumour recurrence (Adam 2003; Hwang 2007) others have shown no difference in the disease-free or overall survival, and no increases in the perioperative difficulty between primary and salvage transplant (Belghiti 2003; Li 2012). Salvage transplant has been proposed as an acceptable treatment method (Wu 2012).

It should be mentioned that a comparison between surgical resection and no intervention or a sham procedure could not be expected to be studied in this systematic review. To the knowledge of the review authors, there are no trials using sham surgery for hepatocellular carcinoma in human beings since the use of sham surgery would be considered unethical.

Why it is important to do this review

While the comparison between surgery and percutaneous therapies for hepatocellular carcinoma has been addressed by a Cochrane review (Galandi 2004) and a Cochrane protocol (Schoppmeyer 2007), a comparison for hepatic resection versus transplantation has not yet been made. Therefore, it seems essential to conduct a systematic review in order to compare the beneficial and harmful effects of surgical resection with those of liver transplantation in patients with hepatocellular carcinoma on the basis of randomised clinical trials.

Objectives

To assess the benefits and harms of surgical resection compared with those of liver transplantation in patients with hepatocellular carcinoma.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials irrespective of blinding, language, publication status, or date. Quasi-randomised studies (for example, allocation by date of birth, day of the week, etc) and observational studies that may be identified in the search results were to be considered for assessment of harms.

Types of participants

Participants with diagnosis of hepatocellular carcinoma (at any stage) according to the definitions of the individual trials or with no explicit definitions.

Types of interventions

We planned to include trials that compared participants undergoing surgical resection of hepatocellular carcinoma liver tissue with participants receiving a liver transplant.

Surgical resection of the liver is employed either alone or with other co-interventions. Co-interventions were to be allowed if they were comparable in all the intervention groups of the randomised clinical trial.

Types of outcome measures

Primary outcome

• One-, three-, and five-year overall survival, and disease-free survival.
• Frequency of adverse events. We defined serious adverse events according to the International Conference on Harmonisation (ICH) Guidelines (ICH-GCP 1997) as any event that leads to death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, and any important medical event which may have jeopardised the patient or requires intervention to prevent it. All other adverse events were considered non-serious.
• Quality of life, according to the measures used in the individual trial.

Secondary outcomes

• Recurrence of hepatocellular carcinoma.
• Time to progression: time from randomisation to progression of disease, recurrence, or death (any cause).
• Time to symptomatic progression: time from randomisation to symptomatic progression of disease, development of recurrent symptoms, or death (any cause).
• Duration of hospital stay.
• Cost-effectiveness: the estimated costs related to the interventions weighed against any possible health gains.

Search methods for identification of studies

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI-EXPANDED) (Royle 2003) until February 2013. The search strategies with the time spans of the searches are given in Appendix 1.

In addition, abstracts from the annual meetings of the American Society of Clinical Oncology, the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL) were handsearched (from 1997 to July 2012) through the work of the Cochrane Hepato-Biliary Group (Gluud 2013). Further trials were sought through scanning the reference lists of relevant articles.

Data collection and analysis

We performed the systematic review following the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2013).

The search strategies were run, and two authors (AT and SNM) individually evaluated whether the trials fulfilled the inclusion criteria. MOS arbitrated in the case of disagreements. Excluded studies were listed with the reasons for exclusion.

Methodological quality is defined by the confidence one has that the design and the report of the randomised trial would restrict bias in the comparison of the intervention (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), risk of bias in a trial can be assessed using risk of bias domains. These are the following:

Allocation sequence generation

- Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent person not otherwise involved in the trial.
- Uncertain risk of bias: the method of sequence generation was not specified.
- High risk of bias: the sequence generation method was not random.

Allocation concealment

- Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (eg, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
- Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
- High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

Blinding of participants, personnel, and outcome assessors

- Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
- Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
- High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.

Incomplete outcome data

- Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
- Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
- High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting*

- Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
- Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.
- High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

*For a trial to be assessed as having low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, eg, published in a paper journal. In the case of trials run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives are provided in the publication's results section, then the trial can be considered to have low risk of bias for the selective outcome reporting domain.

For-profit bias

- Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for-profit support that may manipulate the trial design, conductance or results of the trial.
- Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship is provided.
- High risk of bias: the trial is sponsored by industry or has received other kind of for-profit support.

The trials will be described as having low risk of bias if they are judged with low risk of bias in all individual components of the above mentioned domains. In all other cases, the trials will be judged as having high risk of bias.

Data extraction

The data were individually extracted by AT, AA, and SNM and validated by MOS. Details of study population, interventions, and outcomes were extracted using a standardised data extraction form. This form included at least the following items:

  • General information: title, authors, source, contact address, country, published or unpublished, language, and year of publication.

  • Trial characteristics including design, duration and follow-up, and quality assessment criteria as specified above.

  • Participants: inclusion and exclusion criteria, sample size, baseline characteristics, number of participants allocated to each group, number of cirrhotic people, and people with large tumours (> 10 cm) in each group.

  • Interventions: type of surgical resection (eg, lobar or segmental), comparison intervention, and any collateral interventions.

  • Outcomes: hazard ratios; Mantel-Cox logrank P values or Chi2 values; observed event rates; number of total events; one-, three-, and five-year survival rates; median survival time; time to (symptomatic) progression; recurrence rate; adverse events; quality of life; duration of hospital stay; cost effectiveness.

Data analysis

We planned to use the software package Review Manager 5.2 (RevMan 2012). We planned to use the intention-to-treat principle when analysing the data, that is, participants with missing data were to be considered 'treatment failures'; and to calculate the relative risks (RR) for dichotomous data and mean difference (MD) for continuous data, both with 95% confidence interval (CI). However, since we did not find any randomised clinical trials meeting the inclusion criteria we could not do so. We were also unable to estimate rare events (frequency of adverse events) by the Peto odds ratio (Higgins 2011). We could not use random-effects model (DerSimonian 1986) and fixed-effect model (DeMets 1987) meta-analyses due to the lack of included studies. We had intended to report both results in the case of a discrepancy between the two models (for example, one giving a significant intervention effect and the other no significant intervention effect), otherwise we planned to report only the results from the fixed-effect model.

The overall survival rate was going to be analysed with the hazard ratio (HR) and relative risk (RR), both with 95% confidence intervals (CI). The HR is a more informative measure as it is related to the entire follow-up period (Buyse 1987). The HR provided in each trial report was supposed to be used to calculate the pooled HR. If the exact HR was not mentioned in the report, we could calculate the ln(HR) and its standard error indirectly from other provided summary data (that is, the logrank statistic and its variance from Mantel-Cox logrank P values or Chi2 values, observed event rates, number of total events, number of participants allocated to each group) using an Excel spreadsheet developed by M Sydes and J Tierney, MRC Clinical Trials Unit, London. This is based on the methods for using summary statistics to perform meta-analysis for survival outcomes as described by Parmer et al (Parmar 1998).

Publication bias

A funnel plot for the primary outcome could be used to provide a visual assessment of whether the treatment estimates were associated with study size. We could use two tests to assess funnel plot asymmetry, the adjusted rank correlation test (Begg 1994), and regression asymmetry test (Egger 1997), if we had any or at least 10 included trials.

Statistical heterogeneity

We could explore heterogeneity using the Chi2 test and measure the quantity of heterogeneity by the I2 statistic (Higgins 2011). We could also explore sources of heterogeneity in an assessment of treatment response in subgroup analyses if enough trials were identified. However, due to the lack of any included trials we could not perform these calculations.

Subgroup analyses

We intended to compare trials with low risk of bias to trials with high risk of bias. We also intended to perform a subgroup analysis in order to compare the intervention effect in trials with lower risk of bias (that is, trials with adequate generation of the allocation sequence, allocation concealment, and blinding) to that of trials with high risk of bias (that is, trials having one or more unclear or inadequate components).

Results

Description of studies

After searching the databases, and excluding the duplicate and clearly irrelevant publications, a total of 25 references were identified and assessed for inclusion in the review. None of these publications were randomised clinical trials meeting the inclusion criteria (Figure 1). We summarised the studies found with the searches that were related to liver resection for hepatocellular carcinoma in Table 1 and to liver transplantation in Table 2.

Figure 1.

Study flow diagram.

Table 1. Liver resection
  1. N/A = not available

AuthorNumber of participants

Cirrhosis

 

Mean tumour size

Recurrence proportion

(%)

Mean time to recurrence (months)

3-year survival

(%)

Mean age (Years)Mean follow-up time
Bartlett 20075343%N/A4713.849.455.734 m
Sim 20038153.2%N/AN/A9.6595621 m
Ercolani 2003224100%N/A41.5N/A62.862.535.6 m
Nuzzo 200797N/AN/A46N/AN/A65.5N/A
Chen 200690N/AN/AN/AN/A73.449.4N/A
Bismuth 199360100%N/AN/AN/A52N/AN/A
Fan 199921146%N/A5810.650N/A21 m
Lise 199810078%N/A5012.648N/AN/A
Fong 199915465%N/AN/AN/A5459.5N/A
Llovet 199977100%N/A57N/A626132 m
Belghiti 199147100%N/A60N/A35N/AN/A
Nagasue 199322977.3%N/AN/AN/AN/A60.8N/A
Huang 201177100%7.4 ± 4.3N/AN/A5646.7N/A
Table 2. Liver transplantation
  1. N/A = not available

AuthorType of transplantCriteriaNumber of participantsCirrhosisRecurrence proportion (%)Mean time to recurrence (Months)3-year survival (%)5-year survival (%)Mean age (Years)Mean follow-up time
Mazzaferro 1996Deceased donorMilan48100%8N/AN/A75.4N/A26 m
Jonas 2001Deceased donorMilan120100%16N/AN/A71N/A49 m
Figueras 2001Deceased donor5cm, localised307100%21N/A6763N/A24 m
Yao 2001Deceased donorUCSF70100%11.48.1N/A75.2N/A24 m
Decaens 2006Deceased donorMilan27996%922N/A60.15352.4 m
Deceased donorBeyond Milan, within UCSF4495%137.6N/A45.654.2

48.8

m

Deceased donorBeyond Milan & UCSF14586%4510N/A34.752.126.7
Todo 2004Living donorMilan137100%1.4N/A79.4N/AN/A16 m
Living donorExtended172100%22.2N/A60N/AN/A
Hwang 2005Living donorMilan173100%15.5N/A73.2N/A5026 m
Living donorBeyond Milan64100%N/AN/A
Deceased donorMilan53100%18N/A61.1N/A4916 m
Deceased donorBeyond Milan22100%N/AN/A
Jonas 2007Living donorMilan8100%N/AN/A75N/AN/A26 m
Beyond Milan13100%N/AN/A62N/AN/A
Kwon 2007Living donorMilan85N/A1410.382.679.95128 m
Beyond Milan139N/A20
Sugawara 2007Living donorMilan68N/A4.6N/A94755524 m
Beyond Milan32N/A30N/A70
Soejima 2007Living donorMilan16N/A0N/A100100N/A437 d
Living donorBeyond Milan44N/A18.2N/A7474N/A
Hwang 2007SalvageN/A17N/AN/AN/AN/AN/A49.330.7 m
Chung 1994Deceased DonorN/A2986%N/AN/A46N/A5333 m

Risk of bias in included studies

No trials met the inclusion criteria.

Effects of interventions

No trials were included.

Discussion

Our literature review retrieved no direct head to head comparison of surgical resection versus liver transplantation for hepatocellular carcinoma; therefore, randomised trials seem to be justified. In addition two separate systematic reviews, one addressing the outcomes of surgical resection for hepatocellular carcinoma and one addressing the outcome of liver transplantation, can be done to assess the current literature and compare the two methods indirectly.

We have summarised the studies on these two issues, which we came up with during our search to address the objective of the current systematic review, in Table 1 and Table 2. These tables are by no means comprehensive but represent a fraction of the available studies. By looking at these data, it seems that the two groups (that is, surgical resection and liver transplantation) are rather inhomogeneous and a conclusion cannot be reached, but the two suggested systematic reviews may help resolve the review question.

For future updates and if meta-analyses could be performed, we plan to use trial sequential analysis (CTU 2011; Thorlund 2011), as random errors may play an important role in evaluating meta-analyses due to sparse data and multiplicity from repetitive testing. For this purpose, we will calculate the required information size which is the required sample size for the meta-analysis to detect a 10% relative risk reduction of mortality in the first, third, and fifth year, assuming an average event proportion of 50% in the control group, assuming that 30% of the variation (ie, diversity) in the meta-analysis would be explained by variation across trials, and using statistical error levels of alpha = 5% and beta = 10% (90% or 20% power). Meta-analyses conducted before surpassing their required sample size are considered analogous to interim analyses in a single randomised trial, and thus they necessitate adjustment of the threshold for statistical significance to maintain the pre-determined maximum risk of obtaining a false positive (to be set to alpha = 5% in our analysis). We, therefore, will substitute the conventional 5% threshold for statistical significance with those of Lan-DeMets trial sequential monitoring boundaries (Bangalore 2008; Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009). On the basis of the required information size and risk for type I (5%) and type II (10% or 20%) errors, we will construct trial sequential monitoring boundaries (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010). These boundaries determine the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size. If one of the two trial sequential monitoring boundaries is crossed by the cumulative Z score before the required information size is reached in a cumulative meta-analysis, firm evidence may have been established and further trials may be superfluous. On the other hand, if any of the two boundaries is not surpassed, it is most probably necessary to continue doing further trials in order to detect or reject a certain intervention effect if futility boundaries have not been reached. We will use as default a type I error of 5%, type II error of 10% or 20%, and adjusted information size for heterogeneity within diversity unless otherwise stated (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010).

Authors' conclusions

Implications for practice

Due to a lack of randomised clinical trials, a head to head comparison of liver resection versus liver transplantation as the two major methods of hepatocellular carcinoma treatment was not possible. Hence, we are not able to recommend or refute one intervention over the other.

Implications for research

Well-designed, randomised trials comparing liver transplantation with liver surgical resection as the major methods of hepatocellular carcinoma treatment are needed.

Acknowledgements

Peer Reviewers: Umberto Baccarani, Italy; Alessandro Cucchetti, Italy; David Fuks, France.
Contact Editor: Brian Davidson, UK.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Search strategies

DatabaseTime spanSearch strategy
The Cochrane Hepato-Biliary Group Controlled Trials RegisterFebruary 2013.surg* AND (((hepat* or liver) AND (carcinom* or tumor* or tumour* or neoplasm* or malign* or cancer*)) OR HCC)
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryIssue 1 of 12, 2013.#1 MeSH descriptor Carcinoma, Hepatocellular explode all trees
#2 ((hepat* or liver) and (carcinom* or tumor* or tumour* or neoplasm* or malign* or cancer*)) or HCC
#3 (#1 OR #2)
#4 surg* and resect*
#5 (#3 AND #4)
MEDLINE (Ovid SP)1946 to February 2013.#1 explode "Carcinoma-Hepatocellular"/ all subheadings
#2 ((hepat* or liver) and (carcinom* or tumor* or tumour* or neoplasm* or malign* or cancer*)) or HCC
#3 #1 or #2
#4 surg* and resect*
#5 #3 and #4
#6 random* or blind* or placebo* or meta-analysis
#7 (TG=animals) not ((TG=animals) and (TG=humans))
#8 #6 not #7
#9 #5 and #8
EMBASE (Ovid SP)1974 to February 2013.#1 explode liver resection/
#2 (surg* and resect*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
#3 #1 or #2
#4 exp liver transplantation/
#5 ((liver or hepat*) and transplant*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
#6 #4 or #5
#7 exp liver cell carcinoma/
#8 (((hepat* or liver) and (carcinom* or tumor* or tumour* or neoplasm* or malign* or cancer*)) or HCC).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
#9 #7 or #8
#10 #3 and #6 and #9
#11 (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
#12 #10 and #11
Science Citation Index Expanded (http://www.webofknowledge.com/?DestApp=WOS)1900 to February 2013.#5 #4 AND #3
#4 TS=(random* or blind* or placebo* or meta-analysis)
#3 #2 AND #1
#2 TS=(surg* and resect*)
#1 TS=(((hepat* or liver) and (carcinom* or tumor* or tumour* or neoplasm* or malign* or cancer*)) or HCC)

Contributions of authors

AT: the principal and contact author, development of the concept of the review, search and collection of publications, study selection and quality assessment, data extraction and data entry, interpretation of the results, writing up the review, contacting authors, responding to the peer-reviewers' criticisms, writing and editing the review.

AA: development of the concept of the review, searches and collection of publications, study selection and quality assessment, data extraction and data entry, interpretation of the results, writing up the draft review, contacting authors, responding to the peer-reviewers' criticisms, and updating the review.

SNM: search and collection of publications, study selection and quality assessment, data extraction and data entry, interpret the results, writing and editing the review.

BE: review and revise the review, interpret the results, helping the contact author respond to the peer-reviewers' comments.

MOS: supervisor, interpret the results, review and revise the draft review, act as a third party in the event of disagreement, and help the contact author respond to the peer-reviewers' comments.

Declarations of interest

None known.

Differences between protocol and review

None.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bartlett 2007Patient series.
Bartlett 2008Narrative review.
Belghiti 2003Patient series.
Bismuth 1993Patient series.
Chen 2006Comparing PLAT and resection.
Choti 2002Narrative review.
Chung 1994Patient series.
Colleoni 1998Narrative review.
Decaens 2006Patient series.
Ercolani 2003Patient series.
Fan 1999Patient series.
Figueras 2001Patient series.
Fong 1999Patient series.
Huang 2011Patient series.
Hwang 2005Patient series.
Jonas 2001Patient series.
Jonas 2007Patient series.
Lise 1998Patient series.
Llovet 1999Patient series.
Mazzaferro 1996Patient series.
Nagasue 1993Patient series.
Nuzzo 2007Patient series.
Sim 2003Patient series.
Todo 2004Patient series.
Yao 2001Patient series.

Ancillary