Percutaneous ethanol injection for liver metastases

  • Review
  • Intervention

Authors


Abstract

Background

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Percutaneous ethanol injection (PEI) causes dehydration and necrosis of tumour cells accompanied by small vessel thrombosis, leading to tumour ischaemia and destruction.

Objectives

To study the beneficial and harmful effects of percutaneous ethanol injection compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases.

Search methods

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012.

Selection criteria

We included all randomised clinical trials assessing the beneficial and harmful effects of percutaneous ethanol injection versus no intervention, other ablation methods, or systemic treatments in patients with liver metastases.

Data collection and analysis

We extracted the relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review, as well as information on the design and methodology of the studies. Quality assessment of the trials fulfilling the inclusion criteria and data extraction from the trials retrieved for final evaluation were done by one author and checked by a second author.

Main results

One randomised clinical trial was included, comparing transcatheter arterial chemoembolisation (TACE) + percutaneous intratumour ethanol injection (PEI) versus TACE alone. Forty-eight patients with liver metastases were included; 25 received the intervention with PEI and 23 received TACE alone.

Mortality data were not reported. The trial reported the survival data after one, two, and three years. In the TACE + PEI group, 92%, 80%, and 64% of the patients survived after 1, 2, and 3 years respectively; in the TACE group, 78.3%, 65.2%, and 47.8% of the patients survived after 1, 2, and 3 years respectively. The hazard ratio was 0.57 (95% CI 0.19 to 1.67). The local recurrence was 16% in the TACE + PEI group and 39.1% in the TACE group, resulting in a relative risk (RR) of 0.41 (95% CI 0.15 to 1.07). Forty-five tumours (66.2%) out of 68 tumours in total shrunk by at least 25% in the TACE + PEI group versus 31 tumours (48.4%) out of 64 tumours in total in the TACE group (RR 2.08; 95% CI 1.03 to 4.2). The authors reported some adverse events, but with very few details.

Authors' conclusions

On the basis of one small randomised trial, it can be concluded that addition of PEI to TACE, as compared with TACE alone, in patients with liver metastases seems to bring no clear benefit in terms of survival and local recurrence. The size of the tumour necrosis was larger in the combined treatment group. No intervention-related mortality or major complications were reported. More trials are needed.

Résumé scientifique

Injection percutanée d'éthanol pour le traitement des métastases hépatiques

Contexte

Les tumeurs hépatiques primaires et les métastases hépatiques du cancer colorectal sont les deux tumeurs malignes les plus courantes qui touchent le foie. Le foie est tout juste derrière les ganglions lymphatiques au rang des sites les plus courants pour la maladie métastatique. Plus de la moitié des patients atteints de maladie métastatique hépatique décèderont de complications métastatiques. L'injection percutanée d'éthanol (IPE) provoque la déshydratation et la nécrose des cellules tumorales, qui s'accompagnent d'une thrombose des petits vaisseaux, ce qui conduit à l'ischémie et à la destruction de la tumeur.

Objectifs

Étudier les effets bénéfiques et nocifs de l'injection percutanée d'éthanol comparée à l'absence d'intervention, aux autres méthodes d'ablation ou aux traitements systémiques chez les patients souffrant de métastases hépatiques.

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, le Science Citation Index Expanded, LILACS, et CINAHL jusqu'en décembre 2012.

Critères de sélection

Nous avons inclus tous les essais cliniques randomisés évaluant les effets bénéfiques et nocifs de l'injection percutanée d'éthanol comparée à l'absence d'intervention, aux autres méthodes d'ablation ou aux traitements systémiques chez les patients souffrant de métastases hépatiques.

Recueil et analyse des données

Nous avons extrait les informations pertinentes sur les caractéristiques des participants, les interventions, les critères de jugement des études et des données sur les critères de jugement pour notre revue, ainsi que des informations sur la méthodologie et le plan des études. L'évaluation de la qualité des essais remplissant les critères d’inclusion et l'extraction des données des essais sélectionnés en vue de l'évaluation finale ont été effectuées par un auteur et contrôlées par un deuxième auteur.

Résultats principaux

Un essai clinique randomisé a été inclus, comparant la chimio-embolisation artérielle transcathéter (CEAT) + injection percutanée intratumorale d'éthanol (IPE) à la CEAT seule. Quarante-huit patients souffrant de métastases hépatiques ont été inclus, 25 ayant reçu l'intervention avec l'injection avec IPE et 23 ayant reçu la CEAT seule.

Les données sur la mortalité n'étaient pas indiquées. L'essai indiquait les données de survie après un, deux et trois ans. Dans le groupe CEAT + IPE, 92 %, 80 % et 64 % des patients survivaient après 1, 2 et 3 ans respectivement ; dans le groupe CEAT, 78,3 %, 65,2 % et 47,8 % des patients survivaient après 1, 2 et 3 ans respectivement. Le hazard ratio était de 0,57 (IC à 95 % 0,19 à 1,67). La récidive locale était de 16 % dans le groupe CEAT + IPE et de 39,1 % dans le groupe CEAT, entraînant un risque relatif (RR) de 0,41 (IC à 95 % 0,15 à 1,07). Quarante-cinq tumeurs (66,2 %) sur 68 au total étaient réduites d'au moins 25 % dans le groupe CEAT + IPE contre 31 tumeurs (48,4 %) sur 64 au total dans le groupe CEAT (RR 2,08 ; IC à 95 % 1,03 à 4,2). Les auteurs mentionnaient quelques événements indésirables, mais avec très peu de détails.

Conclusions des auteurs

Sur la base d'un seul essai randomisé de petite taille, on peut conclure que l'addition d'une IPE à la CEAT, par rapport à la CEAT seule, chez les patients souffrant de métastases hépatiques semble n'apporter aucun avantage clair en termes de survie et de récidive locale. La taille de la nécrose tumorale était plus importante dans le groupe de traitement combiné. Aucune mortalité liée à l'intervention ni complications majeures n'ont été signalées. Des essais supplémentaires sont nécessaires.

Plain language summary

Percutaneous ethanol injection for liver metastases

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of patients with metastatic liver disease will die from metastatic complications.

In percutaneous ethanol injection, pure alcohol is injected into liver cancers to kill the cancer cells. The alcohol is injected through the skin (percutaneously) into the tumour using a very thin needle with the help of ultrasound or computed tomography (CT) visual guidance. Alcohol induces tumour destruction by drawing water out of tumour cells (dehydrating them) and thereby altering (denaturing) the structure of the cellular proteins. It may take up to five or six sessions of injections to destroy the cancer.

One randomised trial was included, comparing transcatheter arterial chemoembolisation + percutaneous intratumour ethanol injection with transcatheter arterial chemoembolisation alone. Forty-eight patients with liver metastases were included; 25 received the intervention with percutaneous ethanol injection and 23 received transcatheter arterial chemoembolisation alone.

On the basis of one small randomised clinical trial, it can be concluded that addition of percutaneous intratumour ethanol injection to transcatheter arterial chemoembolisation in patients with liver metastases seems to bring no clear benefit in terms of survival and local recurrence compared with transcatheter arterial chemoembolisation alone. The size of the tumour necrosis was larger in the combined treatment group. No intervention-related mortality or major complications were reported.

More trials are needed before definite conclusions can be made.

Résumé simplifié

Injection percutanée d'éthanol pour le traitement des métastases hépatiques

Les tumeurs hépatiques primaires et les métastases hépatiques du cancer colorectal sont les deux tumeurs malignes les plus courantes qui touchent le foie. Le foie est tout juste derrière les ganglions lymphatiques au rang des sites les plus courants pour la maladie métastatique. Plus de la moitié des patients atteints de maladie métastatique hépatique décèderont de complications métastatiques.

Dans l'injection percutanée d'éthanol, de l'alcool pur est injecté dans les cancers du foie afin de détruire les cellules cancéreuses. L'alcool est injecté à travers la peau (par voie percutanée) dans la tumeur en utilisant une aiguille très fine à l'aide d'un guidage visuel par échographie ou par tomographie informatisée (TI). L'alcool induit une destruction de la tumeur en éjectant l'eau des cellules tumorales (en les déshydratant) et en modifiant (dénaturant) ainsi la structure des protéines cellulaires. Cinq ou six séances d'injections peuvent être nécessaires pour détruire le cancer.

Un essai randomisé a été inclus, comparant la chimio-embolisation artérielle transcathéter + injection percutanée intratumorale d'éthanol à la chimio-embolisation artérielle transcathéter seule. Quarante-huit patients souffrant de métastases hépatiques ont été inclus, 25 ayant reçu l'intervention avec l'injection percutanée d'éthanol et 23 ayant reçu la chimio-embolisation artérielle transcathéter seule.

Sur la base d'un seul essai clinique randomisé de petite taille, on peut conclure que l'addition d'une injection percutanée intratumorale d'éthanol à la chimio-embolisation artérielle transcathéter chez les patients souffrant de métastases hépatiques semble n'apporter aucun avantage clair en termes de survie et de récidive locale en comparaison avec la chimio-embolisation artérielle transcathéter seule. La taille de la nécrose tumorale était plus importante dans le groupe de traitement combiné. Aucune mortalité liée à l'intervention ni complications majeures n'ont été signalées.

D'autres essais seront nécessaires avant de pouvoir tirer des conclusions définitives.

Notes de traduction

Traduit par: French Cochrane Centre 3rd June, 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

Description of the condition

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver (Lau 2000; Michel 2002). Primary liver tumours arise from malignant cells within the liver, and hepatocellular carcinoma represents the most common form of primary liver cancer (Lau 2000; Michel 2002). Metastatic liver disease is more common than primary liver cancer and develops when malignant cells migrate from other organs to the liver (Bilchik 2000; McCarter 2000). The liver is second only to the lymph nodes as the most common site for metastatic disease (Weiss 1986). More than half of the patients with metastatic liver disease will die from metastatic complications (Wood 1976; Markovic 1998).

Metastatic liver disease is frequently associated with primary colorectal carcinoma (Fong 1999), and this carcinoma is the fourth leading cancer in the United States and is second in cancer-related deaths (Jemal 2009). Approximately 50% of colorectal cancer patients will develop recurrence within five years of initial diagnosis, with the liver being the most common site for metastatic disease (Geoghegan 1999). For many patients, the progressive involvement of the liver is the primary determinant of long-term survival. Historically untreated patients with colorectal liver metastases were reported to have a median survival of six to 12 months (McLoughlin 2006). Surgical resection is the only curative option for patients with malignant liver neoplasm, with median survival times of 21 to 46 months or 5-year survival of 20% to 58% (McLoughlin 2006). However, only 20% of patients with hepatic tumours are candidates for resection (Bilchik 2000; Bipat 2007).

Description of the intervention

Percutaneous local ablative therapies are currently considered as the preferred option for early unresectable hepatocellular carcinoma (HCC) (Schoppmeyer 2009). All local ablative techniques have the advantage of preserving the uninvolved liver parenchyma and avoid the morbidity and mortality of major hepatic surgery. Among the percutaneous local ablative therapies, ethanol injection is currently considered as the standard percutaneous technique (Bruix 2001), but acetic acid injections have also been employed. Percutaneous ethanol injection (PEI) causes dehydration and necrosis of tumour cells accompanied by small vessel thrombosis, leading to tumour ischaemia and destruction. PEI is usually carried out under ultrasound guidance, with repeated injections of ethanol on separate days.

How the intervention might work

In this technique, pure alcohol is injected into liver cancers to kill the cancer cells. The alcohol is injected through the skin (percutaneously) into the tumour using a very thin needle with the help of ultrasound or computer tomography (CT) visual guidance. Alcohol induces tumour destruction by drawing water out of tumour cells (dehydrating them) and thereby altering (denaturing) the structure of cellular proteins. It may take up to five or six sessions of injections to destroy the cancer. The number of treatment sessions depends on the size and number of tumours. This type of treatment is most useful for people who have a small number of tumours measuring about 3 cm to 4 cm across.

Why it is important to do this review

In patients with liver metastases, local or regional treatment methods can provide local control but it is uncertain what the long-term outcomes of some of these therapies are. Systematic reviews may help to establish the effectiveness and the trade-offs between the benefits and harms associated with different non-surgical ablation methods for the treatment of all forms of malignant liver tumours (primary and metastases). Systematic reviews published so far focus mostly on primary liver tumours or colorectal cancer liver metastases and include studies up to April 2006 (Llovet 2003; Decadt 2004; ASERNIP-S 2006; Lopez 2006; Sutherland 2006). There is one full Cochrane review of 'Percutanous ethanol injection or percutaneous acetic acid injection for early hepatocellular carcinoma' (Schoppmeyer 2009); however, no such review exists for people with liver metastases. Therefore, a systematic review dealing with all types of malignant liver metastases is warranted.

Objectives

To study the beneficial and harmful effects of percutaneous ethanol injection (PEI) compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised clinical trials assessing beneficial and harmful effects of PEI versus no intervention, other ablation methods, or systemic treatment, irrespective of publication status, language, or blinding. Quasi-randomised and observational studies that were identified in the search for randomised clinical trials were considered only for the reporting of data on harm.

Types of participants

Patients with liver metastases no matter the location of the primary tumour.

Types of interventions

PEI compared with no intervention, other ablation methods, or systemic treatments. Co-interventions were allowed if provided equally to the experimental and control groups of the individual randomised trials.

Types of outcome measures

Primary outcomes

1. Mortality at last follow-up.
2. Time to mortality.
3. All adverse events and complications, separately and in total. The International Conference on Harmonisation (ICH) Guidelines (ICH-GCP 1997) define adverse events as serious and non-serious. A serious fatal or non-fatal adverse event is 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.
4. Quality of life.

Secondary outcomes

1. Failure or recurrence of tumours.
2. Time to progression of liver metastasis.
3. Tumour response measures (complete response, partial response, stable disease, disease progression).

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (Royle 2003). One global search was used for all non-surgical ablation methods for primary malignant liver tumours and liver metastases. Search strategies with the time spans of the searches are given in Appendix 1.

In addition, we assessed for inclusion all US Food and Drug Administration (FDA) approvals and investigational device exemptions as found on the FDA website.

Searching other resources

We searched reference lists of reviews (such as Schwartz 2004 and Lopez 2006), Health Technology Assessment (HTA) reports (such as ASERNIP-S 2006), all Cochrane reviews, and all included trials for relevant studies.

Data collection and analysis

We performed the systematic review following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group module (Gluud 2013), using Review Manager 5 (RevMan 2011).

Selection of studies

Two authors independently evaluated titles and abstracts for ordering papers (RR and MB). Any differences in opinion were resolved by discussion or, if necessary, by consulting a third author (JK). For titles and abstracts that potentially fitted our inclusion criteria, full papers were ordered. These papers were assessed by two independent authors (RR and MB) and differences in opinion were resolved using the above mentioned procedure.

Data extraction and management

We extracted the relevant information on participant characteristics, interventions, trial outcome measures, and data on the outcome measures for our review, as well as information on the design and methodology of the trials. Quality assessment of the trials fulfilling the inclusion criteria and data extraction from the trials retrieved for final evaluation were done by one author (RR, MB, or RW) and checked by a second author (RR, MB, or RW).

Assessment of risk of bias in included studies

The methodological quality of the trials, and hence risk of bias, was assessed based on the domains described below (Schulz 1995; Moher 1998; Kjaergard 2001; Gluud 2008; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a). This assessment was presented by trial and was used to describe the results of each trial in relation to their reliability.

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 (for example, 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-profit bias

- Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for-profit support that may result in manipulation of the trial design, conduct, 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 was provided.
- High risk of bias: the trial was sponsored by industry or had received other kinds of for-profit support.

Other biases

- Low risk of bias: the trial appeared to be free of other sources of bias.
- Uncertain risk of bias: there was insufficient information to assess whether other sources of bias were present.
- High risk of bias: it was likely that potential sources of bias related to the specific trial design used or other bias risks were present.

Trials assessed as having 'low risk of bias' in all of the specified individual domains were considered as 'trials with low risk of bias'. Otherwise, they were considered as trials with 'high risk of bias'.

Measures of treatment effect

For dichotomous variables, we calculated the relative risk (RR) with 95% confidence interval (CI). For continuous variables, we calculated the mean difference and the standardised mean difference (SMD) (for outcomes such as quality of life where different scales could be used) with 95% CI. For outcomes such as hazard ratio for death, we planned to use the generic inverse variance method for the meta-analysis. We calculated pooled estimates using the random-effects model (DerSimonian 1986) and the fixed-effect model (Mantel 1959; Greenland 1985). We planned to present both results if there were discrepancies in the results. If not, we planned to report the random-effects model. We planned to measure the quantity of heterogeneity using the I2 statistic (Higgins 2011).

Unit of analysis issues

The number of randomised participants was used to calculate the estimates of intervention effects and CIs. If cluster randomised trials were identified, the unit of analysis would have been the cluster. For cross-over trials, we planned to include only data from the first intervention period (Higgins 2011).

Dealing with missing data

We planned to analyse data using the intention-to-treat principle, that is, patients with missing data (in all treatment groups of a trial) are considered as treatment failures and all randomised patients are included in the denominator.

Assessment of heterogeneity

We planned to assess heterogeneity using the Chi2 and I2 statistic methods. We planned to discuss any plausible possible causes of heterogeneity.

Data synthesis

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) and the Cochrane Hepato-Biliary Group Module (Gluud 2013).

The evidence synthesis was done in a narrative way, and it was not possible to do meta-analyses. 

In principle, all data are suitable for meta-analysis. We planned to calculate measures of effect as relevant (hazard ratios, odds ratios, relative risks, risk differences, mean differences, and standardised mean differences). Where possible, we planned to calculate hazard ratios using the methods described by Parmar and Tierney (Parmar 1998). We planned to extract information (for example, hazard rates, P values, events, ratios, curve data, and information on follow-up) from the publication and, if necessary, to enter data into a Microsoft Office Excel 2003 spreadsheet to calculate hazard ratios (Tierney 2007). Where data were available for the same outcomes using similar methods, meta-analyses were to be performed. If data could not be meta-analysed statistically, for example in the case of extreme heterogeneity, we planned to present results in a forest plot, without the pooled effect estimate, in order to show the variance of the effects. We planned to include cross-over trials using results of the first period only (before cross-over), as if they were parallel trials.

In cases without heterogeneity and yet meta-analysis was not possible, we planned to present the results in a narrative way, including text, tables, and figures to summarise the data and to allow the reader to judge the results based on the differences and similarities of the included trials and their risk of bias assessment. We planned to group the trials by intervention, patient characteristics, and outcomes and to describe the most important characteristics of the included trials, including a detailed review of the methodological shortcomings of a trial.

We planned to use funnel plots to identify any possible small trial biases, such as publication bias, if data were available. We planned to discuss possible implications of our findings if bias was present.

Where possible, we planned to examine apparent significant beneficial and harmful intervention effects with trial sequential analysis (CTU 2011; Thorlund 2011) in order to evaluate if these apparent effects could be caused by random error (‘play of chance’) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).

We planned to create a 'Summary of findings' table including, where possible, survival, response, recurrence, and adverse events.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were to be performed, if possible, based on prognostic indicators such as age, sex, tumour size, location of primary tumour, and use of any co-interventions.

For an extra subgroup analysis we considered trials with a lower risk of bias, if three or more domain items were met including sequence generation and allocation concealment.

Sensitivity analysis

Outcomes after intervention, six months or less, six to 12 months, and one year or more were to be summarised separately.

Results

Description of studies

Results of the search

Our original searches for "non-surgical ablation methods (and possible combinations) compared with no intervention, each other, combinations of ablation methods, or systemic treatments in patients with primary malignant liver tumours and liver metastases" were performed in December 2012.

The searches produced 5497 references. Based on titles and abstracts, 4869 references were excluded resulting in 628 full papers to be retrieved. In addition, we found 27 references through handsearching. Therefore, 655 full papers were retrieved. Based on full papers we excluded 534 publications, mainly because they were not randomised trials.

A total of 121 papers, describing 84 trials and 144 comparisons, were included in the full review of non-surgical ablation methods in patients with liver metastases or primary malignant liver tumours (Riemsma 2009). One trial was found that was relevant for this review (Liang 2007) (Figure 1).

Figure 1.

Flow diagram of identification of randomised trials for inclusion.

Included studies

We included one randomised trial comparing transcatheter arterial chemoembolisation (TACE) + percutaneous intratumour ethanol injection (PEI) with TACE alone (Liang 2007). Forty-eight patients with liver metastases were included; 25 received the intervention with PEI and 23 received TACE alone. The sites of the primary tumours included the colon (27), stomach (12), pancreas (3), lung (3), breast (2), and ovary (1). Among the 48 participants, nine had other metastases together with liver metastases. Primary cancers were established by surgical resection and pathology. The metastases were diagnosed during the treatment or re-examination by ultrasound B, computed tomography (CT), or magnetic resonance imaging (MRI); nine were established by liver puncture biopsy. The trial period was between November 1998 and April 2003.

The trial included 37 male and 11 female participants. The mean age was 49.3 years, with a range of 34 to 81 years. Seven participants had a single tumour in the liver, 15 participants had two tumours, and 26 participants had three or more tumours. The total number of tumours in the TACE + PEI group was 68, and 64 in the TACE Group. The tumour bulk diameter was on average 3.9 cm, ranging from 1.2 to 7.6 cm. Participants were followed for between 10 and 43 months with examinations using ultrasound B, CT, or MRI.

Excluded studies

There were no observational studies with inclusion criteria matching our review protocol.

Risk of bias in included studies

The trial was described as a randomised clinical trial. However, there was no information to assess sequence generation or allocation concealment. There was also insufficient information to assess whether participants, physicians, or outcome assessors were properly blinded.

The method of analysis was deemed appropriate, and there were no reported missing outcome data. It was not possible to assess whether the trial was free of other problems that could put it at a high risk of bias.

Overall, this trial was assessed as high risk of bias. For an overview of the methodological quality of the included trial, see Figure 2 and Figure 3.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Effects of interventions

Mortality at last follow-up

Mortality data were not reported. The trial reported survival data after one, two, and three years. In the TACE + PEI group, 92%, 80%, and 64% of the participants survived after one, two, and three years respectively; these percentages were 78.3%, 65.2%, and 47.8% for the participants in the TACE group. The hazard ratio was calculated using the Parmar method (Parmar 1998; Tierney 2007); the survival reported in the paper was 0.57 (95% CI 0.19 to 1.67), showing no significant difference between groups.

Time to mortality

Time to mortality was not reported.

Adverse events

The authors reported some adverse events but with very few details. 

Fever, pain in the liver region, nausea, and vomiting were reported in patients undergoing TACE. All disappeared within two to five days after treatment. Burning, painful sensations in the liver region were described in most PEI participants, symptoms like feeling drunk were reported in a few participants. They disappeared with or without special treatment. No complications related to the conduct of the interventional therapy were reported.

Quality of life

The trial did not report on quality of life.

Failure or proportion of patients with recurrence of tumours

The local recurrence was 16% in the TACE + PEI group and 39.1% in the TACE group, resulting in a relative risk (RR) of 0.41 (95% CI 0.15 to 1.07).

Time to progression of liver metastasis

Time to progression of liver metastasis was not reported.

Tumour response

Forty-five tumours (66.2%) out of 68 tumours in total shrunk by at least 25% in the TACE + PEI group versus 31 tumours (48.4%) out of 64 tumours in total in the TACE group (RR 2.08; 95% CI 1.03 to 4.2).

Discussion

Summary of main results

On the basis of one small randomised trial, it can be concluded that addition of PEI to TACE in patients with liver metastases seems to bring no clear benefit in terms of survival and local recurrence compared with TACE alone. The size of the tumour necrosis was larger in the combined treatment group. No intervention-related mortality or major complications were reported.

Due to the presence of one trial only, meta-regression analyses using individual quality criteria were not feasible.

Overall completeness and applicability of evidence

The search strategy was very wide as it was designed for all non-surgical ablation interventions. Additionally, by searching the reference lists of the included trials and by checking recent review articles we made sure that no relevant studies were overlooked.

Quality of the evidence

The trial did not provide sufficient details in order to judge the quality of the randomisation process, allocation concealment, presence of blinding, or selective outcome reporting bias. Therefore, the main limitation of this review is the quality of the available evidence.   

Analyses with trial sequential analysis (TSA) (CTU 2011; Thorlund 2011) have shown that apparent significant beneficial and harmful intervention effects may in fact have been caused by random error (‘play of chance’) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). This was not formally assessed in this review. Accordingly, the significant result for tumour response needs to be interpreted with caution as this result may have been caused by random error.

Potential biases in the review process

Publication bias might be an issue here; however, due to the fact that there was only one trial for this comparison, it is not possible to assess this formally. Another issue is reporting bias; there was no protocol available for the included trial. Therefore we could not assess the extent of this, but it might be an issue (Chan 2004).

Agreements and disagreements with other studies or reviews

No other reviews of PEI for people with liver metastases were found.

Authors' conclusions

Implications for practice

There is insufficient evidence to assess the effect of PEI in liver metastases.

Implications for research

There is a need for good quality, large randomised clinical trials of PEI for people with liver metastases. The most relevant comparators are palliation, chemotherapy, surgery, and other non-surgical ablation methods, especially radiofrequency ablation (RFA). As the quality of the included trial was less than optimal, it is important that the randomisation process is clearly described as well as the interventions. The patient flow should be well specified as well as data handling. The trial must be designed and described following the CONSORT statement (www.consort-statement.org).

Acknowledgements

We would like to thank Christian Gluud for his advice in the preparation of this systematic review.
Thomas Karlas, Germany, and Hans Christian Spangenberg, Germany, were the peer reviewers for the protocol of this systematic review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Search strategies

DatabaseTime spanSearch strategy
Cochrane Hepato-Biliary Group Controlled Trials RegisterDec 2012(((liver or hepatic or hepatocellular* or hepato-cellular*) AND (cancer* or neoplasm* or
malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced)
AND (liver or hepatic))) and (Ablati* OR (injection* and (ethanol or acetic acid)) or PEI or PAI)
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryIssue 12 of 12, 2012.(((liver or hepatic or hepatocellular* or hepato-cellular*) AND (cancer* or neoplasm* or
malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced)
AND (liver or hepatic))) and (rfta or radio-frequ* or radiofrequ* or rfa or rf OR Ablati*
OR (injection* and (ethanol or acetic acid)) or PEI or PAI OR Yttrium Radioisotopes OR
selective internal radi* OR radioemboli* OR radio-emboli* OR sir-sphere* OR
therasphere* OR ((yttrium* or 90y* or radiolabel*) AND microsphere*) OR Embolisation
OR Embolisation OR ((transcatheter or transarterial) and (emboli* or chemoemboli*)) or
TAE or TACE or lipiodolisation or lipiodol embolisation OR lipiodol or HAI or arterial
infusion or targeted chemotherapy OR ((transcatheter or transarterial) and chemoinfusion)
OR Iodized Oil OR thermotherapy OR Hyperthermia OR Microwaves or
coagulation OR cryosurgery)
MEDLINE (OvidSP)1950 to Dec 2012.1 exp Carcinoma, Hepatocellular/
2 exp Liver Neoplasms/
3 hcc.mp.
4 ((liver or hepatic or hepatocellular$ or hepato-cellular$) adj5 (cancer$ or neoplas$ or malign$ or carcinom$ or tumo$)).mp.
5 1 or 2 or 3 or 4
6 exp Neoplasm Metastasis/
7 (metasta* or secondar* or spread or advanced).mp.
8 6 or 7
9 exp Neuroendocrine Tumors/
10 exp Apudoma/
11 exp Carcinoid Tumour/
12 exp Adenoma, Islet Cell/
13 exp Insulinoma/
14 exp Carcinoma, Islet Cell/
15 exp Gastrinoma/
16 exp Glucagonoma/
17 exp Somatostatinoma/
18 exp Vipoma/
19 exp Multiple Endocrine Neoplasia/
20 exp Pancreatic Neoplasms/
21 exp Malignant Carcinoid Syndrome/
22 (neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids).mp.
23 (argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma).mp.
24 (nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses).mp.
25 (multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour).mp.
26 (diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours).mp.
27 (Pancreatic cholera or Verner-Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome).mp.
28 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
29 exp Colorectal Neoplasms/
30 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 neoplas$).tw,mp.
31 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 cancer$).tw,mp.
32 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 carcinoma$).tw,mp.
33 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 tumo$).tw,mp.
34 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 malignan$).tw,mp.
35 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 adenocarcinoma$).tw,mp.
36 29 or 30 or 31 or 32 or 33 or 34 or 35
37 exp Liver/
38 (liver or hepatic).mp.
39 37 or 38
40 28 or 36
41 8 and 39 and 40
42 5 or 41
43 randomised controlled trial.pt.
44 controlled clinical trial.pt.
45 randomized.ab.
46 placebo.ab.
47 randomly.ab.
48 trial.ab.
49 groups.ab.
50 43 or 44 or 45 or 46 or 47 or 48 or 49
51 humans.sh.
52 50 and 51
53 (rfta or radio-frequ$ or radiofrequ$ or rfa or rf).mp.
54 exp Catheter Ablation/
55 53 or 54
56 percutaneous.mp.
57 (ablati* and (therap* or treatment* or radiofrequenc* or cryo*)).mp.
58 ((injection* and (ethanol or acetic acid)) or PEI or PAI).mp.
59 57 or 58
60 56 and 59
61 exp Yttrium Radioisotopes/
62 selective internal radi$.tw,mp.
63 radioemboli$.tw,mp.
64 radio-emboli$.tw,mp.
65 sir-sphere$.tw,mp.
66 therasphere$.tw,mp.
67 ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$).tw,mp.
68 61 or 62 or 63 or 64 or 65 or 66 or 67
69 exp Chemoembolisation, Therapeutic/
70 exp Embolisation, Therapeutic/
71 (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation).mp.
72 exp Infusions, Intra-Arterial/
73 (lipiodol or HAI or arterial infusion or targeted chemotherapy).mp.
74 ((transcatheter or transarterial) and chemo-infusion).mp.
75 exp Iodized Oil/
76 69 or 70 or 71 or 72 or 73 or 74 or 75
77 thermotherapy.mp. or exp Hyperthermia, Induced/
78 exp Microwaves/ or coagulation therapy.mp. or exp Electrocoagulation/
79 exp Catheter Ablation/ or ablation.mp.
80 cryosurgery.mp. or exp Cryosurgery/
81 55 or 60 or 68 or 76 or 77 or 78 or 79 or 80
82 42 and 52 and 81
EMBASE (OvidSP)1974 to Dec 2012.1 Liver-Cell-Carcinoma#
2 Liver-Tumour#
3 hcc AND CLINICAL-TRIAL# AND HUMAN=YES
4 (liver OR hepatic OR hepatocellular$3 OR hepato-cellular$3) NEAR (cancer$3 OR neoplas$3 OR malign$5 OR carcinom$3 OR tumo$3) AND CLINICAL-TRIAL# AND HUMAN=YES
5 1 OR 2 OR 3 OR 4
6 Metastasis#
7 metasta$5 OR secondar$3 OR spread OR advanced
8 6 OR 7
9 Neuroendocrine-Tumour#
10 Apudoma#
11 Carcinoid#
12 Pancreas-Islet-Cell-Tumour#
13 Insulinoma#
14 Pancreas-Islet-Cell-Carcinoma#
15 Gastrinoma#
16 Glucagonoma#
17 Somatostatinoma#
18 Vipoma#
19 Multiple-Endocrine-Neoplasia#
20 Pancreas-Tumour#
21 Carcinoid-Syndrome#
22 neuroendocrine ADJ tumour OR neuroendocrine ADJ tumours OR neuroendocrine ADJ tumour OR neuroendocrine ADJ tumours OR adenoma OR adenomas OR apudoma OR apudomas OR carcinoid OR carcinoids
23 argentaffinoma OR argentaffinomas OR somatostatinoma OR somatostatinomas OR islet ADJ cell ADJ tumour OR islet ADJ cell ADJ tumours OR island ADJ cell ADJ tumour OR island ADJ cell ADJ tumours OR nesidioblastoma
24 multiple ADJ endocrine ADJ adenomatosis OR familial ADJ endocrine ADJ adenomatoses OR familial ADJ endocrine ADJ adenomatosis OR multiple ADJ endocrine ADJ neoplasms OR vipoma OR vipomas OR diarrheogenic ADJ tumour
25 nesidioblastomas OR insulinoma OR insulinomas OR multiple ADJ endocrine ADJ neoplasia OR multiple ADJ endocrine ADJ adenopathy OR multiple ADJ endocrine ADJ adenopathies OR multiple ADJ endocrine ADJ adenomatoses
26 diarrheogenic ADJ tumours OR diarrheogenic ADJ tumour OR diarrheogenic ADJ tumours OR VIP ADJ secreting ADJ tumour OR VIP ADJ secreting ADJ tumours OR VIP ADJ secreting ADJ tumour OR VIP ADJ secreting ADJ tumours
27 Pancreatic ADJ cholera OR Verner-Morrison ADJ syndrome OR Verner ADJ Morrison ADJ syndrome OR watery ADJ diarrhoea ADJ syndrome OR watery ADJ diarrhoea ADJ syndrome OR WDHA OR WDHH OR neuroendocrine ADJ carcinoma OR neuroendocrine ADJ carcinomas OR carcinoid ADJ syndrome
28 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27
29 Colorectal-Tumour#
30 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR neoplas$5
31 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR cancer$3
32 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR carcinoma$5
33 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR tumo$5
34 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR malignan$5
35 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR adenocarcinoma$5
36 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35
37 Liver#
38 liver OR hepatic
39 37 OR 38
40 28 OR 36
41 8 AND 39 AND 40
42 5 OR 41
43 random$7 OR factorial$3 OR crossover$3 OR cross ADJ over$3 OR placebo$3 OR doubl$3 ADJ blind$5 OR singl$3 ADJ blind$5 OR assign$7 OR allocat$5 OR volunteer$3
44 Crossover-Procedure#
45 Double-Blind-Procedure#
46 Randomized-Controlled-Trial#
47 Single-Blind-Procedure#
48 43 OR 44 OR 45 OR 46 OR 47
49 rfta OR radio-frequ$7 OR radiofrequ$7 OR rfa OR rf
50 Catheter-Ablation#
51 49 OR 50
52 percutaneous
53 ablati$5 AND (therap$5 OR treatment$3 OR radiofrequenc$3 OR cryo$7)
54 injection$3 AND (ethanol OR acetic ADJ acid) OR PEI OR PAI
55 53 OR 54
56 52 AND 55
57 Yttrium#
58 selective ADJ internal ADJ radi$7 OR radioemboli$7 OR radio-emboli$7 OR sir-sphere$5 OR therasphere$5
59 (yttrium$7 OR 90y$7 OR radiolabel$7) NEAR microsphere$3
60 57 OR 58 OR 59
61 Chemoembolisation#
62 Artificial-Embolism#
63 (transcatheter OR transarterial) AND (emboli$5 OR chemoemboli$5) OR TAE OR TACE OR lipiodolisation OR lipiodol ADJ embolisation
64 Intraarterial-Drug-Administration#.DE.
65 lipiodol OR HAI OR arterial ADJ infusion OR targeted ADJ chemotherapy
66 (transcatheter OR transarterial) AND chemo-infusion
67 (transcatheter OR transarterial) AND chemo ADJ infusion
68 Iodinated-Poppyseed-Oil#.DE.
69 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68
70 Hyperthermic-Therapy
71 thermotherapy
72 Microwave-Radiation#
73 Cryocoagulation# OR Electrocoagulation# OR Laser-Coagulation#
74 coagulation ADJ therapy
75 Catheter-Ablation#
76 ablation
77 Cryosurgery#.W..DE.
78 70 OR 71 OR 72 OR 73 OR 74 OR 75 OR 76 OR 77
79 51 OR 56 OR 60 OR 69 OR 78
80 42 AND 48 AND 79
81 HUMAN=YES
82 80 AND 81
83 CLINICAL-TRIAL#
84 82 AND 83
Science Citation Index Expanded (http://apps.isiknowledge.com)1970 to Dec 2012.# 70 #69 AND #37 AND #30
# 69 #68 OR #67 OR #66 OR #65 OR #64 OR #54 OR #45 OR #40
# 68 TS=(cryosurgery OR cryo-surgery)
# 67 TS=(ablation*)
# 66 TS=(Microwaves* or Microwave-Radiation* OR coagulation therapy or Electrocoagulation* or Electro-coagulation* or Cryocoagulation* OR Laser-Coagulation* OR Cryo-coagulation* )
# 65 TS= (thermotherapy or Induced Hyperthermia or Hyperthermic Therapy)
# 64 #63 OR #62 OR #61 OR #60 OR #59 OR #58 OR #57 OR #56 OR #55
# 63 TS=Iodinated Poppyseed Oil
# 62 TS=Intra-arterial Drug Administration
# 61 TS=Artificial-Embolism
# 60 TS=Iodized Oil*
# 59 TS=((transcatheter or transarterial) and chemo-infusion)
# 58 TS=(lipiodol or HAI or arterial infusion or targeted chemotherapy)
# 57 TS=Intra-Arterial Infusion*
# 56 TS=(((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation)
# 55 TS=Embolisation
# 54 #53 OR #52 OR #51 OR #50 OR #49 OR #48 OR #47 OR #46
# 53 TS=Yttrium
# 52 TS=((yttrium* and microsphere*) or (90y* and microsphere*) or (radiolabel* and microsphere*))
# 51 TS=therasphere*
# 50 TS=sir-sphere*
# 49 TS=radio-emboli*
# 48 TS=radioemboli*
# 47 TS=selective internal radi*
# 46 TS=Yttrium Radioisotopes
# 45 #44 AND #41
# 44 #43 OR #42
# 43 TS=((injection* and (ethanol or acetic acid)) or PEI or PAI)
# 42 TS=(ablati* and (therap* or treatment* or radiofrequenc* or cryo*))
# 41 TS=percutaneous
# 40 #39 OR #38
# 39 TS=Catheter Ablation
# 38 TS=(rfta or radio-frequ* or radiofrequ* or rfa or rf)
# 37 #36 AND #35
# 36 TS=human*
# 35 #34 OR #33 OR #32 OR #31
# 34 TS=trial*
# 33 TS=random*
# 32 TS=groups
# 31 TS=placebo
# 30 #29 OR #10
# 29 #28 AND #27 AND #11
# 28 #26 OR #19
# 27 TS=(liver or hepatic)
# 26 #25 OR #24 OR #23 OR #22 OR #21 OR #20
# 25 TS=(colon* adenocarcinoma* or rect* adenocarcinoma* or colorect* adenocarcinoma* or bowel adenocarcinoma* or large intestin* adenocarcinoma*)
# 24 TS=(colon* malignan* or rect* malignan* or colorect* malignan* or bowel malignan* or large intestin* malignan*)
# 23 TS=(colon* tumo* or rect* tumo* or colorect* tumo* or bowel tumo* or large intestin* tumo*)
# 22 TS=(colon* carcinoma* or rect* carcinoma* or colorect* carcinoma* or bowel carcinoma* or large intestin* carcinoma*)
# 21 TS=(colon* cancer* or rect* cancer* or colorect* cancer* or bowel cancer* or large intestin* cancer*)
# 20 TS=(colon* neoplas* or rect* neoplas* or colorect* neoplas* or bowel neoplas* or large intestin* neoplas*)
# 19 #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12
# 18 TS=(Gastrinoma or Glucagonoma or Somatostatinoma or Pancreatic Neoplasm*)
# 17 TS=(Pancreatic cholera or Verner-Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome)
# 16 TS=(diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours)
# 15 TS=(multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour)
# 14 TS=(nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses)
# 13 TS=(argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma)
# 12 TS=(neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids)
# 11 TS=(Neoplasm Metastasis or metasta* or secondar* or spread or advanced)
# 10 #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1
# 9 TS=(Liver-Cell-Carcinoma or Liver Cell Carcinoma)
# 8 TS=(liver malign* or hepatic malign* or hepatocellular* malign* or hepato-cellular* malign*)
# 7 TS=(liver tumo* or hepatic tumo* or hepatocellular* tumo* or hepato-cellular* tumo*)
# 6 TS=(liver carcinom* or hepatic carcinom* or hepatocellular* carcinom* or hepato-cellular* carcinom*)
# 5 TS=(liver neoplas* or hepatic neoplas* or hepatocellular* neoplas* or hepato-cellular* neoplas*)
# 4 TS=(liver cancer* or hepatic cancer* or hepatocellular* cancer* or hepato-cellular* cancer*)
# 3 TS=hcc
# 2 TS=Liver Neoplasms
# 1 TS=Hepatocellular Carcinoma
LILACSDec 2012.(Pt RANDOMIZED CONTROLLED TRIAL OR Pt CONTROLLED CLINICAL TRIAL
OR Mh RANDOMIZED CONTROLLED TRIALS OR Mh RANDOM ALLOCATION
OR Mh DOUBLE-BLIND METHOD OR Mh SINGLE-BLIND METHOD OR Pt
MULTICENTER STUDY) OR ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw
acaso or tw placebo or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego)
or (tw doble and tw ciego) or (tw double and tw blind)) and tw clinic$)) AND NOT ((CT
ANIMALS OR MH ANIMALS OR CT RABBITS OR CT MICE OR MH RATS OR
MH PRIMATES OR MH DOGS OR MH RABBITS OR MH SWINE) AND NOT (CT
HUMAN AND CT ANIMALS)) [Palavras] and (liver or hepatic) [Palavras]
CINAHL (EBSCO host)1981 to Dec 2012.

S69 S67 and S68 Limiters - Exclude MEDLINE records

S68 TX random* or placebo* or blind* or trial* or group*
S67 S37 and S66

S66 S40 or S45 or S65

S65 S56 or S57 or S58 or S59 or S60 or S61 or S62 or S63 or S64

S64 TX cryosurgery

S63 MM cryosurgery

S62 TX ablation

S61 MM catheter ablation

S60 TX coagulation therapy

S59 TX electrocoagulation

S58 MM microwaves

S57 TX thermotherapy

S56 MM Hyperthermia, Induced

S55 S49 or S50 or S51 or S52 or S53 or S54

S54 TX iodi?ed oil

S53 TX ( trans?catheter or trans?arterial ) and TX chemo-infusion

S52 TX (lipiodol or HAI or arterial infusion or targeted chemotherapy)

S51 MM Infusions, Intraarterial

S50 TX (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation)

S49 MM Embolization, Therapeutic

S48 S46 or S47

S47 TX ( (yttrium* or 90y* or radiolabel*) ) and TX microsphere*

S46 TX (yttrium radioisotope*) or (selective internal radi*) or radioemboli* or radio-emboli* or sir-sphere* or therasphere*

S45 S41 and S44

S44 S42 or S43

S43 TX ((injection* and (ethanol or acetic acid)) or PEI or PAI)

S42 TX (ablati* and (therap* or treatment* or radiofrequenc* or cryo*))

S41 TX percutaneous

S40 S38 or S39

S39 TX rfta or radio-frequ* or radiofrequ*

S38 MM catheter ablation

S37 S5 or S36

S36 S8 and S32 and S35

S35 S33 or S34

S34 TX liver or hepatic

S33 MM liver

S32 S28 or S31

S31 S29 or S30

S30 TX ( (colon* or rect* or colorect* or bowel or large intestin*) ) and TX ( (neoplas* or cancer* or carcinoma* or tumo?r* or malignan* or adenocarcinoma*) )

S29 MM colorectal neoplasms

S28 S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27

S27 TX Pancreatic cholera or Verner-Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma*

S26 TX VIP secreting tumo?r*

S25 TX familial endocrine adenomatos* or diarrheogenic tumo?r*

S24 TX insulinoma* or (multiple endocrine AND (neoplasia or adenopath* or adenomatos* or neoplasm*))

S23 TX argentaffinoma* or somatostatinoma* or islet cell tumo?r*or island cell tumo?r* or nesidioblastoma*

S22 TX ( (neuroendocrine AND tumo?r*) ) or TX ( adenoma* OR apudoma* OR carcinoid* )

S21 TX malignant carcinoid syndrome Search modes

S20 TX apudoma* OR glucagonoma* OR somatostatinoma* OR vipoma*

S19 MM apudoma OR glucagonoma OR somatostatinoma

S18 MM glucagon

S17 MM gastrointestinal neoplasms

S16 MM endocrine gland neoplasms

S15 MM pancreatic neoplasms

S14 MM gastrinoma

S13 MM insulinoma

S12 MM carcinoma, islet cell

S11 MM adenoma, islet cell

S10 MM carcinoid tumor

S9 MM neuroendocrine tumors

S8 S6 or S7

S7 TX metasta* or secondar* or spread or advanced

S6 MM neoplasm metastasis

S5 S1 or S2 or S3 or S4

S4 TX ( liver or hepatic or hepatocellular* or hepato-cellular* ) and TX ( cancer* or neoplas* or malign* or carcinom* or tumo* )

S3 TX hcc

S2 MM liver neoplasms

S1 MM carcinoma, hepatocellular

Contributions of authors

Review:

JK developed the concept for the project. RR and JK formulated the search strategy and carried out searches. Study inclusion and data extraction were done by MB, RR, and RW. Analyses were performed by MB, RR, and RW. The text of the review was prepared by MB, RR, RW, and JK.

Peer reviewer: Janus Christian Jakobsen, Denmark.
Contact editor: Christian Gluud, Denmark.

Declarations of interest

No conflicts of interest

Sources of support

Internal sources

  • Kleijnen Systematic Reviews Ltd. (KSR), UK.

    KSR funded the updating of the review and producing Cochrane Reviews.

External sources

  • The Dutch Health Care Insurance Board (CVZ), Netherlands.

    This systematic review was funded by the Dutch Health Care Insurance Board (CVZ). CVZ commissioned a systematic review of the effectiveness of non-surgical ablation methods for liver metastases.

Differences between protocol and review

Amended inclusion criteria for data on harm, from: "Quasi-randomised and observational studies that will come up with the search, will be considered only for the report of data on harm" to "Quasi-randomised and other controlled studies that will come up with the search, will be considered only for the report of data on harm".

We removed the domains 'baseline imbalance' and 'early stopping of trials'. The argumentation for not considering baseline imbalance is that it may occur due to random error ('play of chance'), and that such random error is likely to be levelled out by conducting a meta-analysis of several trials. The argumentation for not considering early stopping is that such trials - although they may overestimate intervention effects - are likely to be counterbalanced by trials finding no significant difference. By solely excluding trials that are stopped early one would bias the meta-analysis towards a neutral effect (Gluud 2013).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Liang 2007

  1. a

    CT = computed tomography
    MRI = magnetic resonance imaging

MethodsStudy type: randomised clinical trial.
Location: China.
Inclusion criteria:
• Patients with liver metastases. The metastases were diagnosed during the treatment or re-examination by ultrasound B, CT or MRI or by liver puncture biopsy. No further details reported.
Participants

Total number of patients: 48 patients. The primary tumour sites are: colon 27, stomach 12, pancreas 3, lung 3, breast 2, ovary 1, and 9 had other metastases together with liver metastases.

Child level before surgery: A 33, B 15.

InterventionsTwo treatment groups:
• Group 1: Transcatheter arterial chemoembolisation + percutaneous intratumour ethanol injection (n = 25).
• Group 2: Transcatheter arterial chemoembolisation alone (n = 23).
Outcomes1, 2, 3 year survival, local recurrence, tumour shrinking and adverse events.
NotesThe trial was published in Chinese, we used a translated version.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"48 liver metastases patients were randomised into 2 groups"
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data were reported.
Selective reporting (reporting bias)Unclear riskNot reported.
Other biasUnclear riskNot reported.

Ancillary