Microwave coagulation for liver metastases

  • Review
  • Intervention

Authors


Abstract

Background

Primary liver cancer 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. Microwave coagulation involves placing an electrode into a lesion under ultrasound or computed tomography guidance. The microwave coagulator generates and transmits microwave energy to the electrode. Coagulative necrosis causes cellular death and destroys tissue in the treatment area, resulting in reduction of tumour size.

Objectives

To study the beneficial and harmful effects of microwave coagulation 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, The Cochrane Central Register of Controlled Trials (CENTRAL) inThe Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012.

Selection criteria

We included all randomised clinical trials assessing beneficial and harmful effects of microwave coagulation and its comparators, irrespective of the location of the primary tumour.

Data collection and analysis

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

Main results

One randomised clinical trial fulfilled the inclusion criteria of the review. Forty participants with multiple liver metastases of colorectal cancer and no evidence of extrahepatic disease were randomly assigned. Thirty of these participants (14 females and 16 males) were included in the analysis: 14 participants received microwave coagulation and 16 underwent conventional surgery (hepatectomy or liver resection). The diagnosis of colorectal cancer (Stage IB to IIIC; tumour (T)2 node (N)0 to T3N2) and liver metastases was confirmed by histological assessment. Mean participant age was 61 years. The tumours were resectable. The risk of bias in the trial was judged to be high.

Participants were followed for three years. Mortality at the last follow-up was 64% (9/14) in the microwave group and 75% (12/16) in the conventional surgery group (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.53 to 1.39), that is, no significant difference was observed. In the microwave coagulation group, 71%, 57%, and 14% survived 1, 2, and 3 years, and in the conventional surgery group, the percentages were 69%, 56%, and 23%. The hazard ratio calculated using the Parmar method was 0.91 (0.39 to 2.15).

Mean survival time was 27 months in the microwave group and 25 months in the conventional surgery group, and the mean disease-free interval was 11.3 months in the microwave group and 13.3 months in the hepatectomy group. Differences for both outcomes were not statistically significant. Reported frequency of adverse events was similar between the microwave coagulation and conventional surgery groups, except for the required blood transfusion, which was more common in the conventional surgery group. No intervention-related mortality was observed. After treatment, the carcinoembryonic antigen level decreased significantly in both groups.

Authors' conclusions

On the basis of one randomised clinical trial, which did not describe allocation concealment or blinding, and which excluded from analysis 25% of participants after random assignment, evidence is insufficient to show whether microwave coagulation brings any significant benefit in terms of survival or recurrence compared with conventional surgery for participants with liver metastases from colorectal cancer. The number of adverse events, except for the requirement for blood transfusion, which was more common in the liver resection group, was similar in both groups. At present, microwave therapy cannot be recommended outside randomised clinical trials.

Résumé scientifique

Coagulation par micro-ondes dans le traitement des métastases hépatiques

Contexte

Les cancers hépatiques primaires et les métastases hépatiques du cancer colorectal sont les deux tumeurs malignes les plus fréquentes qui touchent le foie. Le foie est le deuxième organe le plus impliqué par les métastases, après les ganglions lymphatiques. Plus de la moitié des patients atteints de métastases hépatiques décèdent des suites de complications liées à celles-ci. La coagulation par micro-ondes consiste à placer une électrode dans une lésion sous guidage par échographie ou scanner TDM. Le coagulateur à micro-ondes génère une énergie par micro-ondes et la transmet à l’électrode. La nécrose par coagulation provoque la mort des cellules et la destruction des tissus dans la zone traitée, ce qui entraîne une réduction de la taille de la tumeur.

Objectifs

Étudier les effets bénéfiques et nocifs de la coagulation par micro-ondes par rapport 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 des recherches dans le registre des essais contrôlés du groupe Cochrane sur les pathologies hépatobiliaires, le registre Cochrane des essais contrôlés (CENTRAL) dans la Bibliothèque Cochrane, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS et CINAHL, jusqu’à décembre 2012.

Critères de sélection

Nous avons inclus tous les essais cliniques randomisés évaluant les effets bénéfiques et nocifs de la coagulation par micro-ondes et des méthodes de comparaison, quelle que soit la localisation de la tumeur primaire.

Recueil et analyse des données

Nous avons extrait les informations pertinentes sur les caractéristiques des participants, les interventions et les résultats des études et les données sur les mesures de résultats de notre revue, ainsi que des informations sur la conception et la méthodologie des études. L’évaluation du risque de biais des essais, la détermination de leur conformité aux critères d’inclusion, et l’extraction des données des essais retenus pour l’évaluation finale ont été effectuées par un auteur de la revue et vérifiées par un deuxième auteur.

Résultats principaux

Un seul essai clinique randomisé répondait aux critères d’inclusion de la revue. Quarante participants atteints de métastases hépatiques multiples d’un cancer colorectal, sans signe d’atteinte extra-hépatique, étaient randomisés. Trente de ces participants (14 femmes et 16 hommes) ont été inclus dans l’analyse : 14 participants ont été traités par coagulation par micro-ondes et 16 par chirurgie conventionnelle (hépatectomie ou résection hépatique). Le diagnostic de cancer colorectal (stades BI à IIIC ; tumeur (T)2 ganglions (N)0 à T3N2) et de métastases hépatiques a été confirmé par l’examen histologique. La moyenne d’âge des participants était de 61 ans. Les tumeurs étaient résécables. Le risque de biais dans l’essai a été jugé élevé.

Les participants ont été suivis pendant trois ans. La mortalité lors du dernier suivi était de 64 % (9/14) dans le groupe traité par micro-ondes et 75 % (12/16) dans le groupe de chirurgie conventionnelle (risque relatif (RR) 0,86 ; intervalle de confiance (IC) à 95 % de 0,53 à 1,39) ; en d’autres termes, aucune différence significative n’a été observée. Dans le groupe de coagulation par micro-ondes, 71 %, 57 % et 14 % des patients ont survécu à 1, 2 et 3 ans ; dans le groupe de chirurgie conventionnelle, les pourcentages étaient de 69 %, 56 % et 23 %. Le risque relatif calculé en utilisant la méthode Parmar était de 0,91 (0,39 à 2,15).

La survie moyenne était de 27 mois dans le groupe traité par micro-ondes et 25 mois dans le groupe traité par chirurgie conventionnelle, et l’intervalle sans maladie moyen était de 11,3 mois dans le groupe traité par micro-ondes et 13,3 mois dans le groupe d’hépatectomie. Les différences pour les deux critères de jugement n’étaient pas statistiquement significatives. La fréquence rapportée des événements indésirables était similaire entre les groupes de coagulation par micro-ondes et de chirurgie conventionnelle, sauf en ce qui concerne la nécessité d’une transfusion sanguine, plus fréquente dans le groupe de chirurgie conventionnelle. Aucune mortalité liée à l’intervention n’a été observée. Après le traitement, le niveau d’antigène carcinoembryonnaire a diminué significativement dans les deux groupes.

Conclusions des auteurs

Sur la base d’un seul essai clinique randomisé, ne décrivant pas d’assignation secrète ni de mise en aveugle et excluant de l’analyse 25 % des participants après assignation aléatoire, les preuves sont insuffisantes pour déterminer si la coagulation par micro-ondes apporte un quelconque bénéfice significatif en termes de survie ou de récidive, par rapport à la chirurgie conventionnelle, pour les participants atteints de métastases hépatiques du cancer colorectal. Le nombre d’événements indésirables était similaire dans les deux groupes, à ceci près qu’une transfusion sanguine a été plus souvent nécessaire dans le groupe des résections hépatiques. À l’heure actuelle, la thérapie par micro-ondes ne peut pas être recommandée en dehors des essais cliniques randomisés.

Plain language summary

Microwave coagulation for liver metastases

Primary liver cancer 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. Microwave coagulation involves placing an electrode into a lesion under ultrasound or computed tomography guidance. The microwave coagulator generates and transmits microwave energy to the electrode. Coagulative necrosis causes cellular death and destroys tissue in the treatment area, resulting in reduction of tumour size. One randomised clinical trial comparing microwave coagulation with conventional surgery (liver resection) is included in the review: 14 participants received microwave coagulation and 16 participants underwent conventional surgery. The trial was judged to have a high risk of systematic error (ie, overestimation of benefits and underestimation of harms). On the basis of one randomised trial, which did not describe allocation concealment or blinding, and which excluded from analysis 25% of participants after random assignment, evidence is insufficient to show whether microwave coagulation provides any significant benefit in terms of survival or recurrence compared with conventional surgery for participants with liver metastases from colorectal cancer. The number of adverse events, except for the requirement for blood transfusion, which was more common in the liver resection group, was similar in both groups. At present, microwave therapy cannot be recommended outside randomised clinical trials.

Résumé simplifié

Coagulation par micro-ondes dans le traitement des métastases hépatiques

Les cancers hépatiques primaires et les métastases hépatiques du cancer colorectal sont les deux tumeurs malignes les plus fréquentes qui touchent le foie. Le foie est le deuxième organe le plus impliqué par les métastases, après les ganglions lymphatiques. Plus de la moitié des patients atteints de métastases hépatiques décèdent des suites de complications liées à celles-ci. La coagulation par micro-ondes consiste à placer une électrode dans une lésion sous guidage par échographie ou scanner TDM. Le coagulateur à micro-ondes génère une énergie par micro-ondes et la transmet à l’électrode. La nécrose par coagulation provoque la mort des cellules et la destruction des tissus dans la zone traitée, ce qui entraîne une réduction de la taille de la tumeur. Un seul essai clinique randomisé comparant la coagulation par micro-ondes à la chirurgie conventionnelle (résection hépatique) est inclus dans la revue : 14 participants y ont été traités par coagulation par micro-ondes et 16 autres par une intervention chirurgicale conventionnelle. L’essai a été jugé à risque élevé d’erreur systématique (surestimation des effets bénéfiques et sous-estimation des effets nocifs). Sur la base d’un seul essai randomisé, qui ne décrivait pas d’assignation secrète ou de mise en aveugle et qui excluait de l’analyse 25 % des participants après une assignation aléatoire, les preuves sont insuffisantes pour déterminer si la coagulation par micro-ondes apporte un quelconque bénéfice significatif en termes de survie ou de récidive, en comparaison avec la chirurgie conventionnelle, pour les participants atteints de métastases hépatiques du cancer colorectal. Le nombre d’événements indésirables était similaire dans les deux groupes, à ceci près qu’une transfusion sanguine a été plus souvent nécessaire dans le groupe des résections hépatiques. À l’heure actuelle, la thérapie par micro-ondes ne peut pas être recommandée en dehors des essais cliniques randomisés.

Notes de traduction

Traduit par: French Cochrane Centre 9th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Microwave coagulation vs no intervention, other ablation methods, or systemic treatments
  1. 1 The trial did not describe allocation concealment or blinding and excluded 25% of participants after randomisation.
    2 Imprecision because the total number of events is less than 300 (a threshold rule-of-thumb value) (based on Mueller et al. Ann Intern Med 2007;146:878-881; http://www.annals.org/cgi/content/abstract/146/12/878).

Microwave coagulation versus no intervention, other ablation methods, or systemic treatments
Patient or population: participants with liver metastases
Settings: hospitalised
Intervention: microwave coagulation
Comparison: conventional surgery
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Conventional surgery Microwave coagulation
Time to mortality

Follow-up: 3 years
The mean time to mortality in the control groups was
25 months.
The mean time to mortality in the intervention groups was
2 months higher
(0 to 0 higher).
 30
(1 study)
⊕⊝⊝⊝
very low 1,2
 
Disease-free interval

Follow-up: 3 years
The mean disease-free interval in the control groups was
13.3 months.
The mean disease-free interval in the intervention groups was
2 months lower
(0 to 0 higher).
 30
(1 study)
⊕⊝⊝⊝
very low 1,2
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Primary liver cancer and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver (Lau 2000; Michel 2002). Primary liver cancer 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 patients with metastatic liver disease will die from metastatic complications (Wood 1976; Markovic 1998). The most common primary sites for liver metastases are lung, breast, colon and rectum, and uterus. On preoperative imaging, liver metastases are found in 35% of patients with colorectal cancer, and 8% to 30% of other patients will be found to have subsequent liver involvement. Almost half of patients dying from stomach, pancreas, or breast cancer are found to have liver metastases at autopsy; among patients with endometrial cancer, metastasis occurs in about 40% (Hugh 1997).

Colorectal carcinoma is the third leading cancer in the United States and ranks third in cancer-related deaths (9% of all cancer deaths annually) (Jemal 2010). Globally, the age-adjusted annual incidence rate for colorectal cancer is 17.2 per 100,000 (IARC 2008). The highest incidence is observed in North America (age adjusted, 30.1 per 100,000), Australia and New Zealand (age adjusted, 39.0), northern Europe (age adjusted, 30.5), and western Europe (age adjusted, 33.1). Lower incidences are observed in Africa (age adjusted, 5.9) and Asia (age adjusted, 12.9). Globally, the age-adjusted mortality for colorectal cancer is 8.2 per 100,000. In the United States, the five-year survival rate after the diagnosis of colorectal cancer is 66.6% (NCI 2009). Estimated survival in all developed countries analysed together is 55%, and in developing countries, 39% (Parkin 2002). Approximately 50% of patients with colorectal cancer will develop recurrence within five years of initial diagnosis, with the liver the most common site for metastatic disease (Geoghegan 1999).

For other common primary sites of liver metastases, age-standardised incidence and mortality rates per 100,000 people of both sexes are as follows: lung cancer, 23.0 and 19.4; stomach, 14.1 and 10.3; and pancreas, 3.9 and 3.7; and for women, breast, 39.0 and 12.5; and corpus uteri, 8.2 and 2.0 (IARC 2008). In the United States, the five-year survival rate after lung cancer is diagnosed is 16.4%, stomach 26.7%, pancreas 5.7%, breast cancer 89.9%, and corpus uteri cancer 84.1% (NCI 2009). In all developed countries analysed together, the estimated annual survival rate after lung cancer is diagnosed is 13% in men and 20% in women; the estimated survival rate for stomach cancer is 35% in men and 31% in women; for breast cancer, it is 75%; and for cancer of the corpus uteri, it is 82% (Parkin 2002). In all developing countries analysed together, estimated survival after the diagnosis of lung cancer is 12% in both men and women; for stomach cancer, it is 21% in men and 20% in women; for breast cancer, it is 57%; and for cancer of the corpus uteri, it is 67% in women (Parkin 2002).

For many patients, progressive involvement of the liver is the primary determinant of long-term survival. Surgical liver resection is the gold standard treatment for liver metastases, and it is the only curative option for patients with malignant liver neoplasm, with median survival times of 21 to 46 months or five-year survival of 20% to 58% (McLoughlin 2006). However, only 20% of patients with hepatic tumours are candidates for resection. The other patients are excluded from this method of treatment because of multiple metastases, anatomical limitations, inadequate functional liver reserve, extrahepatic metastases, or medical comorbidities (Bilchik 2000; Bipat 2007). Several alternative or adjunctive methods of treatment have been developed for patients with unresectable liver metastases (Boutros 2010), including chemotherapy and local ablative therapies. Chemotherapy can be delivered intra-arterially (5-fluorouracil), and it is called 'regional chemotherapy', or it can be delivered systemically (5-fluorouracil, irinotecan, oxaliplatin, leucovorin, capecitabine). Local tumour ablative techniques include transarterial (chemo)embolisation, percutaneous ethanol injection, microwave coagulation, laser-induced thermotherapy, radiofrequency ablation, and cryosurgical ablation. The most widely employed method is radiofrequency ablation. However, a Cochrane review that assessed the efficacy of radiofrequency ablation on the basis of a single randomised clinical trial and several observational studies concluded that information was insufficient to allow this treatment to be recommended for radical oncological treatment of patients with colorectal cancer metastases (Cirocchi 2012). Cryosurgical ablation, percutaneous ethanol injection, and transarterial chemo(embolisation) are topics of other Cochrane reviews (Riemsma 2010; Bala 2011; Riemsma 2011; Bala 2013). Microwave coagulation was developed to overcome some of the limitations of radiofrequency ablation, such as wider ablation diameter, higher ablation rates, and reduced operative time (Boutros 2010).

Description of the intervention

Microwave coagulation was developed as a surgical technique in the late 1970s, and it has been used in surgery for coagulation (Shibata 2000). Microwave coagulation involves placing an electrode into a lesion under ultrasound or computed tomography guidance (Simon 2005). The microwave coagulator generates and transmits microwave energy to the electrode. An alternating high-frequency (up to 2450 MHz) electromagnetic wave causes molecular vibration of dipoles, which produces heat and thermal coagulation around the electrode. Coagulative necrosis causes cellular death and destroys tissue in the treatment area, resulting in reduction of tumour size (Lau 2003; Simon 2005; Boutros 2010). Microwave coagulation can be applied percutaneously, laparoscopically, and during open surgery. Percutaneous ablation usually can be performed with the patient under conscious sedation (Simon 2005).

How the intervention might work

Microwave radiation refers to electromagnetic wave frequencies from 900 to 2450 MHz. Water molecules are polar, and electromagnetic radiation causes them to flip back and forth; the speed of the process depends on the frequency of the microwave energy. Electromagnetic wave-agitated water molecules produce heat and induce cellular death by coagulation necrosis (Lau 2003; Simon 2005; Boutros 2010).

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 long-term outcomes can be anticipated with some of these therapies. Systematic reviews may help to establish the effectiveness and the trade-offs between benefits and harms associated with different nonsurgical ablation methods for the treatment of all forms of malignant liver tumours (primary and metastases). Reviews and meta-analyses 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; Lopez 2006; Marlow 2006; Sutherland 2006). No Cochrane review has compared microwave coagulation with no intervention, other ablation methods, or systemic treatments in people with liver metastases from any primary source. Therefore, a new review with up-to-date searches that addresses all types of malignant liver metastases has been warranted.

Objectives

To study the beneficial and harmful effects of microwave coagulation 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 the beneficial and harmful effects of microwave coagulation and its comparators, irrespective of publication status, language, or blinding. Quasi-randomised and other controlled studies that came up in the search were considered only for the report of data on harm.

Types of participants

Participants with liver metastases regardless of the location of the primary tumour.

Types of interventions

Microwave coagulation compared with no intervention, other ablation methods, or systemic treatments. Cointerventions were allowed if provided equally to experimental and control groups of an individual randomised trial.

Types of outcome measures

Primary outcomes
  • All-cause mortality at last follow-up and time to mortality.

  • One-year survival, three-year survival, and disease-free survival.

  • 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, or results in persistent or significant disability; as well as any important medical event that may have jeopardised the participant or requires intervention for prevention. All other adverse events are considered non-serious.

  • Quality of life.

Secondary outcomes
  • Cancer mortality.

  • Proportion of participants with failure to clear liver metastases or with recurrence of liver metastases.

  • Time to progression of liver metastases.

  • Tumour response measures (complete response, partial response, stable disease, disease progression).

We extracted data on outcome measures at the end of treatment and at longest follow-up.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) inThe Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (Royle 2003), as well as the World Health Organisation (WHO) International Clinical Trials Registry Platform (WHO 2012).

One global search was used for all non-surgical ablation methods for primary malignant liver tumours and liver metastases. Search strategies along with the time spans of the searches are given in Appendix 1 (up to December 2012). There was no need to improve search strategies.

In addition, we assessed for inclusion of all United States Food and Drug Administration (FDA) approvals and investigational device exemptions as found on the FDA Website (FDA 2013).

Searching other resources

We searched reference lists of reviews (such as Lopez 2006 and Schwartz 2004), health technology assessment (HTA) reports (such as Marlow 2006 (ASERNIP-S)), all Cochrane reviews, and all trials that were included for relevant studies.

Data collection and analysis

Selection of studies

Two review authors (RPR and MMB) independently evaluated titles and abstracts for ordering papers. Any differences in opinion were resolved by discussion or, if necessary, by consultation with a third review author (JK). For titles and abstracts that potentially fit our inclusion criteria, full papers were retrieved. These papers were assessed by two independent review authors (RPR and MMB), and differences in opinion, if any, were resolved using the above-mentioned procedure.

Data extraction and management

We extracted relevant information on participant characteristics, interventions, and study outcome measures, as well as data on outcome measures, for our review, and information on design and methodology of the studies. Quality assessment of the trials, determination of whether they fulfilled the inclusion criteria, and data extraction from retrieved for final evaluation trials were done by one review author (RPR, MMB, or RW) and were checked by a second review author (RPR, MMB, or RW).

Assessment of risk of bias in included studies

We assessed the risk of bias of trials on the basis of the domains described in the following sections of this review (Schulz 1995; Moher 1998; Kjaergard 2001; Gluud 2008; Wood 2008; Higgins 2011; 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 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 adjudicator.

  • Uncertain risk of bias: The trial was described as randomised, but the method of sequence generation was not specified.

  • High risk of bias: The sequence generation method was not, or may not have been, random. Quasi-randomised studies, those using dates, names, or admittance numbers to allocate participants, were inadequate and have been excluded for assessment of benefits but not for assessment of harms.

Allocation concealment

  • Low risk of bias: Allocation was controlled by a central and independent randomisation unit with the use of sequentially numbered, opaque, and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.

  • Uncertain risk of bias: The trial was described as randomised, but 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 known to the investigators who assigned participants, or the study was quasi-randomised. Quasi-randomised studies were excluded for assessment of benefits but not for assessment of harms.

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias: Blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding.

  • Uncertain risk of bias: Information was insufficient to allow assessment of whether the type of blinding used was likely to induce bias on the estimate of effect.

  • High risk of bias: No blinding or incomplete blinding was used, and the outcome or the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data

  • Low risk of bias: The underlying reasons for missingness were unlikely to make treatment effects a departure from plausible values, or proper methods were employed to handle missing data.

  • Uncertain risk of bias: Information was insufficient to allow assessment of whether the missing data mechanism in combination with the method used to handle missing data was likely to induce bias on the estimate of effect.

  • High risk of bias: The crude estimate of effects (eg, complete case estimate) was clearly biased because of the underlying reasons for missingness, and the methods used to handle missing data were unsatisfactory.

Selective outcome reporting

  • Low risk of bias: Predefined, or clinically relevant and reasonably expected, outcomes were reported.

  • Uncertain risk of bias: Not all predefined, or clinically relevant and reasonably expected, outcomes were reported, or they were not reported fully, or it is unclear whether or not data on these outcomes were recorded.

  • High risk of bias: One or more clinically relevant and reasonably expected outcomes were not reported; data on these outcomes were likely to have been recorded.

Other bias

  • Low risk of bias: The trial appeared to be free of other components that could have put it at risk of bias. 

  • Uncertain risk of bias: The trial may or may not be free of other components that could have put it at risk of bias.

  • High risk of bias: Other factors in the trial could have put it at risk of bias (eg, for-profit involvement, authors have conducted trials on the same topic).

Trials judged as having ’low risk of bias’ in all of the above specified individual domains were considered to be ’trials with low risk of bias’. All other instances classify the trials as trials with high risk of bias.

Measures of treatment effect

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

Dealing with missing data

Data were planned to be analysed using the intention-to-treat principle, that is, participants with missing data (in all treatment groups of a trial) were to be considered as treatment failures, and all randomly assigned participants were to be included in the denominator.

Assessment of heterogeneity

Heterogeneity was to be assessed using the Chi2 test and the I2 statistic. Any plausible, possible causes of heterogeneity were to be discussed.

Data synthesis

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) 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, risk ratios, risk differences, mean differences, and standardised mean differences). Where possible, we planned to calculate hazard ratios using methods described by Parmar and Tierney (Parmar 1998). We planned to extract information (eg, hazard rates, P values, events, ratios, curve data, information on follow-up) from the publication and, if necessary, to enter data into a Microsoft Office Excel 2003 spreadsheet for calculation of hazard ratios (Thierney 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 estimate, to show the variance of the effects (Egger 1997). 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 with meta-analysis 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 on the basis of differences and similarities of included trials and their risk of bias assessment. We planned to group the trials by interventions, participant 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 (Egger 1997). We planned to discuss the possible implications of our findings if bias was present.

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

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses where possible on the basis of prognostic indicators such as age, sex, tumour size, location of primary tumour, and use of any cointerventions. For an extra subgroup analysis, a trial with a lower risk of bias was to be defined where three or more domain items were met, including sequence generation and allocation concealment.

Sensitivity analysis

We planned to summarise the separate outcomes after intervention, at six months or less, at six to 12 months, and at one year or longer.

Summary of findings

We summarised the evidence in the Summary of findings for the main comparison using GRADEpro (http://ims.cochrane.org/revman/other-resources/gradepro).

Results

Description of studies

See Characteristics of included 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” (Riemsma 2009) were performed in December of 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. On the basis of review of the full papers, we excluded 534 publications, mainly because they were not randomised trials.

One hundred twenty-one papers, describing 84 trials and 144 comparisons, were included in the full review of non-surgical ablation methods in participants with liver metastases or primary malignant liver tumours (Riemsma 2009). One trial was found to be relevant for this review (Shibata 2000) (Figure 1).

Figure 1.

Flow diagram of identification of randomised trials for inclusion.

Included studies

We included one randomised clinical trial comparing two groups: microwave coagulation versus conventional liver surgery (hepatectomy or liver resection) (Shibata 2000). The trial randomly assigned 40 participants with multiple (fewer than 10) liver metastases of colorectal cancer and with no evidence of extrahepatic disease, ascites, periportal or celiac lymph node metastasis, liver cirrhosis, or chronic hepatitis. However, 10 participants (six from the intervention group and four from the control group) were excluded after the randomisation because they did not fulfil the inclusion criteria of the study, and so only 30 participants were analysed. Fourteen participants received microwave coagulation, and 16 participants underwent conventional surgery.

Microwave coagulation was performed after laparotomy with microwave tissue coagulator at an output of 60 to 100 W for 2 to 20 minutes under the guide of ultrasonography.

Conventional surgery involved lobectomy, segmentectomy, subsegmentectomy, and/or wedge resection.

The 30 participants in the trial were 14 females and 16 males. The diagnosis of participants with colorectal cancer (Stage IB to IIIC; T2N0 to T3N2) and liver metastases was confirmed by histological assessment. The mean age of participants was 61 years. The tumours were resectable. The mean size of the tumour in participants in the intervention group was 27 mm, and 34 mm among participants in the control group. The participants had 2 to 9 metastases: mean 4.1 in the intervention group, and mean 3.0 in the control group. Participants were followed for three years.

Excluded studies

No observational studies had inclusion criteria that matched those of our review protocol.

Risk of bias in included studies

The trial was described as a randomised clinical trial. Overall, we assessed the risk of bias of this trial as high. For an overview of the bias risk 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.

Allocation

The trial was described as a randomised clinical trial. Participants were assigned randomly, without stratification, according to a computer-generated, 1:1 randomisation list for treatment with microwave coagulation versus hepatic resection. Accordingly, the generation of the allocation sequence was considered adequate. However, insufficient information was provided for review authors to judge the presence of allocation concealment.

Blinding

Information was insufficient to allow assessment of whether participants, physicians, or outcome assessors were properly blinded.

Incomplete outcome data

Ten participants were excluded after randomisation, six from the experimental group and four from the control group.

Selective reporting

Clinically relevant and reasonably expected outcomes were reported.

Other potential sources of bias

It was not possible to assess whether the trial was free of other problems that could put it at higher risk of bias.

Effects of interventions

See: Summary of findings for the main comparison Microwave coagulation vs no intervention, other ablation methods, or systemic treatments

See Summary of findings for the main comparison.

Primary outcomes

All-cause mortality at last follow-up and time to mortality
Trial investigators reported that mortality was 64% (9/14) in the microwave group versus 75% (12/16) in the conventional surgery group (RR 0.86, 95% CI 0.53 to 1.39) (our calculation using the Mantel-Haenszel test in RevMan). Because this was based on only one trial, and because the number of events was high, we checked the result using Fisher’s exact test, which produced a two-sided P value of 0.6944, confirming that the difference was not statistically significant.

Mean survival time was 27 months in the microwave group versus 25 months in the conventional surgery group. The difference was not statistically significant (P = 0.83).

One-year survival, three-year survival, and disease-free survival
Estimated survival was reported after one, two, and three years. In the microwave coagulation group, 71%, 57%, and 14% of participants survived for one, two, and three years, and in the conventional surgery group, the percentages of participants who survived were 69%, 56%, and 23%. The hazard ratio calculated using the Parmar method from P = 0.83 and the number of events reported in the paper was 0.91 (0.39 to 2.15) (Parmar 1998; Thierney 2007).

The mean disease-free interval was 11.3 months in the microwave group versus 13.3 months in the hepatectomy group; the difference was not statistically significant (P = 0.47).

Adverse events and complications
No intervention-related mortality was observed. Reported adverse event frequency was similar between the microwave coagulation and conventional surgery groups, except for the outcome 'Required blood transfusion', which was more common in the conventional surgery group (P < 0.05). Other reported complications are described in Table 1.

Table 1. Adverse events or complications in patients with liver metastases treated with microwave coagulation or conventional surgery
 Microwave coagulation groupConventional surgery group
Any adverse event excluding intervention-related bleeding2 (14%)3 (19%)
Intervention-related mortality00
Wound infection01 (6%)
Hepatic abscess1 (7%)0
Intestinal obstruction01 (6%)
Required blood transfusion

0

 

6 (38%)
Bile duct fistula1 (7%)1 (6%)

Quality of life
Quality of life was not reported.

Secondary outcomes

Cancer mortality
The trial did not report this. 

Proportion of participants with failure to clear liver metastases or with recurrence of liver metastases
Failure or proportion of participants with recurrence was not reported.

Time to progression of liver metastasis
Time to progression was not reported.

Tumour response (complete response, partial response, stable disease, disease progression)
This outcome was only measured indirectly in terms of carcinoembryonic antigen level. After treatment, the carcinoembryonic antigen level decreased significantly in both groups (microwave: from 18.5 ± 21.6 ng/mL to 5.8 ± 6.3 ng/mL; P < 0.05; conventional surgery: from 13.5 ± 11.4 ng/mL to 4.1 ± 3.9 ng/mL; P < 0.01). The authors did not report whether the difference between the groups was significant.

Discussion

Summary of main results

On the basis of one randomised clinical trial, which did not describe allocation concealment or blinding and after randomisation excluded 25% of participants from the analyses, evidence is insufficient to show whether microwave coagulation brings any significant benefit in terms of survival or recurrence compared with conventional surgery in participants with liver metastases from colorectal cancer. The number of adverse events, except for the blood transfusion requirement, which was more common in the hepatic resection group, was otherwise comparable in both groups. The trial might have been underpowered to determine the difference in survival between the two groups, as the number of participants required for the trial as calculated by the trial authors was 40; 10 participants were excluded after randomisation, and the final number of participants analysed was only 30. Also, probably because of the small sample sizes, there is a difference between actual mortality rates and estimated survival rates.

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 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 for review authors to judge the quality of allocation concealment or the presence of blinding, and 25% of participants were excluded after randomisation. Therefore, the main limitation of this review was the quality of available evidence.

Analyses with trial sequential analysis (TSA) (CTU 2011; Thorlund 2011) have shown that apparent significant beneficial and harmful intervention effects in fact may have been caused by random error (‘play of chance’) (Bangalore 2008; Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010). This was not formally assessed in this review. Accordingly, any significant results, had they been found, need to be interpreted with caution, as some may have been caused by random errors.

Potential biases in the review process

Publication bias might be an issue here; however, because of the small number of trials (one trial for this comparison), it is not possible to assess this formally.

Agreements and disagreements with other studies or reviews

Three identified reviews assessed the efficacy of microwave coagulation for colorectal cancer liver metastases. National Institute for Health and Clinical Excellence (NICE) guidance based on the review of evidence concluded that microwave ablation for liver metastases should be used only with special arrangements for clinical governance, consent and audit, or research, because the evidence on efficacy is inadequate (NICE 2011). Two other reviews addressing efficacy of microwave coagulation were identified in the literature search. One was limited to studies published in English and included at least 30 participants with hepatocellular carcinoma or colorectal liver metastases who were treated with microwave coagulation (Boutros 2010). The authors included mostly case series and two randomised trials - one included in our review and the other in participants with hepatocellular carcinoma. The authors concluded that microwave coagulation may be optimal when larger necrosis zones and ablation of multiple lesions are the objectives, and that additional randomised trials are needed to compare microwave versus radiofrequency ablation as well as microwave ablation versus surgical resection. Another review published recently aimed to assess the long-term outcomes and complications of various ablative therapies used in the management of participants with liver metastases of colorectal cancer (Pathak 2011). It included 13 studies on microwave coagulation, and one was the randomised trial included in our review. However, the authors analysed data for the cohort of participants receiving microwave coagulation, without comparison with surgical resection.

Authors' conclusions

Implications for practice

Evidence is insufficient to allow assessment of the effect of microwave coagulation versus conventional liver surgery in liver metastases. Microwave coagulation cannot be recommended outside randomised clinical trials.

Implications for research

Good-quality, large, randomised clinical trials of microwave coagulation versus no intervention, other ablation methods, or systemic treatments in participants with liver metastases are needed. Because 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 used. Participant flow should be well specified, as should data handling. The trial must be designed and described in accordance with the SPIRIT (SPIRIT 2013a; SPIRIT 2013b) and CONSORT statement (www.consort-statement.org).

Acknowledgements

Peer reviewers: T. Clark Gamblin, USA; Roberto Cirocchi, Italy; Giuseppe Garcea, UK.
Contact editor: Christian Gluud, Denmark.

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 RegisterDecember 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 Library (Wiley)Issue 11 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 (Ovid SP)1950 to December 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 (Ovid SP)1974 to December 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 December 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

LILACS1982 to December 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]
CINAHL1982 to December 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 Apudoma.mp.

11 exp Carcinoid Tumour/

12 exp Adenoma, Islet Cell/

13 exp INSULINOMA/

14 exp Carcinoma, Islet Cell/

15 exp GASTRINOMA/

16 Glucagonoma.mp. or exp Glucagon/

17 Somatostatinoma.mp.

18 Vipoma.mp.

19 exp Endocrine Gland Neoplasms/ or Multiple Endocrine Neoplasia.mp.

20 exp Pancreatic Neoplasms/

21 Malignant Carcinoid Syndrome.mp. or exp Gastrointestinal Neoplasms/

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 (rfta or radio-frequ$ or radiofrequ$ or rfa or rf).mp.

52 exp Catheter Ablation/

53 51 or 52

54 percutaneous.mp.

55 (ablati* and (therap* or treatment* or radiofrequenc* or cryo*)).mp.

56 ((injection* and (ethanol or acetic acid)) or PEI or PAI).mp.

57 55 or 56

58 54 and 57

59 Yttrium Radioisotopes.mp.

60 selective internal radi$.tw,mp.

61 radioemboli$.tw,mp.

62 radio-emboli$.tw,mp.

63 sir-sphere$.tw,mp.

64 therasphere$.tw,mp.

65 ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$).tw,mp.

66 59 or 60 or 61 or 62 or 63 or 64 or 65

67 exp Chemoembolisation, Therapeutic/

68 exp Embolisation, Therapeutic/

69 (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation).mp.

70 exp Infusions, Intraarterial/

71 (lipiodol or HAI or arterial infusion or targeted chemotherapy).mp.

72 ((transcatheter or transarterial) and chemo-infusion).mp.

73 Iodized Oil.mp.

74 67 or 68 or 69 or 70 or 71 or 72 or 73

75 exp Hyperthermia, Induced/

76 thermotherapy.mp.

77 exp MICROWAVES/

78 Electrocoagulation.mp.

79 coagulation therapy.mp.

80 exp Catheter Ablation/

81 ablation.mp.

82 cryosurgery.mp. or exp CRYOSURGERY/

83 53 or 58 or 66 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82

84 42 and 52 and 83

Contributions of authors

JK developed the concept for the project. RPR and JK formulated the search strategy and carried out searches. Study inclusion and data extraction were done by MMB, RPR, and RW. Analyses were performed by MMB, RPR, and RW. The text of the review was prepared by MMB, RPR, RW, and JK.
All authors agreed on the final version of the review.

Declarations of interest

No conflicts of interest were reported.

Sources of support

Internal sources

  • Kleijnen Systematic Reviews (KSR) Ltd, UK.

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

External sources

  • The Dutch Health Care Insurance Board, 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

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Shibata 2000

Methods

Study type: randomised clinical trial.

Location: Japan, single centre, hospital.

Time frame of the study: 1990 to 1997.

Inclusion criteria: histological confirmation of colorectal adenocarcinoma, multiple but fewer than 10 metastatic tumours in the liver, histological assessment by core needle biopsy of at least one of those tumours, dimension of the largest tumour less than 80 mm (measured in computed tomography with contrast), no evidence of periportal or celiac lymph node metastasis, extrahepatic distant disease, ascites (confirmed by computed tomography and ultrasonography), no sign of liver cirrhosis or chronic hepatitis.
Follow-up: 3 years.

Participants

Total number of participants: 40 randomly assigned, 30 analysed (10 excluded after randomisation: 6 from intervention and 4 from control group for not fulfilling inclusion criteria).

Primary sites: resectable; colorectal cancer, Stage IB to IIIC (T2N0-T3N2).

Mean size of the tumour: mean 27 mm in intervention group and 34 in control group.

Number of tumours: range 2 to 9, mean 4.1 in intervention group, mean 3.0 in control group.

Mean age: 61 ± 10 years.

Males: 57% in intervention group, 38% in control group.

Interventions

Two treatment groups:

  • Group 1: microwave coagulation therapy (14 participants)

  • Group 2: conventional surgery (16 participants).

Microwave coagulation therapy was performed after laparotomy with microwave tissue coagulator at an output of 60 to 100 W for 2 to 20 minutes under the guide of ultrasonography.

Conventional surgery involved lobectomy, segmentectomy, subsegmentectomy, and/or wedge resection.

OutcomesNumber of deaths at the end of follow-up; 1-, 2-, 3-year survival; disease-free interval; tumour response measures; adverse events or complications.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEnrolled participants were assigned randomly, without stratification, according to a computer-generated, 1:1 randomization list to treatment with microwave coagulation or hepatic resection.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High risk10 participants excluded after randomisation.
Selective reporting (reporting bias)Low riskSurvival given with P value and curve.
Other biasUnclear riskInsufficient information.

Ancillary