Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Hepatocellular carcinoma is the fifth most common cancer worldwide. Percutaneous interventional therapies, such as radiofrequency (thermal) ablation (RFA), have been developed for early hepatocellular carcinoma. RFA competes with other interventional techniques such as percutaneous ethanol injection, surgical resection, and liver transplantation. The potential benefits and harms of RFA compared with placebo, no intervention, chemotherapy, hepatic resection, liver transplantation, or other interventions are unclear.

Objectives

To assess the beneficial and harmful effects of RFA versus placebo, no intervention, or any other therapeutic approach in patients with hepatocellular carcinoma.

Search methods

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science to September 2012. We handsearched meeting abstracts from ASCO, ESMO, AASLD, EASL, APASL, and references of articles. We also contacted researchers in the field (last search September 2012).

Selection criteria

We considered for inclusion randomised clinical trials investigating the effects of RFA versus placebo, no intervention, or any other therapeutic approach on hepatocellular carcinoma patients regardless of blinding, language, and publication status.

Data collection and analysis

Two review authors independently performed the selection of trials, assessment of risk of bias, and data extraction. We contacted principal investigators for missing information. We analysed hazard ratios (HR) as relevant effect measures for overall survival, two-year survival, event-free survival, and local recurrences with 95% confidence intervals (CI). In addition, we analysed dichotomous survival outcomes using risk ratios (RR). We used trial sequential analysis to control the risk of random errors ('play of chance').

Main results

We identified no trials comparing RFA versus placebo, no intervention, or liver transplantation. We identified and included 11 randomised clinical trials with 1819 participants that included four comparisons: RFA versus hepatic resection (three trials, 578 participants); RFA versus percutaneous ethanol injection (six trials, 1088 participants) including one three-armed trial that also investigated RFA versus acetic acid injection; RFA versus microwave ablation (one trial, 72 participants); and RFA versus laser ablation (one trial, 81 participants). Ten of the eleven included trials reported on the primary outcome of this review, overall survival. Rates of major complications or procedure-related deaths were reported in 10 trials. The overall risk of bias was considered low in five trials and high in six trials. For a subgroup analysis, we included only low risk of bias trials. Regarding the comparison RFA versus hepatic resection, there was moderate-quality evidence from two low risk of bias trials that hepatic resection seems more effective than RFA regarding overall survival (HR 0.56; 95% CI 0.40 to 0.78) and two-year survival (HR 0.38; 95% CI 0.17 to 0.84). However, if we included a third trial with high risk of bias, the difference became insignificant (overall survival: HR 0.71; 95% CI 0.44 to 1.15). With regards to the outcomes event-free survival and local progression, hepatic resection also yielded better results than RFA. However, the number of complications was higher in surgically treated participants (odds ratio (OR) 8.24; 95% CI 2.12 to 31.95). RFA seemed superior to percutaneous ethanol or acetic acid injection regarding overall survival (HR 1.64; 95% CI 1.31 to 2.07). The RR for mortality was also in favour of RFA, but did not reach statistical significance (150/490 (30.6%) people in the percutaneous ethanol or acetic acid group versus 119/496 (24.0%) people in the RFA group; RR 1.76; 95% CI 0.97 to 3.22). The proportion of adverse events did not differ significantly between RFA and percutaneous ethanol or acetic acid injection (HR 0.70; 95% CI 0.33 to 1.48). Trial sequential analyses revealed that the number of participants in the included trials was insufficient and that more trials are needed to assess the effects of RFA versus other interventions.

Authors' conclusions

The effects of RFA versus no intervention, chemotherapeutic treatment, or liver transplantation are unknown. We found moderate-quality evidence that hepatic resection is superior to RFA regarding survival. However, RFA might be associated with fewer complications and a shorter hospital stay than hepatic resection. We found moderate-quality evidence showing that RFA seems superior to percutaneous ethanol injection regarding survival. There were too sparse data to recommend or refute ablation achieved by techniques other than RFA. More randomised clinical trials with low risk of bias and low risks of random errors assessing the effect of RFA are needed.

摘要

比較射頻燒灼療法與沒有介入措施或是其他介入措施的肝細胞癌症

背景

在全世界中,肝細胞癌症是排名第五名常見癌症。經皮下介入治療,像是射頻燒灼療法[radiofrequency (thermal) ablation (RFA)],已經被發展成用於治療早期肝細胞癌症。射頻燒灼療法與其他介入措施療法不分軒輊,例如經皮穿肝酒精治療術、外科切除或是肝臟移植。 與安慰劑、沒有介入措施、化學治療法、肝臟切除、肝臟移植或是其他治療方式相較之下,射頻燒灼療法的潛在優缺點較不明確。

目的

評估對於肝細胞癌症而言,射頻燒灼療法對照於安慰劑、沒介入措施療法或是任何其他治療方式的優點和缺點。

搜尋策略

我們搜查Cochrane Hepato-Biliary Group Controlled Trials Register、the Cochrane Central Register of Controlled Trials (CENTRAL)、 MEDLINE, EMBASE, 和 ISI 2012的9月份科學網站。我們以人工搜尋方式,搜尋ASCO會議摘要,ESMO,AASLD,EASL,APASL和文章的引用。我們也與該領域的研究人員接觸(最後一次搜索2012年9月)。

選擇標準

我們將隨機對照試驗納入考量,比較射頻燒灼療法和安慰劑、沒有介入措施療法或是其他用於治療肝細胞癌症的治療方式的治療效果,不考量盲性試驗、語言或是出版的立場。

資料收集與分析

兩位回顧作者獨立作業以挑選試驗、偏差風險評估和數據萃取。 我們聯繫主要調查者以獲得遺漏的資訊。我們分析的危險比(hazard ratios),對其相關效果的於總生存率、2年生存率、無事件生存率和局部復發,並有95%信賴區間(confidence intervals)。此外,我們分析了使用風險比(risk ratios)二分法生存結果。我們使用試用序列分析以控制隨機誤差的風險(“play of chance'”)。

主要結果

我們確定沒有任何其他試驗是在比較射頻燒灼療法與安慰劑、沒有介入措施的治療方式或是肝移植。有11個隨機臨床試驗包含1819之參與者進行四項比較:射頻燒灼療法與肝切除術(3個試驗計畫,578位人參與者); 射頻燒灼療法與經皮酒精注射(6個試驗計畫,1088位參與者)。包括一個三方試驗:射頻燒灼療法與醋酸注射液; 射頻燒灼療法與微波消融(1個試驗計畫,72位參與者); 和射頻燒灼療法與雷射燒灼(1個試驗計畫,81位參與者)。11個當中的10個試驗計劃報告了回顧了主要結果並全部倖存,整體主要合併症的生存率或是過程中導致的死亡,也在10個試驗中列出報告。偏差的整體風險被認為在5項試驗中相對較低且在6項試驗較高。對於次組分析,我們只收納低風險偏差之組別。比較射頻燒灼療法與肝切除術的二個低風險偏差試驗中,根據RFA整體生存期(HR 0.56; 95%CI為0.40〜0.78)與2年生存率(HR 0.38; 95%CI為0.17〜0.84),有中度品質證據顯示肝切除術似乎比射頻燒灼療法更有效果。但是,如果將高偏差風險的第三個試驗納入考量,則效果更為顯著(整體生存:HR 0.71; 95%CI為0.44至1.15)。至於無事件生存率和局部惡化,肝切除術也取得了比射頻燒灼療法更好的結果。然而,併發症的數據是高於手術治療參與者(比值比(OR)8.24; 95%CI為2.12至31.95)。藉由整體生存期可知(HR 1.64; 95%CI為1.31〜2.07),射頻燒灼療法似乎優於經皮下酒精注射或醋酸注射。射頻燒灼療法在死亡率中的相對危險比較高,但是並未達到統計學上的意義(150/490 (30.6%),再經皮下酒精注射或是醋酸注射比較119/496 (24.0%) 的人在射頻燒灼療法;其相對危險比1.76 ; 95%,信賴區間為0.97至3.22)。在副作用發生率上的比例射頻燒灼療法和經皮下酒精注射或醋酸注射沒有顯著意義上的不同(95%CI為0.33〜1.48 HR 0.70)。試驗序列分析顯示,參與者納入試驗的數量因不足,故需要更多的試驗以評估射頻燒灼療法相對於其他介入措施的效果。

作者結論

射頻燒灼療法的效果與無介入措施的治療方式、化療治療或肝移植是未知的,中等品質量的證據顯示,肝切除手術的生存率優於射頻燒灼療法,然而,射頻燒灼療法導致較少的術後併發症與較少的住院天數。中等品質的證據顯示,射頻燒灼療法之生存率似乎優於經皮下酒精注射,由於建議或反駁射頻燒灼療法技術的資料過於稀少,因此需要更多低偏差風險與低風險隨機誤差的隨機對照試驗以評估效果。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Résumé scientifique

L'ablation par radiofréquence (thermique) par rapport à l'absence d'intervention ou à d'autres interventions pour le carcinome hépatocellulaire

Contexte

Le carcinome hépatocellulaire est le cinquième cancer le plus fréquent dans le monde entier. Des traitements interventionnels percutanés tels que ablation par radiofréquence ARF (thermale) ont été développés pour les carcinomes hépatocellulaires précoces. L'ARF est en cocurrence avec d'autres techniques interventionnelles telles que l'injection percutanée d'éthanol, la résection chirurgicale, et une greffe du foie. Les bénéfices et les inconvénients potentiels de l'ARF par rapport à un placebo, à l'absence d'intervention, à la chimiothérapie, à la résection hépatique, à la greffe de foie, ou à d'autres interventions ne sont pas clairs.

Objectifs

Évaluer les effets bénéfiques et nocifs de l'ARF versus un placebo, l'absence d'intervention ou à toute autre approche thérapeutique chez les patients atteints de carcinome hépatocellulaire.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d’essais contrôlés du groupe Cochrane sur les affections hépato-biliaires, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE et ISI Web of Science jusqu’à septembre 2012. Nous avons effectué une recherche manuelle dans les résumés de réunions de l'ASCO, ESMO, l’AASLD, EASL, APASL et des références bibliographiques des articles. Nous avons également contacté des chercheurs dans le domaine (dernière recherche en septembre 2012).

Critères de sélection

Nous avons pris en compte pour l'inclusion des essais cliniques randomisés étudiant les effets de l'ARF à un placebo, à l'absence d'intervention ou à tout autre approche thérapeutique pour le carcinome hépatocellulaire de patients indépendamment de la mise en aveugle, de la langue et du type de publication.

Recueil et analyse des données

Deux auteurs de la revue ont effectué indépendamment la sélection des essais, l'évaluation du risque de biais et l'extraction des données. Nous avons contacté les principaux investigateurs pour obtenir des informations manquantes. Nous avons analysé les taux de hasard (HR) pour les mesures pertinentes d'effet sur la survie globale, la survie à deux ans, la survie sans événement et les récidives locales avec un intervalle de confiance (IC) à 95%. En outre, nous avons analysé les données dichotomiques de survie à l'aide des risques relatifs (RR). Nous avons utilisé l'analyse séquentielle d'essais afin de contrôler le risque d'erreurs aléatoires («effet hasard»).

Résultats principaux

Nous n’avons identifié aucun essai comparant l'ARF à un placebo, à l'absence d'intervention, ou une greffe du foie. Nous avons identifié et inclus 11 essais cliniques randomisés avec 1819 participants qui incluent quatre comparaisons: L'ARF versus la résection hépatique (trois essais, 578 participants); l'ARF versus l'injection percutanée d'éthanol (six essais, 1088 participants), y compris un essai composé de trois branches qui ont également étudié l'ARF versus l’injection d'acide acétique; l'ARF versus ablation par micro-ondes (un essai, 72 participants) et l'ARF par rapport à l'ablation par laser (un essai, 81 participants). Dix des onze essais inclus documentaient le critère de jugement principal de cette revue qui était la survie globale. Le taux de complications majeures ou de décès lié à la procédure a été rapporté par 10 essais. Le risque de biais global était considéré comme faible dans cinq essais et élevé dans six essais. Pour une analyse en sous-groupe, nous avons uniquement inclus les essais présentant un faible risque de biais. Concernant la comparaison entre l'ARF et la résection hépatique, il y avait des preuves de qualité moyenne, issues de deux essais présentant un faible risque de biais, dans lesquels la résection hépatique semble plus efficace que l'ARF concernant la survie globale (HR 0,56; IC à 95%, de 0,40 à 0,78) et la survie à deux ans (HR 0,38; IC à 95%, de 0,17 à 0,84). Toutefois, si nous incluons un troisième essai à risque élevé de biais, la différence de survie globale devenait insignifiante (HR 0,71; IC à 95%, de 0,44 à 1,15). En ce qui concerne les critères de jugement de survie sans événement et la progression locale, la résection hépatique donnait également des meilleurs résultats que l'ARF. Cependant, le nombre de complications était plus élevée chez les participants traités chirurgicalement (rapport des cotes (RC) 8,24; IC à 95%, de 2,12 à 31,95). L'ARF semblait plus efficace que l'injection d’acide acétique percutané d'éthanol ou concernant la survie globale (HR 1,64; IC à 95%, de 1,31 à 2,07). Le RR pour la mortalité était également en faveur de l'ARF, mais sans atteindre de signification statistique (150/490 (30,6%) dans le groupe d'acide acétique ou percutanée d'éthanol versus 119/496 (24,0%) dans le groupe de l'ARF; RR 1,76; IC à 95%, de 0,97 à 3,22). La proportion d'événements indésirables ne différait pas significativement entre l'ARF et l' injection d’acide acétique percutané d'éthanol (HR 0,70; IC à 95%, de 0,33 à 1,48). Des analyses séquentielles d'essais ont révélé que le nombre de participants dans les essais inclus était insuffisant et que d'autres essais sont nécessaires pour évaluer les effets de l'ARF par rapport à d'autres interventions.

Conclusions des auteurs

Les effets de l'ARF versus l'absence d'intervention, le traitement par chimiothérapie ou transplantation hépatique sont inconnus. Nous n'avons trouvé des preuves de qualité moyenne indiquant que la résection hépatique est supérieure à une ARF concernant la survie. Cependant, l'ARF pourrait être associée à moins de complications et une hospitalisation plus courte que la résection hépatique. Nous avons trouvé des preuves de qualité modérée indiquant que l'ARF semble plus efficace que l'injection percutanée d'éthanol concernant la survie. Il y avait trop peu de données pour recommander ou réfuter l'ablation par d'autres techniques que l'ARF. Des essais cliniques randomisés supplémentaires avec un faible risque de biais et des faibles risques d'erreurs aléatoires évaluant l'effet de l'ARF sont nécessaires.

Plain language summary

Radiofrequency ablation for the treatment of liver cancer (hepatocellular carcinoma)

Background

Liver cancer (hepatocellular carcinoma) is the fifth most common cancer worldwide. In the majority of patients, hepatocellular carcinoma is diagnosed at advanced stages of the disease and is mostly accompanied by liver cirrhosis. To date, there is no medical cure for patients with hepatocellular carcinoma, and treatment aims to slow tumour growth. In high-income countries, about 30% of patients present with the more favourable early hepatocellular carcinoma. For these patients, percutaneous ablation techniques (destruction of the cancer cells by heat, cold, or chemical substances such as ethanol), surgical resection (removal of part of the liver), and liver transplantation (which is limited by organ donor shortage) are currently considered potentially curative treatments. Radiofrequency (thermal) ablation (RFA) is the most elaborated of the percutaneous interventions, so far. Heat caused by alternating electric current is administered by probes that are inserted through the skin (percutaneously).

Study characteristics

The review authors searched the medical literature in order to clarify the role of RFA for the treatment of hepatocellular carcinoma and to compare its benefits and harms with no treatment, placebo (a pretend treatment), or other treatments (such as hepatic resection, percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), laser or microwave ablation, and liver transplantation). We looked for randomised clinical trials (where people were allocated at random to one of two or more treatments groups) of people with hepatocellular carcinoma who were able to receive RFA. Evidence is current to September 2013.

Key results and quality of evidence

We found no trials comparing RFA versus no intervention, placebo, chemotherapy, or liver transplantation.

The review authors found moderate-quality evidence from two trials with low risk of bias (where there was a low risk of a flaw in study design, method of collecting or interpreting results) randomising 578 patients suggesting that hepatic resection yielded better results regarding overall survival (the length of time that the patient remains alive), event-free survival (time that the person remains free of cancer or a certain symptom relating to cancer), and progression (time that the patient lives with cancer without it getting worse) compared with RFA. However, as resection is a more invasive procedure, resection has an eight times higher risk of major complications compared with RFA. Resected patients stayed twice as long in the hospital as the RFA patients. Moderate-quality evidence suggested that RFA prolongs survival and decreases recurrences (where the cancer returns) compared with PEI or PAI. This conclusion was based on data from six randomised clinical trials with 1088 participants. Some patients developed side effects such as fever, rash, and pain. These occurred at the same frequency in both treatment groups. We calculated the number of patients that would be required to judge a relative risk reduction (relative risk is a comparison of the risk of an event happening for one treatment group compared with another treatment group) for survival of 20%. The review authors found that for both comparisons, that is RFA versus PEI or PAI, and RFA versus resection, the number of patients in the included trials was too low to reach valid conclusions. No firm conclusion can be drawn from the comparison of RFA against other interventional techniques or combination approaches. The information provided by the single trials was limited. More randomised clinical trials with low risks of bias (that is low risks of systematic errors, leading to overestimation of benefits and underestimation of harms) and low risk of play of chance (that is random errors, leading to overestimation or underestimation of benefits and harms) are required.

淺顯易懂的口語結論

治療肝癌的射頻燒灼療法(肝細胞惡性腫瘤)

背景

肝癌(肝細胞惡性腫瘤)是全球第五大最常見的癌症,對多數的病患者而言,被診斷出肝癌都是在疾病的晚期並同時伴隨肝硬化。迄今,肝細胞癌症無任何醫療治癒方法,治療的目的多是減緩腫瘤的生長。在高收入國家,大約30%被診斷出肝細胞癌症病患是處於早期階段,對於這類患者,經皮消融技術(經由熱、冷或化學物質如乙醇以破壞癌症細胞)、手術切除(切除一部分的肝臟)或肝移植(因缺乏捐獻器官而有所限制)是目前認為可能治愈的治療方法。截至目前為止,射頻燒灼療法是最為完整的經皮下介入措施,透過交流電流產生的熱量,經由插入皮膚(經皮的)的探針來投予藥物。

研究特點

回顧作者搜尋醫學文獻,以辨明射頻燒灼療法之於肝細胞癌的治療角色,並比較與安慰劑(假裝處理)、無治療或是其他療法(如:肝切除術、經皮下酒精注射、經皮下醋酸注射、雷射、微波燒灼或肝移植)的優缺點。我們採取隨機對照試驗的方式,選取肝細胞癌的病患與符合射頻燒灼療法方式的病患(參與者隨機分配到任一個治療分組中),證據收集從2013年9月至今。

主要結果和證據品質

我們發現沒有一個試驗是比較射頻燒灼療法與不介入措施療法、安慰劑、化學治療方式或肝移植。

回顧作者發現中等品質的證據是從二個低偏差風險的試驗中得到(低缺陷風險的設計、收集方式或解釋方式),隨機選取578位病患,並比較了建議肝切除術,以獲得更長整體生存率(患者存活的時間長度)、無癌症的生存率(該時間中患者可能無癌症或與無癌症相關聯的症狀)、病程進展中的生存率(患者的生活與癌症相關聯並且越來越差)與射頻燒灼療法之差異。然而,手術是侵入性的治療方式,相較於射頻燒灼療法有8倍的手術合併症風險。接受手術切除的患者待在醫院的時間是接受射頻燒灼療法病患時間的二倍。中等品質的證據顯示,射頻燒灼療法相較於經皮下酒精注射或經皮下醋酸注射,更能延長病患存活時間並減少復發(癌症復發)。結論是基於六個隨機臨床試驗與1088位參與者的數據。有些患者會產生副作用,例如:發燒、皮疹和疼痛,在兩種治療方式中,副作用發生頻率是相同。 我們以20%存活率來計算將會符合相對風險下降率(一組與另一組的風險的比較)的病患數量。回顧作者發現這二種治療方式,即射頻燒灼療法與經皮下酒精注射、經皮下醋酸注射與射頻燒灼療法以及手術切除,在其試驗中的研究患者數量太低,而無法達到有效的結論。沒有明確結論顯示,射頻燒灼療法優於其他介入措施療法或是並用其療法有較佳的結果,經由單一試驗所得出來的結果有限。必須要有更多的隨機臨床試驗伴隨著低風險偏差(即系統誤差的風險低,導致高估其利益和低估其損害)、低風險機會(即隨機誤差,導致高估或低估其優點與缺點)。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Résumé simplifié

L'ablation par radiofréquence pour le traitement du cancer du foie (carcinome hépatocellulaire)

Contexte

Le cancer du foie (carcinome hépatocellulaire) est le cinquième cancer le plus fréquent dans le monde entier. Dans la majorité des patients, le carcinome hépatocellulaire est diagnostiqué à des stades avancés de la maladie et il est le plus souvent accompagné d'une cirrhose du foie. À ce jour, il n'existe aucun remède médical pour les patients atteints de carcinome hépatocellulaire, et le traitement vise à ralentir la croissance tumorale. Dans les pays à revenus élevés, environ 30% des patients présentent les plus favorables stades de carcinome hépatocellulaire. Pour ces patients, les techniques d'ablation percutanée (destruction des cellules cancéreuses par la chaleur, le froid, ou de substances chimiques comme l’éthanol), la résection chirurgicale (ablation de la partie du foie), et une greffe du foie (qui est limitée par la pénurie de don d’organes) sont actuellement considérés comme potentiellement curatifs. L’ablation par radiofréquence ARF (thermale) est la plus élaborée des interventions percutanées jusqu' ici. La chaleur causée par un courant électrique est administrée par des sondes qui sont insérées à travers la peau (voie percutanée).

Caractéristiques de l'étude

Les auteurs de la revue ont consulté la littérature médicale afin de clarifier le rôle de l'ARF pour le traitement du carcinome hépatocellulaire et comparé ses bénéfices et effets indésirables avec l'absence de traitement, un placebo (un faux traitement), ou d'autres traitements (tels que la résection hépatique, l'injection percutanée d'éthanol (IPE), l'injection percutanée d'acide acétique (IPA), l’ablation au laser ou par micro-ondes et une greffe du foie). Nous avons recherché des essais cliniques randomisés (où les personnes ont été assignées au hasard à l'un, deux ou plusieurs groupes de traitements) de personnes atteintes de carcinome hépatocellulaire qui pouvaient recevoir l'ARF. Les preuves actualisées jusqu'en septembre 2013.

Résultats principaux et qualité des preuves

Nous n'avons trouvé aucun essai comparant l'ARF à l'absence d'intervention, un placebo, la chimiothérapie, ou la transplantation hépatique.

Les auteurs de la revue ont trouvé des preuves de qualité moyenne issues de deux essais à faible risque de biais (où il y avait un faible risque méthodologique dans le plan d'étude, la méthode de prélèvement ou l'interprétation des résultats) randomisant 578 patients, ce qui suggérait que la résection hépatique a donné des meilleurs résultats concernant la survie globale (la durée pendant laquelle le patient reste en vie), la survie sans événement (temps pendant lequel la personne reste sans cancer ou sans symptômes liés au cancer), et de progression (temps de vie pendant lequel des patients atteints de cancer sont sans aggravation) par rapport à une ARF. Cependant, comme la résection est une procédure invasive, elle a huit fois plus de risque de complications majeures par rapport à une ARF. Les patients réséqués passaient deux fois plus long temps à l'hôpital que les patients avec ARF. Des preuves de qualité moyenne suggéraient que l'ARF prolonge la survie et réduit le nombre de récidives du cancer en comparaison avec l’IPE ou l'IPA. Cette conclusion était basée sur des données issues de six essais cliniques randomisés portant sur 1088 participants. Certains patients ont développé des effets secondaires comme de la fièvre, éruptions cutanées et douleurs. Ils surviennent à la même fréquence dans les deux groupes de traitement. Nous avons calculé le nombre de patients qui seraient nécessaires pour établir une réduction du risque relatif (il s’agit d’une comparaison de risque d'un événement se produisant pour un groupe de traitement par rapport à un autre groupe de traitement) pour la survie de 20%. Les auteurs de la revue ont constaté que pour les deux comparaisons, ARF versus IPE ou IPA, et ARF versus résection, le nombre de patients dans les essais inclus était trop faible pour tirer des conclusions définitives. Aucune conclusion définitive ne peut être tirée de la comparaison de l'ARF à d'autres techniques d'intervention ou à une combinaison d’approches. Les informations fournies par les essais uniques étaient limitées. Des essais cliniques randomisés supplémentaires avec de faibles risques de biais (faibles risques d'erreurs systématiques conduisant à une surestimation des effets bénéfiques et une sous-estimation des effets nocifs) et un faible risque d'effet de hasard (erreurs aléatoires conduisant à une surestimation ou sous-estimation des effets bénéfiques et délétères) sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. Hepatic resection compared with radiofrequency ablation
  1. CI: confidence interval; HCC: hepatocellular carcinoma; HR: hazard ratio; PAI: percutaneous acetic acid injection; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation.

Hepatic resection compared with radiofrequency ablation for early hepatocellular carcinoma

Patient or population: 578 patients with early HCC

Intervention: hepatic resection

Comparison: RFA

OutcomesHazard ratio (95% CI)No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Overall survival0.71 (0.44 to 1.15)

578

(3)

+++O
moderate
-
2-year survival-0.51 (0.24 to 1.08)

578

(3)

+++O
moderate
-
Event-free survival0.70 (0.54 to 0.91)

578

(3)

+++O
moderate
-
Local progression0.48 (0.28 to 0.82)

168

(1)

⊕⊕⊝⊝
low
Only 1 trial reported on local progression.
Rate of complications8.24 (2.12 to 31.95)

578

(3)

++++
high
Statistical method is: odds ratio (M-H, random, 95% CI)
Length of hospital stay (days)2.18 (1.97 to 2.39)

578

(3)

++++
high
Statistical method is: standard. mean difference (IV, random, 95% CI)
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.

Summary of findings 2 Percutaneous ethanol injection compared with radiofrequency ablation for early hepatocellular carcinoma

Summary of findings 2. Percutaneous ethanol injection compared with radiofrequency ablation for early hepatocellular carcinoma
  1. CI: confidence interval; HCC: hepatocellular carcinoma; HR: hazard ratio; PAI: percutaneous acetic acid injection; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation.

Percutaneous ethanol injection compared with radiofrequency ablation for early hepatocellular carcinoma

Patient or population: 1088 patients with early HCC

Intervention: PEI/PAI

Comparison: RFA

OutcomesHazard ratio (95% CI)No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Overall survival1.64 (1.31 to 2.07)

1088

(6)

⊕⊕⊕⊝
moderate
As there were 2 three-armed trials, we report 6 trials with 8 comparisons.
2-year survival1.82 (1.34 to 2.47)

715

(4)

⊕⊕⊕⊝
moderate
-
Event-free survival1.55 (1.31 to 1.85)

949

(5)

⊕⊕⊕⊝
moderate
-
Local progression2.44 (1.71 to 3.49)

678

(4)

⊕⊕⊕⊝
moderate
-
Rate of complications0.70 (0.33 to 1.48)

1088

(6)

⊕⊕⊕⊝
moderate

Statistical method is: odds ratio (M-H, random, 95% CI).

As there were 2 three-armed trials, it is 5 studies with 7 comparisons.

Length of hospital stay-1.50 (-3.69 to 0.68)

576

(3)

⊕⊕⊕⊝
moderate

Statistical method is: standard. Mean difference (IV, random, 95% CI).

As there were 2 three-armed trials, it is 3 studies with 5 comparisons.

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.

Summary of findings 3 Clinical characteristics of patients treated with radiofrequency ablation or percutaneous ethanol injection

Summary of findings 3. Clinical characteristics of patients treated with radiofrequency ablation or percutaneous ethanol injection
  1. CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; HR: hazard ratio; n.s.: not significant (P value > 0.05); PEI: percutaneous ethanol injection; RFA: radiofrequency ablation.

  Child-Pugh AetiologyTumour Overall survival
Italian Trials ABHBVHCVHBC+HCVAlcoholOthersMean number of nodules1 tumourMean sizeSize < 2 cmHR (95% CI)
Brunello 20080.780.220.040.650.040.140.121.270.782.30.391.14 (0.65 to 2.01)
Giorgio 20110.510.490.410.590.000.000.001.0012.3-1.23 (0.71 to 2.14)
Lencioni 20030.780.220.150.430.250.150.051.390.72.20.255.00 (0.55 to 45.82)
Mean0.690.310.200.560.100.090.051.220.832.270.321.24 (0.84 to 1.83)
East-Asian Trials             
Lin 2004 (RFA vs. PEI)0.770.220.690.29--0.021.310.752.90.292.08 (1.02 to 4.20)
Lin 2005 (RFA vs. PEI)0.750.250.670.31--0.021.260.82.40.62.01 (1.03 to 3.92)
Shiina 20050.730.270.130.81--0.061.630.57-0.441.86 (0.33 to 0.88)
Mean0.750.250.50.47--0.031.400.692.650.521.95 (1.38 to 2.75)
Student's t-testn.s.n.s.n.s.n.s.--n.s.n.s.n.s.n.s.n.s. -

Background

Description of the condition

Epidemiology and risk factors

Hepatocellular carcinoma (liver cancer) is the fifth most common cancer worldwide (El Serag 2007). The highest incidence of hepatocellular carcinoma is found in regions with endemic hepatitis B virus (HBV) such as Eastern Asia and Central Africa. A rising incidence of hepatocellular carcinoma in high-income countries has been reported, along with a decrease in high-incidence areas (El Serag 1999; El Serag 2007; Jepsen 2007). This might be caused by differences in hepatitis C virus (HCV) prevalence (e.g. increase in the USA) (Jepsen 2007), and increased HBV vaccination rates (e.g. decrease in China) (El Serag 2007). Overall, 75% to 80% of patients with primary liver cancer are attributable to persistent viral infections with either HBV (50% to 55%) or HCV (25% to 30%). High consumption of alcohol; cumulative amount of aflatoxins in the liver over time; and metabolic disorders such as non-alcoholic fatty liver disease, haemochromatosis, and alpha-1-antitrypsin deficiency are further risk factors for the development of cirrhosis and subsequent hepatocellular carcinoma (Sørensen 2003; Bosch 2004; EASL-EORTC 2012). Associations of primary liver cancer with diabetes (El Serag 2004), obesity (Calle 2003), and syndromes related to insulin resistance are subject of ongoing research, but their impact is currently unclear.

Prognosis

Liver cancer carries high mortality. In Europe and USA, the five-year survival is below 10% (Schoppmeyer 2009). In most patients, hepatocellular carcinoma is diagnosed at late stages of the disease and is mostly accompanied by liver cirrhosis. In high-income countries, only about 30% of patients present with the more favourable early hepatocellular carcinoma (Bruix 2001). Percutaneous ablation techniques, surgical resection, and liver transplantation are currently considered potentially curative treatments for early hepatocellular carcinoma.

Diagnosis

Due to the neovascularity of hepatocellular carcinoma and its characteristic arterial hypervascularity and venous/late phase washout (so-called hepatocellular carcinoma radiological hallmark) in rapid-sequence cross-sectional imaging, an accurate diagnosis of hepatocellular carcinoma lesions larger than 2 cm in diameter can be made non-invasively in patients with cirrhosis. According to the current guidelines of the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) (EASL-EORTC 2012), non-invasive diagnostic criteria for patients with cirrhosis and hepatocellular carcinoma are:

  • for lesions larger than 2 cm: one positive imaging technique (four-phase computed tomography or dynamic contrast enhanced magnetic resonance imaging (MRI))

  • for lesions from 1 to 2 cm: two coincidental techniques (computed tomography, MRI, or contrast-enhanced ultrasound.

Image-guided biopsies of the tumour are common practice in cases of inconclusive radiological findings, that is, a lesion between 1 and 2 cm in diameter identified by only one imaging modality and such biopsies are mandatory for tumours in non-cirrhotic livers (Takamori 2000; EASL-EORTC 2012). Elevated serum levels of alpha-fetoprotein (AFP) that were proposed in addition to one typical radiological finding at the beginning of the century (Bruix 2001) have been discarded from the diagnostic scheme by the American Association for the Study of Liver Disease (AASLD) (Bruix 2005). Conversely, it is still regarded to be useful by EASL and EORTC (EASL-EORTC 2012).

Description of the intervention

Ablation techniques rely on the possibility to induce cell death by thermal or chemical means. The aim of the ablation is to completely destroy all tumour cells and thus provide cure of the cancer. The underlying liver disease (e.g. cirrhosis or hepatitis) is not affected by the treatment.

Radiofrequency ablation or radiofrequency thermal ablation (RFA) uses frictional heat to induce cell death from coagulation necrosis. After local anaesthesia of the skin, an RFA-electrode is placed into the liver lesion under the guidance of magnetic resonance tomography, computed tomography, or ultrasound (Goldberg 2000). A radiofrequency-current-generator is connected to the needle and a zero-electrode is fixed onto the patient's back. Under short-term analgesia-sedation, energy is applied for a few minutes leading to spheric lesions of about 3 to 5 cm in diameter. When temperatures pace 60 °C, a coagulation necrosis is induced (Minami 2010; EASL-EORTC 2012). Several investigations have shown the efficacy and the safety of the procedure (Rossi 1996; Rossi 1998; Allgaier 1999; Curley 1999; Francia 1999; Goldberg 2000; Grasso 2000; Livraghi 2000; Nicoli 2000). If necessary, the procedure can be repeated to treat larger lesions or patients with more than one liver tumour.

Surgical resection demands a radical resection of the tumours. This is often not feasible due to the impairment of liver function caused by the underlying cirrhosis. Local recurrence and de novo hepatocellular carcinoma at other locations within the liver are about 50% at three years and 70% at five years (Arii 2000; Bismuth 2000; Llovet 2000).

Orthotopic liver transplantation is an alternative approach for selected patients with small hepatocellular carcinoma. The beneficial removal of liver cirrhosis as a predisposing factor for hepatocellular carcinoma is, however, often counterbalanced by progression of the tumour while the patient is waiting for a new organ. Moreover, organ shortage is a major factor limiting the availability of this procedure. The Milan criteria (one tumour of 5 cm or less in diameter, or three tumours with a diameter of 3 cm or less each) are the broadly accepted standard to identify patients suitable for liver transplantation (Mazzaferro 1996). Percutaneous techniques are used with increasing frequency to bridge the waiting time until transplantation (Dubay 2011).

Medical treatment options: Sorafenib, a multi-kinase inhibitor improved median survival by 2.8 months in one trial (Llovet 2008), and was approved for treatment of advanced hepatocellular carcinoma in 2007 (Wörns 2009). Sorafenib has not yet been compared to other interventions for hepatocellular carcinoma in randomised trials.

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. Best results for PEI are achieved in single hepatocellular carcinoma lesions of less than 3 cm in diameter, for which complete remission rates of 70% can be expected. Lower occurrences of complete remission have been observed in larger and multinodular tumours (Livraghi 1995; Lencioni 1997). In one Cochrane review with meta-analysis, we concluded that there was insufficient evidence to determine whether PEI or segmental liver resection was more effective (Schoppmeyer 2009). In a recent up-date of the Schoppmeyer 2009 review, no additional information could be added and there is little evidence to expect such evidence within the next years (Weis 2013).

Percutaneous acetic acid injection (PAI) has been used as an alternative for ethanol in percutaneous treatment (Ohnishi 1998). Contraindications for PEI and PAI are cirrhosis with poor liver function (Child C cirrhosis), complete portal vein thrombosis, and massive ascites. We chose to analyse data from trials using PEI and PAI together because of the similarities between these two interventions in contrast to other treatment modalities. However, when results from individual trials are reported, we will report if PEI or PAI was used. In subgroup analysis, we will assess if there seems to be a difference in the overall survival in trials comparing RFA versus PEI or PAI.

Other interventions: Percutaneous cryoablation or interstitial laser photocoagulation are not yet routine clinical practice.

Why it is important to do this review

Treatment options of hepatocellular carcinoma have substantially increased since the introduction of ablation therapies in the 1990ies. While PEI was still the preferred treatment option at the beginning of the century (Bruix 2001), contradicting results have been reported in recently performed trials. Some were in favour of RFA (Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI), while others showed no differences in the outcome between RFA and PEI (Brunello 2008; Giorgio 2011). In addition, the effects of RFA compared with hepatic resection for hepatocellular carcinoma are unclear. The current recommendations by the EASL and the EORTC are to use hepatic resection as a primary treatment and to use RFA when surgery is not possible (EASL-EORTC 2012). As new trials have been published, we thought that this might change the evidence.

Objectives

To assess the beneficial and harmful effects of RFA versus placebo, no intervention, or any other therapeutic approach in patients with hepatocellular carcinoma.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised clinical trials, irrespective of publication status or blinding. We applied no language limitations.

Types of participants

All patients with hepatocellular carcinoma without contraindications for RFA (e.g. too many or too large tumours, extrahepatic malignant manifestation).

Types of interventions

RFA compared with placebo, no intervention, or any other intervention.

Types of outcome measures

Primary outcome
  • Overall survival.

Secondary outcomes
  • Two-year survival.

  • Event-free survival concerning local recurrences, distant recurrence, de novo (a new) carcinoma, death.

  • Local progression/recurrences.

  • Frequency of complications/serious adverse events. Serious adverse events: Number of participants with serious adverse events defined as "any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity". All other adverse events were be considered as non-serious (ICH-GCP 1997).

  • Quality of life.

  • Duration of hospital stay/health economics.

Search methods for identification of studies

Electronic searches

We performed electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science (Science Citation Index Expanded) (Royle 2003) to 3 September 2012. We did not update searches in CancerLit and Current Contents as well as searches of the journals (Zeitschrift für Gastroenterologie (suspended in 2000) and Endoskopie Heute (suspended in 1999). CancerLit is no longer updated and Current Contents has merged into ISI Web of Science. We used the search strategies with the time spans shown in Appendix 1, which ended September 2012.

Searching other resources  

We also handsearched proceedings of conferences of five oncological and hepatological societies (ASCO, ESMO, AASLD, EASL, APASL), as well as references of articles. We contacted researchers in the field and companies producing RFA equipment for information on further (unpublished) trials.

Data collection and analysis

We performed this systematic review according to a peer-reviewed, published protocol (Galandi 2001), and followed the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato-Biliary Group Module (Gluud 2013). We performed the analyses using Review Manager 5 (RevMan 2012).

Selection of studies

One review author (SW) collected the publications of all trials potentially relevant for this review. Two review authors (SW, KS) independently selected trials for inclusion.

Data extraction and management

Two review authors (SW, AF) independently extracted the data from all trials. We included data from the first versions of the review by Galandi (Galandi 2002; Galandi 2004). We contacted the principal authors of the trials to retrieve missing data. Where there were missing data for an appropriate judgement of the risk of bias, we judged the risk of bias as 'high'. We accepted the original trials' definitions for all beneficial and harmful outcomes although we attempted to extract information on all outcomes specified for this review. We resolved disagreements by discussion. We extracted type and number of serious adverse events, length of hospitalisation, and quality of life if available.

Assessment of risk of bias in included studies

Two review authors (SW, KS) assessed the risk of bias of all trials included in this review, following the risk of bias domains, with definitions presented below (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a; Gluud 2013).

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 were adequate if performed by an independent research assistant 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 (e.g. 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 were 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, had 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 (e.g. in a published protocol) and reported, or all clinically relevant (e.g. overall survival, event-free survival, or adverse events) were reported.

  • Uncertain risk of bias: it was unclear whether all pre-defined and clinically relevant outcomes were reported.

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

Vested interest bias
  • Low risk of bias: the trial appeared to be free of other components (should be listed, e.g. industry bias, academic bias, etc.) that could put it at risk of bias.

  • Uncertain risk of bias: it was unclear whether the trial was at risk of vested interest bias.

  • High risk of bias: there were other factors in the trial that could put it at risk of bias (e.g. for-profit involvement, study authors had conducted trials on the same topic, etc.).

Other bias
  • Low risk of bias: no other potential source of bias could be detected.

  • Uncertain risk of bias: potential sources of bias could not be ruled out (e.g. missing outcome definition, unclear baseline differences, etc.).

  • High risk of bias: other relevant sources of bias were present (e.g. small cohorts, significant baseline differences, etc.).

A trial was considered with a low risk of bias, if it was assessed with low risk of bias in all of the specified bias risk domains, and a trial was considered with high risk of bias, if one or more of the specific domains were assessed to be unclear or with high risk of bias.

We solved disagreements by discussion, or by contacting the Cochrane Hepato-Biliary Group in Copenhagen.

Units of analysis issues

We did not include cluster randomised trials. We did not expect or identify cross-over trials due to the nature of the disease and the interventions investigated. We included trials with three or more treatment groups if pair-wise comparison of a single intervention versus RFA was possible and if inclusion criteria of both intervention groups fulfilled the inclusion criteria. In order to exclude analysis bias by multiple counting of the shared intervention group, the shared intervention group was split into a corresponding number of subgroups with smaller sample size. We analysed and included each pair-wise comparison separately. We measured two survival outcomes. We analysed recurrence-free survival and overall survival separately.

Dealing with missing data

We considered missing data in the judgement of selective and incomplete reporting bias. In case of missing data that prevented trials from being included, we contacted trialists and requested missing data. In addition, we aimed to obtain hazard ratios (HRs) and standard deviations or Kaplan Meier survival plots for the survival outcome measures when these were not available from the original publication.

Assessment of heterogeneity  

We performed analyses of heterogeneity between trials by calculating the Chi2 statistic using Review Manager 5 (RevMan 2012). In addition, we assessed heterogeneity by calculating the I2 statistic (Higgins 2011), measuring the inconsistency among the trials and describing the percentage of variability in effect estimates that occurred due to heterogeneity rather than chance. For I2 statistics, the following thresholds were applied: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We planned to do funnel plots if more than 10 trials were identified to give an overview regarding potential reporting bias and other bias sources (Higgins 2011).

Data synthesis

Meta-analysis

We performed the meta-analyses according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato-Biliary Group Module( Gluud 2013 ). We extracted HRs as relevant effect measures for overall survival, two-year survival, event-free survival, and local recurrences with 95% confidence intervals (CI) from publications. Alternatively, we estimated HRs from log rank Chi2 statistics, log rank P values and given (total or group-wise) numbers of events, observed-to-expected event ratios, or Kaplan-Meier curves with patients at risk given, using methods presented by Machin 1997 and Parmer 1998. In addition, we calculated risk ratios (RR) together with their 95% CIs for survival. We used odds ratios (OR) together with their 95% CIs to characterise effect differences between RFA and other interventions regarding dichotomous outcomes such as complication rates and the inverse-variance method for measures on metric scale according to the protocol.

We assigned trials to subcategories according to their type of control intervention. We presented pooled effects within each subcategory and as overall estimate of effects. We analysed trials comparing RFA versus two other interventions within a three-armed design in that both comparisons were included independently within the respective subcategory using the given - or estimated - effect differences. The sample size or events or both, observed in the RFA group, allowed only once for the overall analysis to maintain the total sample sizes or events.

We used random-effects models to analyse the effect sizes (DerSimonian 1986). In comparison to fixed-effect model meta-analyses, these are more conservative and result in wider CIs of the meta-analysed effect estimates, in order to avoid over-optimistic significances. In contrast, random-effects models put too much weight on small trials (which are often more biased). Therefore, we also conducted fixed-effect model meta-analysis and reported results from both models if the results differed. In the absence of relevant heterogeneity, both models will result in nearly identical effect estimations.

For all available outcomes, we presented data tables or forest plots. The risk of bias within the trials was considered a potential source of heterogeneity, and, therefore, it was assessed in detail according to the methodology described above. We intended to perform a subgroup analysis to compare trials with low risk of bias with the overall evidence received from all suitable trials.

We performed statistical analyses using Review Manager 5 Software (RevMan 2012).

Trial sequential analysis

We applied trial sequential analysis (CTU 2011; Thorlund 2011) because cumulative meta-analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Wetterslev 2008). To minimise random errors, we calculated the required information size (i.e. the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) (Wetterslev 2008). The required information size calculation should also account for the heterogeneity or diversity present in the meta-analysis (Wetterslev 2008; Wetterslev 2009). In our meta-analysis, the required information size was based on the event proportion in the control group; assumption of a plausible RR reduction of 20%, or on the RR reduction observed in the included trials with low risk of bias; a risk of type I error of 5%; a risk of type II error of 20%; and the assumed diversity of the meta-analysis (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010). The underlying assumption of trial sequential analysis was that testing for significance may be performed each time a new trial is added to the meta-analysis. We have added the trials according to the year of publication, and if more than one trial has been published in a year, we added trials alphabetically according to the last name of the first author. Based on the required information size, we constructed trial sequential monitoring boundaries (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). These boundaries determined the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size; if the trial sequential monitoring boundaries were crossed before the required information size was reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. In contrast, if the boundaries were not surpassed, it was most probably necessary to continue doing trials in order to detect or reject a certain intervention effect if the trial sequential monitoring boundaries for futility were not crossed. If the latter was the case, futility could be declared (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).

Summary of findings tables

We summarised the evidence in the 'Summary of findings' tables using GRADEpro (ims.cochrane.org/revman/other-resources/gradepro). We used the GRADE classification in order to judge the quality of evidence.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Our literature search revealed 2008 references. We removed 718 duplicates. From the remaining 1290 references, we identified 11 randomised clinical trials that fulfilled our inclusion criteria (Characteristics of included studies). We identified no additional trials from other sources. Two trials still await classification with insufficient information that were reported in meeting abstracts available to date and with no additional information from the study authors (Di Costanzo 2011; Kuansheng 2011; Characteristics of studies awaiting classification). One trial was still ongoing (NCT00814242; Characteristics of ongoing studies). We excluded 23 studies due to insufficient design or lack of relevant information (Figure 1; Characteristics of excluded studies).

Figure 1.

Study flow diagram of the literature search as well as number and reasons of excluded studies.

Included studies

We included and analysed 11 trials in this review. The trials included 1819 randomised participants. We found no trials comparing RFA versus placebo, no intervention, chemotherapy, or liver transplantation.

Three trials with 578 participants compared RFA versus hepatic resection (Chen 2006; Huang 2010; Feng 2012).

Six trials with 1088 participants compared RFA versus PEI (Lencioni 2003; Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI); Shiina 2005; Brunello 2008; Giorgio 2011). Two of the trials with 344 participants randomised participants to three intervention groups (Lin 2004 (RFA vs. PEI); Lin 2004 (RFA vs. PEI-hd); Lin 2005 (RFA vs. PEI); Lin 2005 (RFA vs. PAI)). In one trial, RFA was compared with a standard dose of PEI (Lin 2004 (RFA vs. PEI)), and versus a high dose of PEI (Lin 2004 (RFA vs. PEI-hd)). In the other trial, RFA was compared with PEI (Lin 2005 (RFA vs. PEI)) and versus PAI (Lin 2005 (RFA vs. PAI)).

One trial each compared RFA versus microwave ablation (n = 72 participants) (Shibata 2002) and versus laser ablation (n = 81 participants) (Ferrari 2007).

Regarding the comparison of RFA versus other interventions, 10 out of 11 comparisons (including also the two three-armed trials) reported on the primary outcome, overall survival (Analysis 1.1). Two-year survival could be extracted from seven trials (with nine comparisons) (Analysis 2.1). Data on event-free survival were available from eight trials and on local progression were available from six trials (Analysis 3.1; Analysis 4.1). Rates of major complications or procedure-related deaths, or both, were reported in all trials.

Excluded studies

Reasons for excluding identified studies were as follows: one trial compared RFA alone with RFA plus hepatic arterial occlusion (Kobayashi 2007), one with RFA plus PEI (Zhang 2007), and two with RFA plus transarterial chemo-embolisation (TACE) (Morimoto 2010; Morimoto 2011). Ten studies were not randomised clinical trials (Buscarini 1996; Goldberg 1998; Cuschieri 1999; Jiao 1999; Livraghi 1999; Kurokohchi 2005; Zhang 2005; Lü 2006; Khan 2007; Ohmoto 2009). Five studies were retrospective cohort studies (Amarnath 2006; Ueno 2009; Opocher 2010; Sreenivasan 2010; Gory 2012). One publication was retracted (Cheng 2008). One study did not include patient data but was a Markov model analysis (Cho 2010). Akamatsu et al switched patients from PEI to RFA during the study (Akamatsu 2004). It was unclear whether randomisation was performed in two trials (Gan 2004; Chen 2005). We contacted the study authors but they did not reply and, therefore, we did not include the trials (Gan 2004; Chen 2005). RFA was also used to treat portal vein thrombosis in one study and, therefore, the effects of RFA on tumour growth could not be extracted (Giorgio 2011a). Peng et al only included patients with recurrent hepatocellular carcinoma. As this cohort displays differences to patients with newly diagnosed hepatocellular carcinoma, we did not include this trial (Peng 2012). One trial used laparoscopic RFA and was excluded (Santambrogio 2012).

Risk of bias in included studies

Overall, risk of bias was low in six trials and high in five trials. We only included the low risk of bias trials in the subgroup analysis.

Allocation

Generation of allocation sequence and allocation concealment

Allocation generation was done by a computer in seven trials, by random numbers in three trials (Shiina 2005; Giorgio 2011; Feng 2012), and the method of the allocation generation was not reported in one trial (Shibata 2002). The Shibata trial was described as a randomised trial. However, we were unable to obtain the missing information on allocation generation by the study authors. Concealed allocation was ensured by using a computer-based procedure in six trials, by sealed envelopes in three trials (Shibata 2002; Brunello 2008; Huang 2010), and by a coded list in one trial (Giorgio 2011). For the remaining trial, the study authors did not describe if allocation concealment was performed (Ferrari 2007).

Blinding

Our most important outcomes were survival and tumour recurrence, which are unlikely to be significantly influenced by lack of blinding of both participants and outcome assessors. Moreover, as treatment modalities such as RFA and hepatic resection differ substantially with regard to the degree of invasiveness, procedure performance, etc., reasonable blinding to the treatment of an investigator or an informed patient is unlikely. Objective outcomes such as adverse events were blinded in one trial only and, therefore, only this trial was judged as a low risk of bias trial (Giorgio 2011); all other trials had a high risk of bias (Analysis 5.1).

Incomplete outcome data

An intention-to-treat (ITT) analysis was explicitly stated in five trials (Shiina 2005; Chen 2006; Brunello 2008; Huang 2010; Feng 2012). Chen et al reported on 19 patients randomised to RFA who had later been subjected to resection (Chen 2006). These participants were excluded from the primary analysis. Results were adequately presented for both the ITT and the per-protocol analysis. The ITT results were considered for the meta-analysis of the data. Similarly, in Huang 2010, seven patients were switched from RFA to the resection group on their own decision but were analysed according to ITT (used in this review) and per-protocol. In two trials, it was unclear whether incomplete outcome data had been adequately addressed (Shibata 2002; Ferrari 2007).

Selective reporting

Ten trials were free of selective outcome reporting bias as the most relevant clinical outcome (overall survival was not reported in Shibata 2002). The other 10 trials reported outcomes in a sufficiently detailed manner to allow estimations of HR based on Parmar's method (Parmer 1998).

Vested interest bias

Relevant vested interest bias such as industry funding or relevant academic bias was unclear in two trials (Ferrari 2007; Shibata 2002), and not present in any of the trials as stated in the manuscript or directly by the study authors. Lin et al. performed two randomised clinical trials during the same time period. Patients were assigned to one of the trials according to their hospital admission week (Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI)) However, we judged this to have low risk of bias.

Other source of bias

Other sources of bias, namely possible premature stopping (Brunello 2008), an unusual high number of patients switching groups (Chen 2006) or undefined outcomes (Ferrari 2007) were present in three trials and we judged them to have an unclear risk of bias.

Overall bias risk assessment

Overall risk of bias was low in five trials and high in six trials (Figure 2; Figure 3). For a subgroup analysis, we only included low risk of bias trials.

Figure 2.

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

Figure 3.

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

Effects of interventions

See: Summary of findings for the main comparison Hepatic resection compared with radiofrequency ablation; Summary of findings 2 Percutaneous ethanol injection compared with radiofrequency ablation for early hepatocellular carcinoma; Summary of findings 3 Clinical characteristics of patients treated with radiofrequency ablation or percutaneous ethanol injection

Radiofrequency ablation versus hepatic resection

Comparison for efficacy outcomes

Three randomised clinical trials were identified that compared RFA versus hepatic resection (Chen 2006; Huang 2010; Feng 2012), of which two had low risk of bias (Huang 2010; Feng 2012), and one had high risk of bias (Chen 2006). Analysing the results from all three trials using a random-effects model showed no significant difference between the compared interventions regarding overall survival (HR 0.71; 95% CI 0.44 to 1.15) (Analysis 1.1) and two-year survival (HR 0.51; 95% CI 0.24 to 1.08) (Analysis 2.1). Meta-analysis using a fixed-effect model showed a result in favour of hepatic resection compared with RFA on overall survival (HR 0.76; 95% CI 0.58 to 1.00) (Analysis 1.2). In addition to the calculation of the HR, dichotomous outcomes on overall survival could be extracted from the two trials with low risk of bias (Huang 2010; Feng 2012; Analysis 1.3). In concordance with the HR analysis, resection yielded statistically significant improved survival both using the fixed-effect and random-effects model meta-analyses (RR fixed 0.61; 95% CI 0.44 to 0.82 and RR random 0.60; 95% CI 0.44 to 0.82).

Trial sequential analysis

Heterogeneity was present (I2 = 67%, P value = 0.05). The diversity-adjusted required information size (DARIS) was calculated based upon a proportion of deaths of 30% in the resection group; a relative risk reduction (RRR) of 20%; an alpha of 5% (a); a beta of 20% (b); and an assumed squared diversity (D) of 30%. This diversity may be an underestimation of the diversity of both the present and future meta-analyses, but has the advantage of narrowing the distance between the accrued and the required information size. Trial sequential analysis was only possible for two trials (Huang 2010; Feng 2012), as we could not calculate dichotomous outcomes for the third trial (Chen 2006). Calculating the number of patients needed in order to judge an RRR of 20%, 2455 participants would need to be recruited. Even with the patients of the third trial, only 578 patients were randomised to RFA versus resection. Therefore, no firm evidence for benefit or harm has been reached yet (Figure 4). As can be seen from the figure, the cumulative Z-score did not cross the trial sequential monitoring boundaries and did reach the area of futility.

Figure 4.

Trial sequential analysis for the comparison radiofrequency ablation versus hepatic resection on mortality in patients with hepatocellular carcinoma.

The diversity-adjusted required information size (DARIS) was calculated based upon a proportion of deaths of 30% in the percutaneous ethanol injection group (PEI); a relative risk reduction (RRR) of 20%; an alpha of 5% (a); a beta of 20% (b); and an assumed squared diversity (D) of 30%. The cumulative Z-score never crossed the alpha-spending monitoring boundary for harm and did not reach the beta-spending monitoring boundaries (the area of futility), which was not even drawn by the program. Therefore, further randomised trials are needed.

Subgroup analysis

In a subgroup analysis that included low-risk of bias trials only, results indicated that hepatic resection yields better results than RFA regarding overall survival (HR 0.56; 95% CI 0.40 to 0.78) (Analysis 1.3) and two-year survival (HR 0.38; 95% CI 0.17 to 0.84) (Analysis 2.2). Regarding event-free survival, the results indicated that hepatic resection seemed better than RFA (HR 0.70; 95% CI 0.54 to 0.91) (Analysis 3.1). Only one trial reported on local progression and found hepatic resection was superior to RFA (HR 0.48; 95% CI 0.28 to 0.82) (Analysis 4.1).

Comparison for safety outcomes

Major complications (including one procedure-related death) were only reported in 55% of patients in the surgery arm of one trial (OR 8.24; 95% CI 2.12 to 31.95) (Analysis 5.1) (Chen 2006).

Comparison for economic outcomes

Our results show that RFA was associated with shorter duration of hospital stay compared with surgery (standardised mean difference 2.18 days; 95% CI 1.97 to 2.39).

Radiofrequency ablation versus percutaneous ethanol injection/percutaneous acetic acid injection

Comparison for efficacy outcomes

Six trials compared RFA with PEI of which four had a low risk of bias (Lencioni 2003; Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI); Shiina 2005) and two had a high risk of bias (Brunello 2008; Giorgio 2011). The overall effects of RFA seemed superior to PEI regarding overall survival (HR 1.64; 95% CI 1.31 to 2.07) (Analysis 1.1), two-year survival (HR 1.82; 95% CI 1.34 to 2.47) (Analysis 2.1), event-free survival (HR 1.55; 95% CI 1.31 to 1.85) (Analysis 3.1), and local progression (HR 2.44; 95% CI 1.71 to 3.49) (Analysis 4.1). No significant difference was found if only the result from the four trials with low risk of bias were meta-analysed (overall survival: HR 1.19; 95% CI 0.79 to 1.77). One trial compared the two interventions for single and very small (2 cm or less) hepatocellular carcinoma and found no differences in overall survival (Giorgio 2011) (Summary of findings 2).

In addition to the calculation of the HR, dichotomous outcomes (RR) on overall survival were calculated from all six trials. There was no significant difference between the RFA group versus the PEI/PAI group (RR 1.76; 95% CI 0.97 to 3.22) (Analysis 6.1).

In addition, a subgroup analysis was performed in order to compare the results for overall survival of RFA versus PEI and RFA versus PAI. RFA versus PAI was only investigated in one three-armed trial (Lin 2005 (RFA vs. PAI)), as compared to the six trials that investigated RFA versus PEI (Lencioni 2003; Lin 2004 (RFA vs. PEI); Shiina 2005; Lin 2005 (RFA vs. PEI); Brunello 2008; Giorgio 2011). In a test of subgroup differences, we found no significant difference between the effect of RFA versus PEI or PAI (P value = 0.75) (Analysis 1.5). The body of evidence was not changed if the comparison of RFA versus PAI was excluded (Analysis 1.5; Analysis 5.2; Analysis 5.5).

Trial sequential analysis on overall mortality

Heterogeneity was not detected (I2 = 0%, P value = 0.70). The DARIS was calculated based upon a proportion of deaths of 30% in the PEI group; an RRR of 20%; an alpha of 5% (a); a beta of 20% (b); and an assumed squared diversity (D) of 30%. Trial sequential analysis with data from six trials that compared RFA with PEI found that only 986 patients of the DARIS of 2455 were accrued (40.2%) in order to obtain a risk reduction of 20%. As can be seen, the cumulative Z-score did not cross the trial sequential monitoring boundaries for benefit, harm, or futility (Figure 5).

Figure 5.

Trial sequential analysis for the comparison radiofrequency ablation versus percutaneous ethanol injection group (PEI) on mortality in patients with hepatocellular carcinoma.

The diversity-adjusted required information size (DARIS) was calculated based upon a proportion of deaths of 30% in the PEI group; a relative risk reduction (RRR) of 20%; an alpha of 5% (a); a beta of 20% (b); and an assumed squared diversity (D) of 30%. As it can be seen, the cumulative Z-score has never crossed the alpha-spending monitoring boundary for benefit and has not reached the beta-spending monitoring boundary (the area of futility). Therefore, further randomised trials are needed.

Subgroup analysis

A subgroup analysis including low-risk of bias trials only, was performed for all comparisons, but it did not change the body of evidence (Analysis 2.3; Analysis 3.2; Analysis 4.1; Analysis 5.3; Analysis 5.4).

A separate post-hoc analysis of the three trials conducted in Italy compared to the three trials conducted in Asia that compared RFA with PEI was performed. In Italian patients, there was no difference between treatment groups (HR 1.24; 95%; CI 0.84 to 1.83), while in Asian patients, the RFA seemed superior to PEI (HR 1.95; 95% CI 1.38 to 2.75). We found no statistically significant difference between the two subgroups (P value = 0.09) (Analysis 6.3).

Comparison for safety outcomes

All studies reported on minor complications. In six trials (Lencioni 2003; Lin 2004 (RFA vs. PEI); Lin 2004 (RFA vs. PEI-hd); Lin 2005 (RFA vs. PAI); Lin 2005 (RFA vs. PEI); Shiina 2005; Brunello 2008; Giorgio 2011), serious adverse events occurred. One trial reported a procedure-related death within the PEI group (Brunello 2008). The proportion of patients with a serious adverse event did not differ significantly between the compared intervention groups (PEI/PAI versus RFA; OR 0.70; 95% CI 0.33 to 1.48) (Analysis 5.1).

Comparison for economic outcomes

Duration of hospital stay was documented in three trials including five comparisons (Lin 2004 (RFA vs. PEI); Lin 2004 (RFA vs. PEI-hd); Lin 2005 (RFA vs. PAI); Lin 2005 (RFA vs. PEI); Shiina 2005). However, the settings of the trials differed due to regional habits. While Shiina 2005 treated all patients as inpatients until treatment success was documented by computed tomography, PEI/PAI patients in the Lin trials were routinely treated as outpatients in the cases when there was no severe adverse effect during the first PEI/PAI session (Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI)). Shiina 2005 reported a shorter hospitalisation time within the RFA group. These patients showed a shorter mean duration of hospital stay for the few complications that occurred. Due to the heterogeneous settings - also demonstrated by high Chi2 values and the small number of trials with available data, no valid conclusions can be deduced to date with regards to length of hospital stay (standardised mean difference -1.50; 95% CI -3.69 to 0.68). Giorgio 2011 reported the cost of interventions and found PEI to be 100 times less expensive than RFA (EUR1359 versus EUR171,000, P value < 0.0001). The study authors included the costs of the radiofrequency generator into this calculation.

Radiofrequency ablation versus percutaneous microwave coagulation

Comparison for efficacy outcomes

Only one trial examined the effects of RFA versus percutaneous microwave coagulation. Shibata et al randomised 72 patients with 94 hepatic tumour nodules to RFA versus percutaneous microwave coagulation (Shibata 2002). Data on overall survival, two-year survival, and event-free survival could not be extracted as the data presentation was based on tumour nodules and were not done patient-wise. There was no significant difference between RFA and percutaneous microwave coagulation regarding local progression (HR 2.14; 95% CI 0.67 to 6.80) (Analysis 4.1).

Comparison for safety outcomes

No death or other serious adverse events were observed during the trial in the RFA or percutaneous microwave coagulation group. In the RFA group, one patient had a segmental hepatic infarction. In the percutaneous microwave coagulation group, one patient each developed liver abscess, cholangitis, subcutaneous abscess, and skin burn. The OR of major complications was 4.38 (95% CI 0.46 to 41.22).

Comparison for economic outcomes

There were no data for economic outcomes. Data on the duration of hospital stay were not presented.

Radiofrequency ablation versus percutaneous laser ablation

One trial randomised 40 patients to RFA versus 41 patients to laser ablation (Ferrari 2007). There were no significant differences between RFA and percutaneous laser ablation with regards to overall survival (HR 1.62; 95% CI 0.62 to 4.22) (Analysis 1.1), event-free survival (HR 1.20; 95% CI 0.50 to 2.89) (Analysis 3.1), and local progression (HR 1.12; 95% CI 0.40 to 3.09) (Analysis 4.1)..

Comparison for safety outcomes

There were no data reported on safety outcomes.

Comparison for economic outcomes

There were no data reported on economic outcomes.

Quality of life

None of the identified trials reported on quality of life.

Discussion

Hepatocellular carcinoma represents a major health problem worldwide. Various therapeutic approaches such as percutaneous, transarterial, and surgical interventions are available. Prognosis and therapeutic options of patients with hepatocellular carcinoma depend on tumour extension and liver function, which is often reduced by underlying liver cirrhosis. Though sophisticated prognostic classifications such as the Barcelona Clinic Liver Cancer (BCLC), a more pragmatic approach based on number and size of tumour lesions is widely used to stratify patients (EASL-EORTC 2012). The Milan criteria define "early hepatocellular carcinomas" as a single tumour of 5 cm or less or up to three tumours of 3 cm or less (Mazzaferro 1996). The Milan criteria are also used to evaluate patients for orthotopic liver transplantation. Advanced stages of disease include extensive liver involvement and extrahepatic disease. Intermediate stages are ill-defined to date and belong to none of the former two groups. Furthermore, all treatments for hepatocellular carcinoma (excluding orthotopic liver transplantation) are reserved for patients with mild and moderate functional impairment of the liver. In our review, we aimed to determine the role of RFA as compared with any other intervention in patients with 'early hepatocellular carcinoma'. The primary outcome of our analyses was overall survival, which is the most relevant outcome for patients.

Summary of main results

In contrast to two former versions of this systematic review (Galandi 2002; Galandi 2004), new data on RFA for hepatocellular carcinoma has accumulated so that 11 randomised clinical trials have assessed RFA: three trials compared RFA versus resection (Chen 2006; Huang 2010; Feng 2012); six trials RFA versus PEI (Lencioni 2003; Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI); Shiina 2005; Brunello 2008; Giorgio 2011); one trial RFA versus PAI (Lin 2005 (RFA vs. PAI); one trial RFA versus microwave ablation (Shibata 2002); and one trial RFA versus laser ablation (Ferrari 2007). This represents an expansion of nine new trials with 1643 new participants.

Radiofrequency ablation versus hepatic resection

Our Cochrane systematic review included three randomised clinical trials comparing RFA versus surgical resection. Two of the identified trials had a low risk of bias (Huang 2010; Feng 2012), while the third trial had a high risk of bias (Chen 2006).

Analysing all three trials, there was no significant difference in the HR and the RR for overall survival (Analysis 1.1) and the HR for two-year survival (Analysis 2.1) between the treatment groups, but we found the outcome to be in favour of the surgically treated patients regarding event-free survival (Analysis 3.1) and local progression (Analysis 4.1). In the analysis of the two trials with a low risk of bias, hepatic resection resulted in an increased overall survival (Analysis 2.2) and increased two-year survival (Analysis 2.2) when compared with RFA using traditional and naive statistical boundaries. We conclude that there is moderate-quality evidence from randomised clinical trials that hepatic resection yields better results regarding benefits. However, the rate of complications is remarkably higher and the hospital stay is longer in the surgical resection group (Analysis 5.1). In order to become certain about the balance between benefits and harms, it would be necessary to conduct larger well-designed randomised clinical trials (Implications for research).

Radiofrequency ablation versus local ablative interventions

In summary, our meta-analysis adduces moderate-quality evidence compiled from six randomised clinical trials that RFA seems superior to PEI/PAI regarding overall survival, two-year survival, event-free survival, and local recurrence, with a similar frequency of major complications (Lencioni 2003; Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI); Shiina 2005; Brunello 2008; Giorgio 2011) (Summary of findings 2). In the comparison of RFA versus PEI, the low technical and instrumental requirements for PEI should also be taken into consideration (Schoppmeyer 2009). PEI may possibly also be a treatment option for very early hepatocellular carcinoma (single lesion 3 cm or less) (Giorgio 2011). There is evidence from single comparisons suggesting that RFA seems better than PAI and high-dose PEI (Lin 2004 (RFA vs. PEI-hd); Lin 2005 (RFA vs. PAI)). RFA was only compared with laser ablation and microwave coagulation in one randomised clinical trial (Shibata 2002; Ferrari 2007). The trial comparing RFA versus laser ablation found no difference between treatment modalities regarding the outcomes event-free survival and local progression (Ferrari 2007). No survival data were available for microwave coagulation. In conclusion, among the available local ablative therapies, RFA seemed to be the most efficient and safe technique of all the assessed local ablative therapies.

Italian versus East Asian trials

The trials comparing RFA versus PEI/PAI were performed either in Italy (Lencioni 2003; Brunello 2008; Giorgio 2011), or in East-Asia (Lin 2004 (RFA vs. PEI); Lin 2005 (RFA vs. PEI); Shiina 2005). Interestingly, there was no evidence for prolonged overall survival in European patients when treated with RFA compared with PEI (HR 1.24; 95% CI 0.84 to 1.83) (Summary of findings 3), while East-Asian studies suggested that overall survival was superior after RFA (HR 1.95; 95% CI 1.38 to 2.75). In one post-hoc analysis, we compared both subgroups and found no significant difference between the groups (P value = 0.09). Therefore, undefined technical differences in tumour ablation, reporting bias, or chance might account for the difference between the European and Asian trials. However, this could be addressed in further trials.

Ongoing trials

In addition to the included trial publications, we found three additional ongoing trials. One randomised clinical trial seeks information on RFA versus resection for hepatocellular carcinoma adjacent to large vessels (NCT00814242). Randomised trials comparing (chemo-)embolisation versus supportive care suggest that (chemo-)embolisation may increase survival (Llovet 2003; Llovet 2003b); however, one Cochrane systematic review found no convincing evidence that transarterial (chemo)embolisation was superior compared with no intervention for unresectable hepatocellular carcinoma (Oliveri 2011). We plan to include the information from these trials in the next update of our meta-analysis.

Overall completeness and applicability of evidence

Efficacy outcomes were properly addressed in most trials. However, this was not the case for the pre-specified outcomes in this review, quality of life and health economics. None of the trials assessed effects of RFA on quality of life and only one trial reported on health economics. Giorgio et al. found RFA to be 100 times more expensive than PEI (Giorgio 2011). The study authors included the cost of the PEI needles and the cost of a radiofrequency generator. However, in contrast to the needles used for PEI, the generator can be used multiple times, and as such, this comparison has to be interpreted very cautiously. For the comparison between RFA and hepatic resection, only retrospective data with inherent high risk of bias are available. One Japanese working group compared medical costs in 213 patients who received either RFA or hepatic resection (Ikeda 2005). Resection yielded lower recurrence rates as compared with RFA while increasing hospital stay. As a consequence, RFA had to be repeated in a higher number of patients. The study authors stated that repeated RFA was cheaper than resection (1,086,000 Japanese yen (JPY) versus 1,745,100 JPY; conversion rate 100 JPY = EUR0.71, at December 2013).

The relevance of other alternative interventional therapies such as laser and microwave ablation remains undetermined. No randomised clinical trial compared RFA versus no treatment, with best supportive care, or with cryoablation. Given the large differences in survival between treatment and no treatment groups in cohort studies, randomised trials with an untreated arm are neither likely to be performed nor ethically justifiable. One unresolved problem of local percutaneous ablation techniques and hepatic resection is the appearance of disease at disseminated areas of the body, and the fact that new tumours often emerge in the remaining cirrhotic liver tissue. Orthotopic liver transplantation is the only treatment that also removes underlying cirrhosis. Randomised clinical trials comparing the effectiveness of RFA versus orthotopic liver transplantation or versus RFA as a bridging therapy to liver transplantation have not been performed.

The current guidelines by the EASL and EORTC state that RFA is the interventional treatment of choice in patients that are not suitable for hepatic resection. If RFA is not feasible, PEI is recommended (EASL-EORTC 2012). In our meta-analysis, we found moderate evidence to support this recommendation, but too few patients were included in order to draw firm conclusion on the pre-specified survival outcomes. To the best of our knowledge, this meta-analysis is the first that includes the trials by Giorgio 2011 and Feng 2012 and thus it provides the best evidence available to date.

Quality of the evidence

The Cochrane Collaboration stresses the importance of good-quality trials. It is recognised to date that methodological quality of trials influences estimates of intervention effects( Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a). Considering possible sources of bias, we found five trials with low risk of bias. Six trials had methodological weaknesses that qualified them as trials with high risk of bias but were still eligible for inclusion (Shibata 2002; Chen 2006; Ferrari 2007; Brunello 2008; Giorgio 2011; Feng 2012). In summary, we found moderate-quality evidence derived from six trials with 1088 participants that RFA is superior to PEI regarding efficacy outcomes, while at the same time, the risk of adverse events does not seem to differ between the two treatment modalities (Summary of findings 2). As for the comparison between RFA and hepatic resection, there is moderate-quality evidence from two low risk of bias trials that randomised 398 patients that hepatic resection is more effective than RFA regarding overall survival and two-year survival. However, if a third trial with an additional 168 patients and a high risk of bias is included, the evidence becomes weak. With regards to the outcomes event-free survival and local progression, hepatic resection was found to yield better results than RFA regardless of the inclusion of the third trial with high risk of bias. In order to strengthen the body of evidence, more trials with low risk of bias are needed. There is high-quality evidence that complication rates were consistently higher in patients treated with hepatic resection (Summary of findings for the main comparison). Due to their high risk of bias, no firm conclusions regarding the pre-specified outcomes can be drawn for other interventional therapies.

Trial sequential analysis revealed that less than half of the required number of patients was recruited into the eligible trials in order to judge an RRR of 20% (Figure 4; Figure 5). In addition, the calculation of the RR for the comparison RFA versus PEI did not reach statistical significance (Analysis 1.2). Therefore, we conclude that there is only moderate-quality evidence to support RFA versus PEI or hepatic resection (Summary of findings for the main comparison; Summary of findings 2).

Potential biases in the review process

We excluded two trials from the analysis as it was unclear whether they were randomised clinical trials. We tried to contact the study authors but did not receive any replies (Gan 2004; Chen 2005). If these trials had been eligible for inclusion, we might have obtained information about the efficacy of RFA compared with chemotherapy and TACE. In addition, the two studies awaiting classification might have added important data to the meta-analysis (Di Costanzo 2011; Kuansheng 2011).

Agreements and disagreements with other studies or reviews

Radiofrequency ablation compared with hepatic resection

Some non-randomised studies (Abu-Hilal 2008; Ueno 2009; Cho 2010), one Markov model analysis (Molinari 2009), and one prior meta-analysis (Zhou 2010) reported superiority of hepatic resection as compared with RFA with regards to survival and recurrence. Although the post-interventional morbidity was less in RFA-treated patients, this did not significantly influence mortality. These results are in agreement with our review results.

Radiofrequency ablation compared with percutaneous ethanol injection or percutaneous acetic acid injection

In addition to the above mentioned meta-analysis (Zhou 2010), three meta-analyses on the effects of RFA on hepatocellular carcinoma have been published (Cho 2009; Bouza 2009; Lau 2009). Cho et al investigated the three-year survival in randomised clinical trials comparing RFA versus PEI for small hepatocellular carcinoma (Cho 2009). The four identified trials were also included in our review. The Lencioni trial included in our analyses was not considered for missing three-year survival rates. In accordance with our analyses, the study authors found evidence that RFA treatment was superior to PEI (OR 0.48; 95% CI 0.34 to 0.67, P value < 0.001). Another meta-analysis identified six studies that compared RFA versus PEI (Bouza 2009). An important difference to our analysis was that the previous authors included a quasi-randomised trial (Livraghi 1999). The RR for one-, two-, three-, and four-year survival, the local recurrence rates as well as the complications were assessed. There was strong (overall survival, one-year disease-free survival, disease free-survival, complete tumour response, major complications) or very strong (one-, two-, three-year survival, total complications) evidence in favour of RFA versus PEI. Lau and Lai referred to four categories in their trial publication: RFA versus other ablative techniques, RFA for unresectable hepatocellular carcinoma, RFA as a bridging therapy for liver transplantation, and RFA for recurrent hepatocellular carcinoma after hepatectomy (Lau 2009). We acknowledge this holistic and thorough approach. However, there are some major differences to our work. First, existing data were included regardless of the quality of trials. For instance, the trial of Lü 2006 was excluded from our analysis since effects of RFA were not extractable (see Characteristics of excluded studies table). Second, quantitative meta-analyses of the data were not performed. Thus, the conclusions presented there should be considered with caution.

Authors' conclusions

Implications for practice

In this update of the previous Cochrane review from 2004 (Galandi 2004), we identified 11 trials comparing radiofrequency ablation (RFA) versus other interventions that fulfilled the inclusion criteria. There is moderate-quality evidence from two trials with low risk of bias that hepatic resection seems to yield better results than RFA in patients with early hepatocellular carcinoma. This is counterbalanced by an increased rate of adverse events and by a longer hospital stay in surgically treated patients requiring a cautious choice of the appropriate therapy for any individual patient. There is moderate-quality evidence that RFA seems to be to be more effective than percutaneous ethanol injection (PEI) or percutaneous acetic acid injection (PAI) in early hepatocellular carcinoma. However, trial sequential analyses showed that only 40% of the required number of patients were recruited in order to judge a relative risk reduction of 20%, therefore, more trials with low risk of bias are needed to confirm our results. A small number of studies have been conducted to compare RFA versus other interventions such as microwave and laser ablation. Due to a high risk of bias in these trials, these interventions cannot yet be recommended for clinical practice.

Implications for research

The is a need for well-designed, sufficiently powered, multicentre trials with low risk of bias comparing RFA versus hepatic resection, PEI, or PAI in patients with hepatocellular carcinoma. Although there is evidence from two low risk of bias trials that hepatic resection yields better survival rates, more data are needed in order to confirm these results. There is a lack of evidence whether RFA can be used as a bridging therapy for patients that are listed for liver transplantation.

In general, trial outcomes should comprise overall survival, event-free survival, adverse events, and quality of life. With regards to increasing financial restrictions in public healthcare systems, the economic costs should also be investigated. In addition, a sufficiently extended follow-up period should be ensured in every trial. To obtain a higher level of external validity, trials involving RFA should be conducted as multicentre trials because surgical as well as percutaneous interventions are strongly affected by the individual experience of the physician(s)/investigator(s).

Acknowledgements

We thank Dr. Galandi for handing over this meta-analysis to us. We also thank Dimitrinka Nikolova, Sarah Klingenberg, and Christian Gluud from the Cochrane Hepato-Biliary Group for their patience and ongoing support. We are grateful to Dr. Hannelore Tenckhoff from HepNet for database assistance and Ping La from the Children's Hospital of Philadelphia for the translation of the Chinese publications. We also want to express our thanks to Christian Gluud from the Cochrane Hepato-Biliary Group for the help with the trial sequence analysis.

Peer reviewers: Ronald L. Koretz, USA.
Contact editor: Christian Gluud, Denmark.

Data and analyses

Download statistical data

Comparison 1. Overall survival
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Overall survival: control interventions versus RFA12 Hazard Ratio (Random, 95% CI)Subtotals only
1.1 Resection versus RFA3578Hazard Ratio (Random, 95% CI)0.71 [0.44, 1.15]
1.2 PEI or PAI versus RFA81088Hazard Ratio (Random, 95% CI)1.64 [1.31, 2.07]
1.3 Laser ablation versus RFA181Hazard Ratio (Random, 95% CI)1.62 [0.62, 4.22]
2 Fixed-effect model3 Hazard Ratio (Fixed, 95% CI)0.76 [0.58, 1.00]
3 Trials with low risk of bias2 Hazard Ratio (Random, 95% CI)0.56 [0.40, 0.78]
4 Resection versus RFA, dichotomous outcome2398Risk Ratio (M-H, Random, 95% CI)0.60 [0.44, 0.82]
5 PEI or PAI versus RFA81088Hazard Ratio (Random, 95% CI)1.64 [1.31, 2.07]
5.1 PEI versus RFA7994Hazard Ratio (Random, 95% CI)1.62 [1.27, 2.07]
5.2 PAI versus RFA194Hazard Ratio (Random, 95% CI)1.82 [0.94, 3.55]
Analysis 1.1.

Comparison 1 Overall survival, Outcome 1 Overall survival: control interventions versus RFA.

Analysis 1.2.

Comparison 1 Overall survival, Outcome 2 Fixed-effect model.

Analysis 1.3.

Comparison 1 Overall survival, Outcome 3 Trials with low risk of bias.

Analysis 1.4.

Comparison 1 Overall survival, Outcome 4 Resection versus RFA, dichotomous outcome.

Analysis 1.5.

Comparison 1 Overall survival, Outcome 5 PEI or PAI versus RFA.

Comparison 2. Two-year survival
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Control interventions versus RFA9 Hazard Ratio (Random, 95% CI)Subtotals only
1.1 Resection versus RFA3578Hazard Ratio (Random, 95% CI)0.51 [0.24, 1.08]
1.2 PEI/PAI versus RFA6715Hazard Ratio (Random, 95% CI)1.82 [1.34, 2.47]
2 Resection versus RFA, low risk of bias trials2398Hazard Ratio (Random, 95% CI)0.38 [0.17, 0.84]
3 PEI or PAI versus RFA, low risk of bias trials5576Hazard Ratio (Random, 95% CI)1.98 [1.41, 2.78]
Analysis 2.1.

Comparison 2 Two-year survival, Outcome 1 Control interventions versus RFA.

Analysis 2.2.

Comparison 2 Two-year survival, Outcome 2 Resection versus RFA, low risk of bias trials.

Analysis 2.3.

Comparison 2 Two-year survival, Outcome 3 PEI or PAI versus RFA, low risk of bias trials.

Comparison 3. Event-free survival
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Event-free survival: control interventions versus RFA11 Hazard Ratio (Random, 95% CI)Subtotals only
1.1 PEI/PAI versus RFA7949Hazard Ratio (Random, 95% CI)1.55 [1.31, 1.85]
1.2 Resection versus RFA3578Hazard Ratio (Random, 95% CI)0.70 [0.54, 0.91]
1.3 Laser ablation versus RFA181Hazard Ratio (Random, 95% CI)1.20 [0.50, 2.89]
2 PEI or PAI versus RFA, low risk of bias trials6678Hazard Ratio (Fixed, 95% CI)1.59 [1.33, 1.90]
Analysis 3.1.

Comparison 3 Event-free survival, Outcome 1 Event-free survival: control interventions versus RFA.

Analysis 3.2.

Comparison 3 Event-free survival, Outcome 2 PEI or PAI versus RFA, low risk of bias trials.

Comparison 4. Local progression/recurrences
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Local progression: control intervention versus RFA9 Hazard Ratio (Random, 95% CI)Subtotals only
1.1 PEI/PAI versus RFA6678Hazard Ratio (Random, 95% CI)2.44 [1.71, 3.49]
1.2 Resection versus RFA1168Hazard Ratio (Random, 95% CI)0.48 [0.28, 0.82]
1.3 Microwave ablation versus RFA172Hazard Ratio (Random, 95% CI)2.14 [0.67, 6.80]
1.4 Laser ablation versus RFA181Hazard Ratio (Random, 95% CI)1.12 [0.40, 3.09]
Analysis 4.1.

Comparison 4 Local progression/recurrences, Outcome 1 Local progression: control intervention versus RFA.

Comparison 5. Other secondary outcomes
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Rate of complications: RFA versus other interventions12 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Resection versus RFA3559Odds Ratio (M-H, Random, 95% CI)8.24 [2.12, 31.95]
1.2 PEI/PAI versus RFA81088Odds Ratio (M-H, Random, 95% CI)0.70 [0.33, 1.48]
1.3 Microwave ablation versus RFA172Odds Ratio (M-H, Random, 95% CI)4.38 [0.46, 41.22]
2 Rate of complications: PEI or PAI versus RFA81088Odds Ratio (M-H, Random, 95% CI)0.70 [0.33, 1.48]
2.1 PEI versus RFA7994Odds Ratio (M-H, Random, 95% CI)0.79 [0.37, 1.72]
2.2 PAI versus RFA194Odds Ratio (M-H, Random, 95% CI)0.09 [0.00, 2.00]
3 PEI/PAI versus RFA, low risk of bias trials6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4 Length of hospital stay; control interventions versus RFA (days)8 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Resection versus RFA3559Std. Mean Difference (IV, Random, 95% CI)2.18 [1.97, 2.39]
4.2 PEI/PAI versus RFA5576Std. Mean Difference (IV, Random, 95% CI)-1.50 [-3.69, 0.68]
5 Length of hospital stay; PEI or PAI versus RFA (days)5576Std. Mean Difference (IV, Random, 95% CI)-1.50 [-3.69, 0.68]
5.1 PEI versus RFA4482Std. Mean Difference (IV, Random, 95% CI)-1.47 [-4.23, 1.30]
5.2 PAI versus RFA194Std. Mean Difference (IV, Random, 95% CI)-1.66 [-2.16, -1.17]
Analysis 5.1.

Comparison 5 Other secondary outcomes, Outcome 1 Rate of complications: RFA versus other interventions.

Analysis 5.2.

Comparison 5 Other secondary outcomes, Outcome 2 Rate of complications: PEI or PAI versus RFA.

Analysis 5.3.

Comparison 5 Other secondary outcomes, Outcome 3 PEI/PAI versus RFA, low risk of bias trials.

Analysis 5.4.

Comparison 5 Other secondary outcomes, Outcome 4 Length of hospital stay; control interventions versus RFA (days).

Analysis 5.5.

Comparison 5 Other secondary outcomes, Outcome 5 Length of hospital stay; PEI or PAI versus RFA (days).

Comparison 6. PEI or PAI versus RFA, overall survival, other
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PEI versus RFA, dichotomous outcome6986Risk Ratio (M-H, Random, 95% CI)1.76 [0.97, 3.22]
2 PEI/PAI versus RFA, low risk of bias trials6 Hazard Ratio (Random, 95% CI)1.93 [1.46, 2.55]
3 PEI versus RFA, Italian versus Asian trials6915Hazard Ratio (Random, 95% CI)1.60 [1.24, 2.08]
3.1 Italian trials3512Hazard Ratio (Random, 95% CI)1.24 [0.84, 1.84]
3.2 Asian trials3403Hazard Ratio (Random, 95% CI)1.95 [1.38, 2.75]
Analysis 6.1.

Comparison 6 PEI or PAI versus RFA, overall survival, other, Outcome 1 PEI versus RFA, dichotomous outcome.

Analysis 6.2.

Comparison 6 PEI or PAI versus RFA, overall survival, other, Outcome 2 PEI/PAI versus RFA, low risk of bias trials.

Analysis 6.3.

Comparison 6 PEI or PAI versus RFA, overall survival, other, Outcome 3 PEI versus RFA, Italian versus Asian trials.

Appendices

Appendix 1. Search strategies

Name of databaseTime spansSearch strategyHits
The Cochrane Hepato-Biliary Controlled Trials RegisterSeptember 2012.(((radiofrequenc* or radio-frequenc* or 'radio frequenc*') AND (ablation* or therap* or treat*)) OR RFTA or RFA or RFT or RFCA) AND ((hepat* or liver) AND (carcinom* or tumour* or tumour* or neoplasm* or malign* or cancer*))35
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryIssue 8 of 12, 2012.

#1 MeSH descriptor Catheter Ablationexplode all trees

#2 (radiofrequenc* or radio-frequenc* or radio frequenc*) AND (ablation* or therap* or treat*)

#3 (RFTA or RFA or RFT or RFCA)

#4 (#1 OR #2 OR #3)

#5 MeSH descriptor Carcinoma, Hepatocellularexplode all trees

#6 ((hepat* or liver) AND (carcinom* or tumour* or tumour* or neoplasm* or malign* or cancer*))

#7 HCC

#8 (#5 OR #6 OR #7)

#9 (#4 AND #8)

94
MEDLINE (Ovid SP)1946 to September 2012.

#1. exp Catheter Ablation/

#2. ((radiofrequenc* or radio-frequenc* or radio frequenc*) and (ablation* or therap* or treat*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

#3. (RFTA or RFA or RFT or RFCA).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

#4. #1 or #2 or #3

#5. exp Carcinoma, Hepatocellular/

#6. exp Liver Neoplasms/

#7. ((hepat* or liver) and (carcinom* or tumour* or tumour* or neoplasm* or malign* or cancer*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

#8. HCC.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

#9. #5 or #6 or #7 or #8

#10. #4 and #9

#11. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

#12. #10 and #11

330
EMBASE (Ovid SP)1974 to September 2012.

#1 exp radiofrequency ablation/

#2 exp catheter ablation/

#3 (radiofrequenc* or radio-frequenc* or radio frequenc*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#4 (ablation* or therap* or treat*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#5 #4 and #3

#6 (RFTA or RFA or RFT or RFCA).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#7 6 or 1 or 2 or 5

#8 exp liver cell carcinoma/

#9 (hepat* or liver).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#10 (carcinom* or tumour* or tumour* or neoplasm* or malign* or cancer*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#11 10 and 9

#12 HCC.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#13 8 or 11 or 12

#14 7 and 13

#15 (random* or blind* or placebo* or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

#16 15 and 14

748
Science Citation Index Expanded (ISI Web of Science)1900 to September 2012.

# 1 TS=(radiofrequenc* or radio-frequenc* or radio frequenc*)

# 2 TS=(ablation* or therap* or treat*)

# 3 #2 AND #1

# 4 TS=(RFTA or RFA or RFT or RFCA)

# 5 #4 OR #3

# 6 TS=(hepat* or liver)

# 7 TS=(carcinom* or tumour* or tumour* or neoplasm* or malign* or cancer*)

# 8 #7 AND #6

# 9 TS=HCC

# 10 #9 OR #8

# 11 #10 AND #5

# 12 TS=(random* or blind* or placebo* or meta-analys*)

# 13 #12 AND #11

801

What's new

DateEventDescription
19 September 2013New citation required and conclusions have changed

The conclusions of the previous published review were:

"Radiofrequency thermal ablation seems a potentially promising technique for the treatment of small hepatocellular carcinoma. However, more randomised clinical trials are needed."

The conclusions reached in this second update are:

"The effects of RFA versus no intervention, chemotherapeutic treatment, or liver transplantation are unknown. We found moderate-quality evidence that hepatic resection is superior to RFA regarding survival. However, RFA might be associated with fewer complications and a shorter hospital stay than hepatic resection. We found moderate-quality evidence showing that RFA seems superior to percutaneous ethanol injection regarding survival. There were too sparse data to recommend or refute ablation achieved by techniques other than RFA. More randomised clinical trials with low risk of bias and low risks of random errors assessing the effect of RFA are needed."

18 June 2013New search has been performedThis is the second update of a review originally published in 2002 (Galandi 2002) and then updated in 2004 (Galandi 2004). Since 2004, 10 new randomised trials comparing radiofrequency ablation (RFA) with other interventions have been published. These trials account for a substantial increase in the available data and were included in the current review.
18 June 2013AmendedThe review was revised following the latest Cochrane methodology as well as Cochrane Hepato-Biliary Group methodological guidelines.

Contributions of authors

Konrad Schoppmeyer and Sebastian Weis searched the literature, extracted the data, and drafted the manuscript.
Annegret Franke extracted the data and performed the statistical evaluation. Annegret Franke also took part in the quality assessment of the trials.
Joachim Mössner critically reviewed the manuscript.
Janus Jakobsen performed the analysis for the summary of finding tables and critically reviewed the manuscript.

Declarations of interest

None.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.

Differences between protocol and review

  1. To date the term radiofrequency thermal ablation (RFTA) is not routinely used. It was replaced with the more common term radiofrequency ablation (RFA).

  2. The authoring team changed.

  3. Random-effects models were applied.

  4. CancerLit evolved into MEDLINE in 2003. The database was not searched again. Current Contents is represented by ISI Web of Science and was not searched again.

  5. Trial sequential analysis (TSA) and report of dichotomous outcomes for the outcome overall survival was included following the requirements of The Cochrane Hepato-Biliary Group.

Notes

This is the second update of a review published in 2002 (Galandi 2002), and first updated in 2004 by Galandi 2004.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Brunello 2008

MethodsRandomised trial.
Participants

139 patients: RFA = 70; PEI = 69.

Recruitment: January 2001 to September 2004.

Country: Italy.

InterventionsRFA versus PEI.
Outcomes

Primary outcome: complete response at 1 year.

Secondary outcome: early complete response (at 30-50 days after treatment), complications, survival, costs.

Inclusion Criteria
  • Child-Pugh cirrhosis A and B.

  • 1 to 3 nodules, each ≤ 30 mm.

  • HCC confirmed by radiology or histology.

Exclusion Criteria
  • no liver cirrhosis.

  • Child-Pugh cirrhosis C.

  • platelet count < 40,000 mm3.

  • INR > 1.75.

  • prothrombin time > 40 seconds.

  • hypovascular HCC.

  • lesions not detectable by ultrasound.

  • lesions close to gallbladder, hilum, colon, stomach (< 1 cm).

  • venous invasion.

  • metastasis.

  • tumour > 30 mm.

  • patients suitable for liver transplantation or resection.

Follow-up26 months.
Notes

Patients suitable for resection were excluded.

Patients with incomplete response (2 cycles) were further treated with PEI, RFA, or TACE.

Intention-to-treat analysis for complete response and survival was performed.

Trial stopped early after conclusive interim analysis indicating effects that exceeded the expectations.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber and reasons for drop-outs were reported.
Selective reporting (reporting bias)Low riskAll outcomes were appropriately reported.
Other biasUnclear risk

An interim analysis was carried out after 3 years leading to the interruption of the study, because the difference in 1-year complete response rate (the primary endpoint) was larger than expected. It remains unclear, whether this was a preplanned analysis. In addition, the impact on survival (a secondary endpoint) remains speculative.

More patients received a second treatment cycle in the PEI group.

Vested interest bias?Low riskNo previous RFA trial was performed by this group. Industry or other funding bias was ruled out.
Overall risk of bias assessmentHigh riskHigh risk of bias (other bias unclear: number of second treatment cycles; baseline imbalance unclear; interim analysis not mentioned as preplanned).

Chen 2006

MethodsRandomised trial.
Participants

180 patients: partial hepatectomy = 90; percutaneous local ablative therapy = 90.

Recruitment: November 1999 to June 2004.

Country: China.

InterventionsRFA versus hepatic resection.
Outcomes

Primary outcome: tumour recurrence rate at 2 years.

Secondary outcomes: overall survival, tumour-free survival, pain, length of hospital stay.

Inclusion Criteria
  • HCC confirmed histologically or by 2 imaging procedures + AFP > 400 ng/mL.

  • 1 HCC nodule ≤ 5 cm.

  • aged 18 to 75 years.

  • no extrahepatic metastasis.

  • no radiological evidence of invasion into major portal/hepatic vein branches.

  • Child-Pugh cirrhosis A with no history of encephalopathy, ascites refractory to diuretics, or variceal bleeding.

  • indocyanine green retention at 15 minutes < 30%.

  • platelet count > 40,000 mm3.

  • suitable for surgical or percutaneous local ablative therapy treatment.

Exclusion Criteria
  • none quoted.

Follow-upRFA 27.9 ± 10.6 months, resection 29.2 ± 11.9 months
Notes

19 patients who were randomised to RFA withdrew their consent and received resection. Survival analysis according to the intention-to-treat principle.

When residual tumour was present, RFA or PEI and TACE were performed. Only 62% of patients were treated with RFA once.

2 patients randomised to surgery were treated with PEI because of disseminated disease.

Focal nodular hyperplasia was found in 1 patient instead of HCC.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskComputer at a central registry.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs were reported.
Selective reporting (reporting bias)Low riskAll outcomes were appropriately reported.
Other biasUnclear riskA high percentage of patients randomised to the percutaneous local ablative therapy arm withdrew their consent and received surgical resection. They were analysed in an intention-to-treat analysis.
Vested interest bias?Low riskNo previous RFA trial was performed by this group. Industry or other funding bias was ruled out.
Overall risk of bias assessmentHigh riskHigh risk of bias (other bias: > 20% withdrawals in the percutaneous local ablative therapy arm; baseline imbalance; source of funding).

Feng 2012

MethodsProspective randomised trial.
Participants

168 patients: RFA = 84; surgical resection = 84.

Recruitment: January 2005 to March 2008.

Country: China.

InterventionsRFA versus hepatic resection.
Outcomes

Primary outcome: 3-year survival.

Secondary outcomes: 1- and 2- year survival, tumour recurrence, complications.

Inclusion Criteria
  • diagnosis of HCC confirmed at study authors' hospital.

  • no more than 2 nodules.

  • tumour diameter < 4 cm.

  • Child–Pugh cirrhosis A or B.

  • no intrahepatic and extrahepatic metastases.

  • no invasion of the portal vein.

  • no invasion of the hepatic vein trunk or secondary branches.

  • indocyanine green retention at 15 minutes < 30%.

  • platelet count > 50,000 mm3.

  • prolonged prothrombin time of < 5 seconds.

  • no other previous anti-tumour therapy.

  • suitable candidates for both hepatic resection and RFA.

Exclusion Criteria
  • patients met the inclusion criteria but declined to participate.

  • severe portal hypertension.

  • history of oesophageal variceal haemorrhage.

  • severe hypersplenism syndrome.

  • refractory ascites.

  • patients whose permanent pathology after treatment suggested metastatic

  • liver cancer or primary liver cancer of another tissue type.

  • patients who were willing to receive a liver transplantation

Follow-up36 months.
NotesThe absolute number of deaths that occurred in the resection group were 18 including 1 patient died of a cerebral vascular accident. 24 patients died in the RFA group including one patient who died in a motor vehicle accident.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number generator.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs reported.
Selective reporting (reporting bias)Low riskPower calculation performed. Intention-to-treat analysis performed.
Other biasLow risk

Zelen method used for stratification. Written informed consent signed after agreement with randomisation.

Patients who died of causes unrelated to HCC were judged as lost to follow-up.

Vested interest bias?Low riskNo previous RFA trial was performed by this group. Industry or other funding bias was ruled out.
Overall risk of bias assessmentLow riskHigh risk of bias due to unclear other bias.

Ferrari 2007

MethodsRandomised trial.
Participants

81 patients: RFA = 40; laser ablation = 41.

Recruitment: January 2003 to December 2005.

Country: Italy.

InterventionsRFA versus laser ablation.
OutcomesSurvival, complications, complete tumour ablation, disease recurrence.
Inclusion Criteria
  • histologically confirmed HCC.

  • single nodule ≤ 40 mm or no more than 3 nodules ≤ 30 mm each.

  • no previous HCC treatment.

  • performance status ECOG 0-2.

  • cardiac and pulmonary function WHO 0-2.

  • aged 19 to 82 years.

  • underlying liver cirrhosis.

  • delayed inclusion.

  • prothrombin activity < 40%.

  • INR > 1.99.

  • platelet count > 40,000 mm3.

Exclusion Criteria
  • tumour invasion into vessels or main bile duct.

  • extrahepatic metastases.

  • Child-Pugh C cirrhosis.

  • severely decompensated cirrhosis.

  • major oesophageal varices.

Follow-upNot stated.
Notes

No primary and secondary endpoints were defined.

The study authors stated that there were no complications at all.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskComputer randomisation.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported.
Selective reporting (reporting bias)Low riskAll relevant outcomes were reported.
Other biasUnclear risk

Outcomes not defined.

Unclear whether normalisation of coagulation did improve Child-Pugh status.

Vested interest bias?Unclear riskNo previous RFA trial was performed by this group. Industry or funding bias could not be ruled out.
Overall risk of bias assessmentHigh riskHigh risk of bias.

Giorgio 2011

MethodsRandomised trial.
Participants

285 patients: RFA = 142; PEI = 143.

Recruitment: January 2005 to January 2010.

Country: Italy.

InterventionsRFA versus PEI.
Outcomes

Primary outcome: 5-year survival, rate of recurrence.

Secondary survival: feasibility of both procedures considering segmental location.

Inclusion Criteria
  • single nodule ≤ 3 cm.

  • Child-Pugh cirrhosis A or B.

  • no ascites.

  • no portal vein or segmental portal thrombosis.

Exclusion Criteria
  • > 1 nodule.

  • > 3 cm in diameter.

  • Child-Pugh C cirrhosis.

  • patients eligible for resection or liver transplantation.

  • patients with extrahepatic diseases.

Follow-up8 to 68 months.
Notes

Additional information from study authors was obtained: HR of overall survival.

14 patients randomised to RFA could not be treated by RFA and were not included in the survival analysis.

Patients and field staff were blinded to treatment assignment.

In addition, the total number of deaths were obtained from the study authors and were: HCC < 3 cm treated with PEI 45; HCC < 3 treated with RFA 30; HCC < 2 cm treated with PEI 14; HCC < 2 cm treated with RFA 11.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number generator.
Allocation concealment (selection bias)Low riskCoded list.
Blinding of survival outcomesLow riskPatients and field staff blinded to treatment.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs reported, but 14 patients randomised to RFA were treated with PEI and not included in the survival analysis.
Selective reporting (reporting bias)Low riskAll relevant outcomes were reported. HR was given only for overall survival.
Other biasLow riskThere was no other source of bias detected.
Vested interest bias?Low riskVested interest bias such as academic bias or industry funding, etc. was not present.
Overall risk of bias assessmentHigh riskHigh risk of bias.

Huang 2010

MethodsRandomised trial.
Participants

230 patients: RFA 115; surgical resection 115.

Recruitment: March 2003 to January 2005.

Country: China.

InterventionsRFA versus hepatic resection.
Outcomes

Primary outcome: overall survival.

Secondary outcome: recurrence-free survival, overall recurrence, adverse events, length of hospital stay.

Inclusion Criteria
  • diagnosis of HCC confirmed in the study hospital.

  • tumour within the Milan criteria.

  • no extrahepatic metastasis or obvious vascular invasion.

  • Child-Pugh cirrhosis A or B.

  • no previous or simultaneous malignancies.

  • indocyanine green retention at 15 minutes < 20%.

  • platelet count > 50,000 mm3 or correctable by transfusion.

  • prothrombin time < 5 seconds.

  • HBV-DNA quantification in HBV-infected patients < 10,000 copies/mL.

  • no previous HCC treatment.

  • suitable to be treated by resection or RFA.

Exclusion Criteria
  • severe portal hypertension with history of oesophageal variceal haemorrhage, with large oesophageal varices, refractory ascites.

  • willing to receive liver transplantation.

Follow-up1 to 60 months.
Notes

Study authors reported limitations of the trial. Patients that were willing to receive liver transplantation were excluded.

Subgroup analysis regarding solitary HCC < 3 cm, solitary HCC 3 to 5 cm and multifocal HCC.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influenced by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and protocol violations were reported.
Selective reporting (reporting bias)Low riskAll relevant outcomes were reported.
Other biasLow riskNo other source of bias.
Vested interest bias?Low riskNo previous RFA trial was performed by this group. Industry or other funding bias was ruled out.
Overall risk of bias assessmentLow riskLow risk of bias regarding efficacy outcomes.

Lencioni 2003

MethodsRandomised controlled trial.
Participants

102 patients: RFA = 52; PEI = 50.

Recruitment: unclear.

Country: Italy, Germany.

InterventionsRFA versus PEI.
OutcomesPrimary outcome: overall survival.
Secondary outcome: local recurrence free and event free (metastasis, new HCC) survival, adverse events.
Inclusion Criteria
  • adults with cirrhosis and (a) single HCC ≤ 5 cm in diameter or (b) 3 HCCs each ≤ 3 cm in diameter.

  • HCCs all located at least 1 cm from the hepatic hilum or the gall bladder.

  • absence of vascular invasion or extrahepatic metastases.

  • Child-Pugh cirrhosis A or B.

  • prothrombin activity > 50%.

  • platelet count > 50,000 mm3

  • no previous treatment for HCC.

  • ineligibility for surgical resection or transplantation.

  • written informed consent.

Exclusion Criteria
  • none given.

Follow-upRFA mean 22.9 months, PEI mean 22.4 months.
Notes

2 patients randomised to RFA were excluded due to violation of the inclusion criteria (1 with a large carcinoma > 5 cm and 1 with extrahepatic tumour).

Histological confirmation of HCC was only obtained in 45/102 patients.

Based on contact with the statistician of the trial we have been informed that the risk ratios are indeed HRs.

No sample size calculation reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskCentral registry.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for drop-out/withdrawal stated.
Selective reporting (reporting bias)Low riskAll relevant outcomes were reported.
Other biasLow riskNo other source of bias.
Vested interest bias?Low riskNo previous randomised controlled trials but retrospective studies published. Industry or other funding bias was excluded.
Overall risk of bias assessmentLow riskLow risk of bias regarding efficacy outcomes.

Lin 2004 (RFA vs. PEI)

MethodsRandomised trial.
Participants

157 patients: RFA 52; high-dose PEI 53; PEI 52.

Recruitment: April 2000 to April 2002.

Country: Taiwan.

Interventions

RFA versus high-dose PEI versus PEI.

Comparison 1: RFA versus PEI.

Outcomes

Primary outcome: local tumour progression.

Secondary outcome:complete tumour necrosis, overall survival, cancer-free survival.

Inclusion Criteria
  • histologically or cytologically confirmed HCC.

  • 1 to 3 nodules up to 4 cm.

  • Child-Pugh cirrhosis A or B.

Exclusion Criteria
  • Child-Pugh cirrhosis C.

  • previous HCC treatment.

  • tumour within 5 mm of liver hila or common bile duct.

Follow-up4 to 43 months.
Notes

6 patients with PEI, 3 patients with high-dose PEI, and 2 patients with RFA did not receive a complete treatment course or did not achieve complete necrosis and underwent TACE.

Patients of both PEI arms treated as outpatients as long as no adverse event occurred.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskLocked computer.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs were reported.
Selective reporting (reporting bias)Low riskAll relevant outcomes were reported.
Other biasLow riskNo source of other bias.
Vested interest bias?Low risk

The same research group performed another randomised clinical trial at the same time. Patients were assigned to 1 of the parallel trials depending on hospital admission during alternative weeks.

Previous retrospective trial on PEI for HCC.

Overall risk of bias assessmentLow riskLow risk of bias regarding efficacy outcomes.

Lin 2004 (RFA vs. PEI-hd)

MethodsRandomised trial.
Participants

157 patients: RFA = 52; high-dose PEI = 53; PEI = 52.

Recruitment: April 2000 to April 2002.

Country: Taiwan.

Interventions

RFA versus high-dose PEI versus PEI.

Comparison 2: RFA versus high-dose PEI.

Outcomes

Primary outcome: local tumour progression.

Secondary outcome: complete tumour necrosis, overall survival, cancer-free survival.

Inclusion Criteria
  • histologically or cytologically confirmed HCC.

  • 1 to 3 nodules up to 4 cm.

  • Child-Pugh cirrhosis A or B.

Exclusion Criteria
  • Child-Pugh cirrhosis C.

  • previous HCC treatment.

  • tumour within 5 mm of liver hila or common bile duct.

Follow-up4 to 43 months.
Notes

6 patients with PEI, 3 patients with high-dose PEI, and 2 patients with RFA did not receive a complete treatment course or did not achieve complete necrosis and received TACE.

Patients of both PEI arms treated as outpatients as long as no adverse event occurred.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Blinding of survival outcomesLow risk 
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs were reported.
Selective reporting (reporting bias)Low risk 
Other biasLow risk 
Vested interest bias?Low risk 
Overall risk of bias assessmentLow risk 

Lin 2005 (RFA vs. PAI)

MethodsRandomised trial.
Participants

187 patients: RFA = 62; PEI = 62; PAI = 63.

Recruitment: April 2000 to June 2002.

Country: Taiwan.

Interventions

RFA versus PEI versus PAI.

Comparison 1: RFA versus PAI.

Outcomes

Primary outcome: local recurrence.

Secondary outcome: overall survival, cancer-free survival.

Inclusion Criteria
  • 1 to 3 HCC nodules each ≤ 3 cm.

  • > 1 cm distance to hepatic hilum.

  • absence of extrahepatic 3 cm metastasis or vascular invasion.

  • liver cirrhosis Child A or B.

  • prothrombin time 3 seconds less than control values

  • platelet count > 50,000/mm3.

  • no previous treatment.

Exclusion Criteria
  • Child-Pugh cirrhosis C.

  • previous HCC treatment.

  • tumour located within 1 cm of the liver hilum or common bile duct.

Follow-up41 to 44 months.
Notes
  • 4.8% major complications in RFA, 0% in the PAI and PEI groups.

  • 11 patients had a treatment failure and were treated with additional therapies.

  • Planned early stopping if there was a survival benefit for 1 of the treatments as evaluated every 3 months.

  • patients of PEI/PAI arms treated as outpatients as long as no adverse events occurred.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Blinding of survival outcomesLow risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Other biasLow risk 
Vested interest bias?Low risk 
Overall risk of bias assessmentLow risk 

Lin 2005 (RFA vs. PEI)

MethodsProspective randomised trial.
Participants

187 patients: RFA = 62; PEI = 62; PAI = 63.

Recruitment: April 2000 to June 2002.

Country: Taiwan.

Interventions

RFA versus PEI versus PAI.

Comparison 1: RFA versus PEI.

Outcomes

Primary outcome: local recurrence.

Secondary outcome: overall survival, cancer-free survival.

Inclusion Criteria
  • 1 to 3 HCC nodules each ≤ 3 cm.

  • > 1 cm distance to hepatic hilum.

  • absence of extrahepatic metastasis or vascular invasion.

  • Child-Pugh cirrhosis A or B.

  • prothrombin time 3 seconds less than control values.

  • platelet count > 50,000/mm3.

  • no previous treatment.

Exclusion Criteria
  • Child-Pugh cirrhosis C.

  • previous HCC treatment.

  • tumour located within 1 cm of the liver hilum or common bile duct.

Follow-up4 to 44 months.
Notes
  • 4.8% major complications in RFA, 0% in the PAI and PEI groups.

  • 7 patients had a treatment failure and were treated with additional therapies.

  • Planned early stopping if there was a survival benefit for 1 of the treatments as evaluated every 3 months.

  • patients of PEI/PAI arms treated as outpatients as long as no adverse events occurred.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomisation.
Allocation concealment (selection bias)Low riskLocked computer.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs did not occur.
Selective reporting (reporting bias)Low riskAll outcomes were addressed.
Other biasLow riskLocal recurrence was primary outcome, not survival, thus sample size calculation was based on local recurrence.
Vested interest bias?Low risk

The same trial group performed another randomised clinical trial at the same time. Patients were assigned to 1 of the parallel trials depending on hospital admission during alternative weeks.

Previous retrospective trial on PEI for HCC.

Overall risk of bias assessmentLow riskLow risk of bias regarding efficacy outcomes.

Shibata 2002

MethodsRandomised trial.
Participants

72 patients: RFA = 36; percutaneous microwave ablation = 36.

Recruitment: March 1999 to October 2000.

Country: Japan.

InterventionsRFA versus percutaneous microwave coagulation.
OutcomesPrimary outcome: tumour recurrence.
Secondary outcome: pain, complications, duration of the procedure.
Inclusion Criteria
  • HCC diagnosis confirmed by ultrasound-guided needle biopsy.

  • a solitary HCC nodule ≤ 4 cm in diameter or 2 or 3 HCC nodules ≤ 3 cm in diameter.

  • informed consent.

Exclusion Criteria
  • none given.

Follow-up6 to 27 months.
Notes

No data on survival were reported.

Detailed description of complications was included.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Low riskSealed envelope.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not reported. No intention-to-treat analysis. Apparently all patients received the assigned treatment.
Selective reporting (reporting bias)High riskSurvival was not a defined outcome and not reported.
Other biasLow riskNo other source of bias.
Vested interest bias?Unclear riskNo previous RFA trial was performed by this group. Industry or funding bias could not be ruled out.
Overall risk of bias assessmentHigh riskHigh risk of bias.

Shiina 2005

  1. a

    AFP: alpha-fetoprotein; DNA: deoxyribonucleic acid; ECOG: Eastern Cooperative Oncology Group; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HR: hazard ratio; INR: international normalised ratio; PAI: percutaneous acetic acid injection; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation; TACE: transarterial chemoembolisation; WHO: World Health Organization.

MethodsRandomised trial.
Participants

232 patients: RFA = 118; PEI = 114.

Recruitment: April 1999 to January 2001.

Country: Japan.

InterventionsRFA versus PEI.
Outcomes

Primary outcome: overall survival.

Secondary outcome: overall recurrence, local tumour progression.

Inclusion Criteria
  • histopathologically or radiologically confirmed HCC.

  • lesions were unresectable or the patient had refused surgery.

  • 1 to 3 HCC nodules each ≤ 3 cm.

  • Child-Pugh cirrhosis A or B.

  • no extrahepatic metastasis or vascular invasion; no previous or simultaneous malignancies.

Exclusion Criteria
  • refractory ascites.

  • platelet count < 50,000/mm3

  • prothrombin activity below < 50%.

Follow-up0.6 to 4.3 years (median 3.1 years).
Notes

No patients were excluded for lesion location.

Detection of fourth lesion in 3 RFA patients and 4 PEI patients.

Intention-to-treat analysis performed.

More experienced physician performed the difficult lesions.

Adverse events reported.

All patients were treated as inpatients until computed tomography stated treatment success.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number generator.
Allocation concealment (selection bias)Low riskComputer.
Blinding of survival outcomesLow riskSurvival outcomes may not be significantly influences by a lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patient was lost to follow-up. An intention-to-treat analysis was performed.
Selective reporting (reporting bias)Low riskAll outcomes reported.
Other biasLow riskThere was no other bias.
Vested interest bias?Low riskNo previous RFA trial was performed by this group. Industry or other funding bias was ruled out.
Overall risk of bias assessmentLow riskLow risk of bias regarding efficacy outcomes.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    HCC: hepatocellular carcinoma; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation.

Akamatsu 2004Randomised trial (using sealed envelopes) that was not included due to the following reasons: patients were switched from PEI to RFA as soon as this technique was available. Randomisation of 6 versus 10 patients. Therefore, the study design was considered insufficient to evaluate RFA effects.
Amarnath 2006Retrospective review.
Buscarini 1996Not a controlled trial.
Chen 2005Randomisation not clear. Study authors did not reply to our contact approaches via email.
Cheng 2008Publication retracted in May 2009.
Cho 2010Not a controlled trial. Markov model analysis.
Cuschieri 1999Not a controlled trial.
Gan 2004Randomisation not clear. Study authors did not reply.
Giorgio 2011aRFA also used to treat portal vein thrombosis.
Goldberg 1998Not a controlled trial.
Gory 2012Retrospective multicentre analysis.
Jiao 1999Not a controlled trial.
Khan 2007Not a randomised trial.
Kobayashi 2007RFA compared with combination treatment.
Kurokohchi 2005Not a randomised trial.
Livraghi 1999Controlled trial without randomisation.
Different diagnostic follow-up schedules in the 2 treatment groups.
No data concerning overall survival.
Lü 2006Radiofrequency or microwave ablation therapy applied in 1 group compared with surgical resection in the other group. Therefore, RFA effects were not extractable.
Morimoto 2010RFA compared with combination treatment.
Morimoto 2011RFA compared with combination treatment.
Ohmoto 2009Not a controlled trial.
Opocher 2010Retrospective cohort study.
Peng 2012Only recurrent HCC treated.
Santambrogio 2012Not a percutaneous intervention.
Sreenivasan 2010Retrospective cohort study.
Ueno 2009Retrospective cohort study.
Zhang 2005Quasi-randomised trial.
Zhang 2007RFA compared with combination treatment.

Characteristics of studies awaiting assessment [ordered by study ID]

Di Costanzo 2011

MethodsRandomised clinical trial.
Participants

80 patients: RFA = 40; laser ablation = 40.

Recruitment: January 2009 to October 2010.

Country: Italy.

InterventionsRFA versus laser ablation.
Outcomes

Primary outcome: complete tumour ablation, time to recurrence.

Secondary outcome: overall survival.

NotesFrom the meeting abstract. Insufficient information to judge bias, randomisation process, etc. Author contact failed.

Kuansheng 2011

  1. a

    RFA: radiofrequency ablation.

MethodsRandomised clinical trial.
Participants

168 patients: RFA = 84; surgical resection = 84.

Recruitment: December 2004 to October 2007

Country: most likely China.

InterventionsRFA versus surgical resection.
Outcomes1-, 2- and 3-year survival.
NotesFrom the meeting abstract. Insufficient information to judge bias, randomisation process, etc. Probably data published in the trial by Feng et al (Feng 2012).

Characteristics of ongoing studies [ordered by study ID]

NCT00814242

  1. a

    AFP: alpha-fetoprotein; HCC: hepatocellular carcinoma; RFA: radiofrequency ablation.

Trial name or titleHepatectomy Versus Radiofrequency Ablation for Hepatocellular Carcinoma Adjacent to Major Blood Vessels.
MethodsRandomisation unclear.
Participants
  • approximately 120 participants.

Inclusion:

  • HCC at complex site (see below).

  • Child-Pugh cirrhosis.

  • no dysfunction in major organs; blood routine, kidney function, cardiac function, and lung function are basically normal.

  • aged 18 to 70 years.

InterventionsRFA versus surgery.
Outcomes

Primary:

  • tumour recurrence rate after 1 and 2 years.

  • disease-free survival.

  • overall survival.

Secondary:

  • overall survival rate in 1, 2, 3, or 5 years.

  • disease-free survival in 1, 2, 3, or 5 years.

  • hepatic function of patients after surgery.

  • complications and the decline level of serum AFP concentration.

Starting dateDecember 2008
Contact informationFeng Shen, MD, Study Chair.

Lehua Shi, MD, telephone: 0086-21-25070784.
Email: shilh@ehbh.cn.

Yong Xia, MD, telephone: 0086-21-25074943.
Email: xiay99@hotmail.com.
NotesHepatoma at a complex site (8 segment of liver, caudate lobe, the substantial depth of liver below hepatic integument adjacent to the trunk of inferior vena cava, hepatic vein, and portal vein).

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