The combination of transcatheter arterial chemoembolisation (TACE) and thermal ablation versus TACE alone for hepatocellular carcinoma

BoZhi Liu; YongChao Zhang; Hui Chen; Wei Li; Emmanuel Tsochatzis

doi:10.1002/14651858.CD013345.pub2

. 2022 Jan 4;2022(1):CD013345. doi: 10.1002/14651858.CD013345.pub2

The combination of transcatheter arterial chemoembolisation (TACE) and thermal ablation versus TACE alone for hepatocellular carcinoma

BoZhi Liu ¹, YongChao Zhang ¹, Hui Chen ², Wei Li ^1,^✉, Emmanuel Tsochatzis ³

Editor: Cochrane Hepato-Biliary Group

PMCID: PMC8724539 PMID: 34981511

Abstract

Background

Hepatocellular carcinoma is the sixth most common cancer worldwide. Hepatic resection is regarded as the curative therapy for hepatocellular carcinoma. However, only about 20% of people with hepatocellular carcinoma are candidates for resection, which highlights the importance of effective nonsurgical therapies. Until now, transcatheter arterial chemoembolisation (TACE) is the most common palliative therapy for hepatocellular carcinoma, but its clinical benefits remain unsatisfactory. During recent years, some studies have reported that the combination of TACE plus thermal ablation can confer a more favourable prognosis than TACE alone. However, clear and compelling evidence to prove the beneficial or harmful effects of the combination of TACE and thermal ablation therapy is lacking.

Objectives

To assess the beneficial and harmful effects of the combination of thermal ablation with TACE versus TACE alone in people with hepatocellular carcinoma.

Search methods

We performed searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index‐Science. We endeavoured to identify relevant randomised clinical trials also in the China National Knowledge Infrastructure (CNKI) and Wanfang databases. We searched trial registration websites for ongoing studies. We also handsearched grey literature sources. The date of last search was 22 December 2020.

Selection criteria

We planned to include all randomised clinical trials comparing the combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma, no matter the language, year of publication, publication status, and reported outcomes.

Data collection and analysis

We planned to use standard methodological procedures expected by Cochrane. We planned to calculate risk ratios (RRs) with the corresponding 95% confidence intervals (CIs). For time‐to‐event variables, we planned to use the methods of survival analysis and express the intervention effect as a hazard ratio (HR) with 95% Cl. If the log HR and the variance were not directly reported in reports, we planned to calculate them indirectly, following methods for incorporating summary time‐to‐event data into meta‐analysis. We planned to assess the risk of bias of the included studies using the RoB 2 tool. We planned to assess the certainty of evidence with GRADE and present the evidence in a summary of findings table.

Main results

Out of 2224 records retrieved with the searches, we considered 135 records eligible for full‐text screening. We excluded 21 of these records because the interventions used were outside the scope of our review or the studies were not randomised clinical trials. We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, either from the study authors or through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants, based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies.

Accordingly, we found no confirmed randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma for inclusion in our review.

We identified five ongoing trials, by handsearching in clinical trial websites.

Authors' conclusions

We could not find for inclusion any confirmed randomised clinical trials assessing the beneficial or harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma. Therefore, our results did not show or reject the efficiency of the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma.

We need trials that compare the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma, not eligible for treatments with curative intent (liver transplantation, ablation surgical resection) and who have sufficient liver reserve, as assessed by the Child Pugh score, and who do not have extrahepatic metastases. Therefore, future trial participants must be classified at Barcelona Clinic Liver Cancer Stage B (intermediate stage) (BCLC‐B) or an equivalent, with other staging systems.

Plain language summary

The combination of transcatheter arterial chemoembolisation and thermal ablation versus TACE alone for hepatocellular carcinoma

Background

Hepatocellular carcinoma (a common kind of liver cancer) is the sixth most common cancer in the world. Transcatheter arterial chemoembolisation (TACE) (injecting agents into the feeding vessels of the tumour to reduce the blood supply to the tumour and kill the tumour) is the most common therapy for hepatocellular carcinoma, but the clinical outcome is poor. In recent years, the combination of TACE plus thermal ablation (killing the tumour cell by producing heat or cold) has shown better efficacy than TACE alone. However, evidence to prove the beneficial or harmful effect of the combination of TACE with ablation for people with hepatocellular carcinoma is still lacking.

Aim

We aimed to assess the beneficial and harmful effects of the combination of TACE with thermal ablation versus TACE alone for hepatocellular carcinoma.

Key results

We considered 135 records eligible for full‐text screening. We excluded 21 of these records because the interventions used were outside the scope of our review or the studies were not randomised clinical trials. We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, either from the study authors or through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants, based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies.

We identified five ongoing trials, by handsearching in clinical trial websites.

Conclusions

We found no confirmed randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma for inclusion in our review. Therefore, we cannot conclude anything on the treatment of hepatocellular carcinoma using TACE plus thermal ablation versus TACE alone.

Background

Description of the condition

Hepatocellular carcinoma is the most predominant form of primary liver cancer, accounting for approximately 90% of occurrences, and it represents an increasing serious health problem worldwide (Mohd 2013; Laursen 2014; National Center for Health Statistics (US) 2015). The pathogenesis of hepatocellular carcinoma is a highly complex process which usually occurs in the context of liver cirrhosis, mainly involving chronic inflammation injury and the accumulation of genetic alterations (Schulze 2016). Hepatocellular carcinoma is the sixth most common cancer and the second most common cancer‐related cause of death worldwide. Around 782,000 people are diagnosed and 746,000 die from hepatocellular carcinoma every year worldwide, with China accounting for about 50% of the total number of cancers and deaths (Torre 2015; Forner 2018). The incidence of hepatocellular carcinoma varies among different global regions. Approximately 80% of hepatocellular carcinomas occur in sub‐Saharan Africa and eastern Asia, due to the high prevalence of hepatitis B virus infection and the intake of aflatoxin B1, with an incidence of over 20 per 100,000 individuals (El‐Serag 2012). An intermediate hepatocellular carcinoma burden occurs in Mediterranean countries, with an incidence of 10 to 20 per 100,000 individuals. In America, the incidence is lower than 5 per 100,000 individuals (Mittal 2013). The main causes of hepatocellular carcinoma in Europe and America is hepatitis C virus infection and alcohol abuse (Trad 2017). Hepatocellular carcinoma incidence among men is four to eight times higher than among women (Yang 2014). Most hepatocellular carcinoma patients are older than 45 years (Llovet 2016).

The most prevalent staging system for hepatocellular carcinoma is the Barcelona Clinic Liver Cancer (BCLC) system which divides hepatocellular carcinoma into five stages based on the size and number of tumours, vascular invasion, and liver function (EASL‐EORTC 2012). The main risk factors are liver cirrhosis, infection with hepatitis B virus and C virus, intake of toxic substance (alcohol and aflatoxin B1), and metabolic syndromes (diabetes, obesity, non‐alcoholic fatty liver disease, and hereditary haemochromatosis). Approximately 80% of hepatocellular carcinoma develops in people with liver cirrhosis (Kew 2014). The hepatocellular carcinoma mortality among men with a high baseline body mass index is five times higher than among men with a normal body mass index (Forner 2018). Other risk factors include age, tobacco use, and coinfection of human immunodeficiency virus (HIV). Diagnosis of hepatocellular carcinoma is confirmed by either histopathological biopsy or imaging techniques (ultrasound, contrast‐enhanced computed tomography, or contrast‐enhanced magnetic resonance imaging (MRI)) according to the current practice guideline of the American Association for the Study of Liver Diseases (AASLD) (Bruix 2011).

The treatment for hepatocellular carcinoma can be divided into curative therapies and palliative therapies. Resection, liver transplantation, and locoregional ablation are radical therapies with the curative intention of prolonging survival. However, only 20% of hepatocellular carcinoma patients, mostly diagnosed by regular screening, may gain survival benefit from resection and liver transplantation (Abdel‐Rahman 2013). Curative ablation is recommended for patients with only two or three nodules which are less than 3 cm or a single nodule. The palliative therapies mainly involve transcatheter arterial chemoembolisation (TACE), sorafenib, and systemic treatment, with no, or moderate survival benefits (Oliveri 2011; Chacko 2016).

Description of the intervention

In this review, we planned to focus on the combination of TACE with sequential thermal ablation therapy. During this combined therapy, TACE is performed firstly for all baseline tumours, followed by thermal ablation on all baseline tumours or only tumours that remain active after TACE. Baseline tumours refer to all active tumours before TACE. Active tumours are defined as 'living' tumours, which show characteristic vascular features of hepatocellular carcinoma — arterial hyper‐vascularisation with washout in the portal venous system or the late phase at contrast‐enhanced computed tomography, or contrast‐enhanced MRI.

TACE is the most common treatment for hepatocellular carcinoma, which is recommended as the first‐line treatment for intermediate stage hepatocellular carcinoma, according to the BCLC staging system (EASL‐EORTC 2012). The mechanism of TACE consists of the injection of chemotherapeutic drugs, lipiodol and vascular occlusive agents into the hepatic artery; these can inhibit tumour growth, promote cell death, and maybe prolong survival (Oliveri 2011). The rationale for TACE is based on the concept that most of the blood supply of intra‐hepatic tumours is provided by the hepatic artery, while 75% of the blood flow of the normal liver parenchyma is supplied by the portal vein (Vogl 2003). Therefore, TACE can lead to selective necrosis of the liver tumour while it hardly affects normal liver parenchyma (Jaeger 1996). Alternatively, TACE can also be used to downsize a tumour or as a bridge to liver transplantation (Martin 2015).

Thermal ablation refers to the ablation therapies that induce irreversible cellular injury of tumour cells through heat mechanisms or cold mechanisms. Most kinds of ablation therapies are performed using a percutaneous approach, under real‐time contrast‐enhanced computed tomography, dynamic MRI, or ultrasound guidance. A puncture needle is used to lead the electrode into the target. After setting appropriate output power and duration, the electrode begins to produce heat or cold to surrounding tissue to induce complete necrosis (Ahmed 2011).

There are five main thermal ablation techniques (Goldberg 2003): radiofrequency ablation (Ahmed 2011), microwave ablation (Brace 2007; Lubner 2013; Poggi 2015), laser ablation (Ahmed 2011), ultrasound ablation (Wijlemans 2012), and cryoablation (Rubinsky 1990; Ahmed 2011)

Radiofrequency ablation is the most widely used and the most well‐studied thermal ablation, and it is regarded as the standard therapy for BCLC‐A tumours which are not suitable for surgery (EASL‐EORTC 2012). It has been proved to have a therapeutic efficacy similar to that of surgical resection or liver transplantation for hepatocellular carcinoma with a diameter within 3 cm (Zhu 2016). Radiofrequency ablation can induce complete necrosis of surrounding tissue by generating heat. The radiofrequency ablation technique also serves as a model for exploring the use of thermal ablation in clinical practice.

Microwave ablation can induce tumour cell death by microwave heating, which is generated by dielectric hysteresis (Ahmed 2011). Microwave ablation can reduce tumour tissue in a more efficient way by producing faster heating and higher temperatures compared to radiofrequency ablation (Brace 2007; Yang 2007). Furthermore, microwave ablation, compared to radiofrequency ablation, has better performance on overcoming heat sink effect (Ahmed 2011). However, microwave ablation is still a novel ablation technique; more details should be explored in further clinical practice.

Laser ablation is an ablative therapy that can induce electromagnetic heating to increase tissue temperatures to lethal levels by laser beam and results in complete necrosis of surrounding tissue (Ahmed 2011).

Ultrasound ablation therapy can concentrate intersecting beams of ultrasound on a target tumour through an acoustic lens and thus induce irreversible damage (Zhu 2013a).

Cryoablation destroys cells by the application of alternating freezing and thawing to induce irreversible cellular injury (Awad 2009; Song 2016a).

How the intervention might work

TACE is a palliative therapy, with a tumour response rate of 24% to 53% (Yang 2009). Generally, several sessions of TACE are needed to achieve a high necrosis rate and local tumour control (Satake 2008). Due to high toxicity and adverse effects of chemotherapeutic agents, repeated TACE may result in liver failure (Li 2010). Besides, the incomplete necrosis of the tumour after TACE may cause intra hepatic recurrence of malignancy (Wu 2005).

Thermal ablation is a minimally invasive and curative therapy, with a complete necrosis rate of 76% to 100% for small hepatocellular carcinoma (Morimoto 2010); and 30% to 70% for larger hepatocellular carcinoma (Livraghi 2000). In patients with early‐stage hepatocellular carcinoma (BCLC 0 or A) who are not suitable for resection, ablation therapy achieved five‐year survival rates of 50% to 70% (EASL‐EORTC 2012). The main advantages of thermal ablation include effective tumour ablation, preservation of maximal normal liver parenchyma, and low rates of complications (Yang 2009). The introduction of the mechanism of five types of thermal ablation therapies is shown below.

During radiofrequency ablation, an electrical circuit is created between a radiofrequency probe, the patient, and the grounding pads (Ahmed 2011). The alternating current leads to frictional agitation at the ionic level and heat generation around the probe (Corwin 2001). Dehydration and subsequent carbonisation of surrounding tissues would occur when the temperature is above 100°C (Poggi 2015).

Microwave ablation generates heat through a process known as dielectric hysteresis, in which polar molecules in tissue (primarily water) are forced to continuously realign with the oscillating electric field (Lubner 2013). Thus, the kinetic energy of reformed molecules and the temperature of tissue increase. Microwave power can produce extremely high temperatures (> 150 °C) and induce necrosis of tissue (Brace 2007).

Laser ablation treats the tumour by irradiating it with a laser beam, which is an efficient and precise energy source for tissue heating (Ahmed 2011).

Ultrasound ablation is a non‐invasive therapy. The main mechanism of ultrasound ablation is the thermal energy deposition by a focussed ultrasound beam. The targeted tissue absorbs a significant amount of energy from a highly directional ultrasound beam, resulting in elevation of temperature (Wijlemans 2012).

Cryoablation is an ablative technique which can induce protein denaturation, cellular dehydration and subsequent tissue necrosis by the application of extreme low temperatures to tumour tissue (Rubinsky 1990; Wu 2015).

The rationale of the combination of TACE and sequential ablation is that sequential ablation therapy can remedy the limitation of TACE alone. Firstly, ablation therapy can directly destroy tumour tissue, increase complete necrosis rate and produce a favourable prognosis (Li 2010); secondly, sequential ablation therapy reduces the time needed for interventional treatment, which reduces liver damage and improves quality of life (Li 2016). In addition, the combination of TACE and sequential ablation has synergistic effects on treating liver tumours. The occlusion of hepatic arteries achieved by TACE can reduce blood flow and decrease the heat sink effect, which is helpful for enlarging the ablation zone and achieving complete necrosis (Peng 2013).

Why it is important to do this review

Hepatic surgical resection is regarded as a curative therapy for hepatocellular carcinoma. However, only about 20% of hepatocellular carcinoma patients are candidates for surgical resection, which highlights the importance of effective non‐surgical therapies (Yin 2014). Until now, TACE is the most commonly used palliative therapy for hepatocellular carcinoma, but the effect remains unsatisfactory (Oliveri 2011). In recent years, the combination of TACE plus thermal ablation has shown better survival than TACE alone for people with hepatocellular carcinoma. Some studies have reported that the combination modality can confer a more favourable prognosis than TACE alone for different stages of hepatocellular carcinoma (Yang 2009; Azuma 2016; Hyun 2016; Song 2016a). However, there is still a lack of clear and compelling evidence on the beneficial or harmful effect of the combination of TACE and thermal ablation therapy. Therefore, we embarked on this Cochrane Review hoping to provide the best available level of evidence of the role of the combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma.

Objectives

To assess the beneficial and harmful effects of the combination of TACE plus thermal ablation compared with TACE alone in people with hepatocellular carcinoma.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include all randomised clinical trials comparing the combination of TACE and thermal ablation with TACE alone for hepatocellular carcinoma, irrespective of publication status or blinding.

Types of participants

All trial participants older than 18 years, with hepatocellular carcinoma, diagnosed by either histopathological biopsy or the radiological criteria in clinical practice guidelines.

Types of interventions

Experimental intervention

A combination of TACE plus thermal ablation. Thermal ablation can be performed with any of the following techniques: radiofrequency ablation, microwave ablation, laser ablation, ultrasound ablation, and cryoablation.

Control intervention

TACE alone

For both experimental group and control groups, we planned to include all TACE treatments irrespective of dosage and types of chemotherapeutic drugs, and vascular occlusive agents (Imai 2014).

Types of outcome measures

We planned to measure the outcomes listed below. We planned to base our primary conclusions on the outcome results at the longest follow‐up. We planned to include trials regardless of whether they reported on our outcomes of interest.

Primary outcomes

All‐cause mortality.
Progression‐free survival. This is defined as the period from the date of first treatment to the date of the first documented disease progression by either radiological assessment or liver biopsy or death caused by any reason, whichever happened first.
Proportion of participants with serious adverse events. We planned to use the definition of serious adverse events in the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997): that is, any untoward medical occurrence that results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or any medical event that might have jeopardised the patient, or required intervention to prevent it. All other adverse events were considered as non‐serious adverse events. We planned to accept all reported serious adverse events assessed at variable time points throughout the conduct of the review. If possible, we noted the period of reported serious adverse events and classified them as short‐term (primary observed period) and long‐term serious adverse events.

Secondary outcomes

Tumour response. We planned to evaluate the tumour response according to the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) guideline (Lencioni 2010), as follows.
- Complete response (CR): disappearance of any intratumoural arterial enhancement in all target lesions.
- Partial response (PR): at least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions.
- Progressive disease (PD): an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.
- Stable disease (SD): any cases that do not qualify for either partial response or progressive disease.

Whenever appropriate, we also planned to consider other criteria, such as World Health Organization (WHO) criteria (Kim 2015) and the Response Evaluation Criteria in Solid Tumours (RECIST) guideline (Therasse 2000). However, the mRECIST guideline was considered as the main tool.

Proportion of participants with adverse events not considered serious. We planned to accept all reported non‐serious adverse events assessed at variable time points throughout the conduct of the review. If possible, we planned to note the period of reported non‐serious adverse events and classify them as short‐term (primary observed period) and long‐term adverse events.
Health‐related quality of life as defined by the trial authors (short term: up to one year; medium term: one to five years; long term (primary time point): beyond five years).
Duration of hospital stay.

Search methods for identification of studies

Electronic searches

We performed electronic searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register (searched through the Cochrane Library; December 2020), The Cochrane Central Register of Controlled Trials (CENTRAL; 2020, issue 12) in the Cochrane Library, MEDLINE (PubMed; December 2020), Embase (www.embase.com; December 2020), LILACS (Bireme; 1982 to December 2020), Science Citation Index Expanded (Web of Science; 1900 to December 20209), and Conference Proceedings Citation Index‐Science (Web of Science; 1990 to December 2020). We also endeavoured to identify relevant RCTs in the China National Knowledge Infrastructure (CNKI) and Wanfang databases. Appendix 1 shows the search strategies with the time spans of the searches.

Searching other resources

We checked the reference lists of potentially relevant articles identified in the electronic searches. We also searched trial registration resources such as ClinicalTrials.gov, Chinese Clinical Trial Register (ChiCTR), and the World Health Organisation (WHO) International Clinical Trial Registry Platform (www.who.int/ictrp) to identify study protocols of the identified studies from the electronic searches and also to identify ongoing studies. We also handsearched grey literature sources, such as meeting abstracts and internal reports. We adapted the same or similar search terms to those used in the searching of English electronic databases.

During the selection of trials, whenever we identified observational studies of interest to the topic of this review (i.e. quasi‐randomised studies, cohort studies, case‐control studies, case reports, and case series) and also reporting on harms, we planned to discuss the data on harm in the review discussion part. We also planned to create a table with the extracted data on harm. In this way, we pay attention to late‐occurring or rare events which are often underreported or overlooked by trialists (Storebø 2018).

Data collection and analysis

Selection of studies

We merged all search results and removed duplicates by using reference management software. Two review authors (BZL and WL) independently examined titles and abstracts of the electronic search output to remove obviously irrelevant publications. After the initial assessment, we retrieved the full text of all potentially eligible articles, and we linked together multiple reports of the same trial.  Two review authors (BZL and WL) independently screened the full text to evaluate whether these trials met the inclusion criteria. We resolved disagreements on the eligibility of a trial by discussion. We consulted HC (the last author) or we wrote to the original trial investigators when necessary, to clarify trial eligibility. Then, we made a final decision on which trials fulfilled the inclusion criteria of our review. We did not blind our selection process regarding article information. We recorded the details of the whole screening process in a PRISMA flow chart. We also added information on the excluded studies in the 'Characteristics of excluded studies' table.

Data extraction and management

Two authors (BZL and YCZ) planned to independently extract the data from all included publications on the trials and complete the 'Characteristics of included studies' table. We planned to contact the authors of original trials whenever needed. We planned to resolve disagreement by discussion. We planned to consult HC (another review author), or we planned to write to the original trial investigators whenever needed. Two authors (HC and WL) planned to enter data into Review Manager 5. We planned to double‐check that the data had been entered correctly by comparing the data presented in the systematic review with those in the data extraction form, which we had pre‐piloted for the purpose of the review.

We planned to extract the following trial characteristics.

Source (e.g. author, year of publication, contact details, journal citation, trial registration, ethics committee approval)
Methods (e.g. trial design, total trial duration, sequence generation, allocation sequence concealment, blinding and other concerns about bias)
Participants (e.g. age, sex, country, number randomised, number lost to follow‐up/withdrawn, number analysed, inclusion criteria, exclusion criteria, diagnostic criteria)
Interventions (e.g. intervention, comparison)
Outcomes (for each outcome listed in the protocol, e.g. outcome definition and unit of measurement (if relevant), time points reported, scales, intensity)
Miscellaneous (e.g. funding for trial, a notable conflict of interests of trial authors).

Assessment of risk of bias in included studies

Two review authors (BZL and WL) planned to independently assess the risk of bias in the included studies. We planned to assess risk of bias by using the RoB 2 tool, according to Chapter 8 in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019a). We planned to use the following domains.

Domain 1: bias arising from the randomisation process;

Domain 2: bias due to deviations from intended interventions;

Domain 3: bias due to missing outcome data;

Domain 4: bias in measurement of the outcome;

Domain 5: bias in selection of the reported report.

For each domain, there are a series of signalling questions: 'Yes’, ‘Probably yes’, ‘Probably no’, ‘No’, and ‘No information’.

Based on the replies, we planned to reach a risk‐of‐bias judgement, and we assigned one of three levels to each domain: ‘low risk of bias’, ‘some concerns’, or ‘high risk of bias’, following the RoB 2 tool (Sterne 2019).

Overall risk of bias

The following definitions of risk of bias were considered.

Low risk of bias: the trial is judged to be at low risk of bias for all domains for this result.

Some concerns: the trial is judged to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain.

High risk of bias: the trial is judged to be at high risk of bias in at least one domain for this result; or the trial is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result.

We planned to present information in support of each response in the free‐text box alongside the signalling questions and judgements. Additionally, for domain 2, we planned to assess the effect of the assignment to the intervention.

In this review, we planned to assess the risk of bias in the following outcome results: all‐cause mortality; time to progression; serious adverse events; tumour response rate; and health‐related quality of life, all at the longest follow‐up.

Measures of treatment effect

For dichotomous variables, we planned to calculate the risk ratio (RR) and 95% confidence interval (CI) and Trial Sequential Analysis adjusted‐CI.

For continuous variables, we planned to use the mean difference (MD) (if all studies were made on the same scale) or the standardised mean difference (SMD) (if different scales were used) with 95% CI and Trial Sequential Analysis adjusted‐CI.

For time‐to‐event variables, we planned to use the methods of survival analysis and express the intervention effect as a hazard ratio (HR) with 95% Cl. If the logHR and their variance were not directly reported in reports, we planned to calculate them indirectly, following the methods introduced by Tierney 2007.

Unit of analysis issues

We planned to set the unit of analysis according to the methods mentioned in Chapter 6 and Chapter 23 in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019b; Higgins 2019c).

We planned to analyse data at the single randomised individual level (Higgins 2019b). In trials with a two‐parallel‐group design, we planned to compare the experimental intervention group versus the control group. In the trials with a parallel‐group design with more than two intervention groups, if relevant, we planned to compare separately each of the experimental groups with half of the control group if used within the same comparison (Higgins 2019c).

When only a subset of relevant participants was included in a trial, we planned to consider the trial only when the results were presented separately for the subgroup of interest for this review.

For cluster‐randomised trials, we planned to analyse data by using the average cluster size and an estimate of the intraclass correlation coefficient (ICC) and the design effect to calculate effective sample size (Higgins 2019b; Higgins 2019c).

For crossover trials, we planned to only include data from the first intervention period to avoid carry‐over effects (Higgins 2019a).

Dealing with missing data

We planned to contact the original investigators to request missing data; and we planned to extract all data for an intention‐to‐treat (ITT) analysis if data were available. Otherwise, we planned to perform available case analyses, which assume that data are missing at random. We planned to assess if this assumption was reasonable by collecting data on the number of participants excluded or lost to follow‐up, and the reasons for loss to follow‐up by treatment group, from each included study (as reported). We planned to address the potential impact of missing data on the findings of the review in the Discussion section.

Assessment of heterogeneity

We planned to assess clinical and methodological heterogeneity by carefully examining the characteristics and design of the included trials. We planned to assess the presence of clinical heterogeneity by comparing effect estimates in people with different BCLC stage of hepatocellular carcinoma, different Child‐Pugh Class of liver function, different criteria on assessment of tumour response and different follow‐up time. Different study designs and risk of bias may contribute to methodological heterogeneity.

We planned to explore statistical heterogeneity by the Chi² test with significance set at a P value of less than 0.10. In addition, we planned to access the degree of heterogeneity by using the I² statistic, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error.

Interpretation of I² is listed as follows.

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*

*The importance of the observed value of I² depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity, e.g. P value from the Chi² test, or a confidence interval for I².

Assessment of reporting biases

We planned to assess reporting bias by drawing funnel plots if ten or more trials were included.

Data synthesis

Meta‐analysis

We aimed to conduct this review following the instructions stated in Chapter 10 in Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2019). We planned to meta‐analyse data whenever possible. Otherwise, we planned to provide a summary of the trial results in a narrative way. We planned to perform the primary analyses by pooling the results of all eligible trials, regardless of their risk of bias. We planned to analyse data using the Review Manager 5 software (Review Manager 2014) and RevMan Web provided by Cochrane (RevMan Web 2019). We aimed to perform all meta‐analyses using the random‐effect model because we expected that the included trials would be heterogeneous. We planned to present dichotomous outcomes as RR with 95% CI. We planned to present continuous outcomes as MD or SMD, with 95% CI.

Subgroup analysis and investigation of heterogeneity

We aimed to assess differences between subgroups using the formal test for subgroup differences in Review Manager Web (RevMan Web 2019). We aimed to conduct the following subgroup analyses.

Trials at low risk of bias, at some concern, and at high risk of bias
Different ablation methods

Sensitivity analysis

We planned to perform sensitivity analyses by excluding studies at high risk of bias. Additionally, if cluster‐randomised studies were found, we planned to perform sensitivity analysis to investigate possible effects of the randomisation unit. We planned to assess the intervention effect on mortality at one, three, and five years. We planned to repeat our analyses with the fixed‐effect model.

We also planned to use Trial Sequential Analysis to assess imprecision for the following outcomes: all‐cause mortality; time to progression; serious adverse events; tumour response; and quality of life (Thorlund 2011; Castellini 2018; Gartlehner 2019).

Trial Sequential Analysis

To control random errors from sparse data and repeated significance testing, we planned to apply Trial Sequential Analysis in our meta‐analysis (Thorlund 2011; TSA 2011; Wetterslev 2017). Trial Sequential Analysis is a methodology that includes a combination of techniques, providing the threshold for a statistically significant treatment effect and the threshold for futility. Conclusions conducted by Trial Sequential Analysis indicate the potential to be more reliable than those using traditional meta‐analysis techniques (Thorlund 2011; Wetterslev 2017).

For dichotomous outcomes, we aimed to calculate the required meta‐analysis information size based on the event proportion in the control group; assumption of a plausible RR reduction of 20% or the RR reduction observed in the included trials at low risk of bias; a risk of type I error of 2.5% because of our three primary outcomes and 2.0% because of four secondary outcomes (Jakobsen 2014); a risk of type II error of 10%; and the assumed diversity of the meta‐analysis (Wetterslev 2009). For continuous outcomes, we aimed to calculate the required information size based on the SD observed in the control group of trials with low risk of bias and a minimal relevant difference of 50% of this SD, an alpha of 2.5%, a beta of 10%, and the diversity suggested by the trials in the meta‐analysis.

The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We aimed to add the trials according to the year of publication. If more than one trial was published during the same year, we planned to add trials alphabetically according to the last name of the first author. We aimed to construct trial sequential monitoring boundaries on the basis of the required information size (Wetterslev 2008; Thorlund 2011; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that does not reach the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may, perhaps, have been established and further trials may be superfluous. On the other hand, if the boundaries are not surpassed, it probably is necessary to continue conducting trials in order to detect or reject a certain intervention effect. That is determined by assessing if the cumulative Z‐curve crosses the trial sequential boundaries for futility.

Summary of findings and assessment of the certainty of the evidence

We aimed to create the Summary of findings tables using GRADEpro GDT software (GRADEpro GDT). We aimed to assess all‐cause mortality, progression‐free survival, serious adverse events, tumour response rate, and health‐related quality of life. We planned to provide a range of follow‐up, and median follow‐up, for all outcomes.

We aimed to use the GRADE approach to assess the certainty of evidence based on risk of bias, indirectness of evidence (population, intervention, control, outcomes), unexplained heterogeneity, inconsistency of results (including problems with subgroup analyses), imprecision of results, and a high probability of publication bias (Atkins 2004). The details are shown as follows:

(1) Risk of bias or limitations in the detailed design and implementation: the results of assessment of risk of bias by using RoB 2 tool in included RCTs were to be fed directly into the domain of 'Risk of bias' in GRADE. In particular, ‘low’ risk of bias would indicate ‘no limitation’; ‘some concerns’ would indicate either ‘no limitation’ or ‘serious limitation’; and ‘high’ risk of bias would indicate either ‘serious limitation’ or ‘very serious limitation’. We also planned to use our judgements to decide between alternative categories, depending on the likely magnitude of the potential biases. (2) Unexplained heterogeneity or inconsistency of results: when studies yield widely differing estimates of effect (heterogeneity or variability in results), investigators should look for robust explanations for that heterogeneity. (3) Indirectness of evidence: two types of indirectness are relevant. First, a review comparing the effectiveness of alternative interventions (say A and B) may find that randomised trials are available, but they have compared A with placebo and B with placebo. Second, a review may find randomised trials that meet eligibility criteria but address a restricted version of the main review question in terms of population, intervention, comparator or outcomes. (4) Imprecision of results: when studies include few participants or few events, and thus have wide confidence intervals, review authors can lower their rating of the certainty of the evidence. (5) High probability of publication bias: the certainty of evidence level may be downgraded if investigators fail to report studies on the basis of results (typically those that show no effect: publication bias) or outcomes (typically those that may be harmful or for which no effect was observed: selective outcome non‐reporting bias).

We planned to define the levels of evidence as 'high', 'moderate', 'low', or 'very low' certainty. These grades are defined as follows.

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Results of the search

Appendix 1 shows the search strategies. We identified 2803 records through the electronic database search of the Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 8), CENTRAL (n = 224), PubMed (n = 173), Embase (n = 825), LILACS (n = 2), Web of Science (n = 735), CNKI (n = 457), and Wanfang databases (n = 379).

After removing duplicates, we screened the titles and abstracts of 2224 records. In total, we considered 135 records eligible for full‐text screening. We excluded 21 of these records (see below). We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, neither from the study authors nor through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies (Omata 2010; EASL‐EORTC 2012; Heimbach 2018).

We identified five ongoing trials, by hand‐searching in clinical trial websites (see Characteristics of ongoing studies).

The details of our selection are shown in the flow diagram (Figure 1).

Study flow diagram Date of last search 22 December 2020

Included studies

We were unable to identify any randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma. Please see above.

Excluded studies

The reasons for exclusion of the 21 studies are shown in Characteristics of excluded studies. The main reasons for exclusion of the studies were that studies used interventions outside the scope of our review, or studies were not randomised clinical trials.

Risk of bias in included studies

There were no trials to assess.

Effects of interventions

We could not assess the beneficial or harmful effects of the combination of TACE with ablation versus TACE alone for people with hepatocellular carcinoma, as we could find no trials for inclusion.

Discussion

Summary of main results

Although we identified 114 potentially eligible studies, claiming to assess the beneficial or harmful effects or both combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma, these are all listed as awaiting classification and were not analysed.

There are a number of points that deserve attention and discussion.Firstly, there was absence of evidence of randomisation in the published reports, i.e. that the participants were indeed randomised. This means that the randomisation process was not described, or that the study authors did not provide details on the randomised trial design; there was no description of the methods used for generation of the allocation sequence and allocation concealment. Secondly, study authors, except for one, did not reply to our requests for missing information. We identified no multiple publications of the studies in order to check for required information. Furthermore, we could not obtain information from the study authors on the registration of the study protocol and on study approval by regional research ethics committees. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Thirdly, there was no mention of ethical approval of the studies with appropriate approval number and documentation of the ethical review board. Fourthly, none of the 113 studies conducted after 2005 or the one study from 2003 (Jin 2003) were registered at the protocol stage as per current requirement for randomised clinical trials. There was no study registration number or similar identification and no published protocol, and we were not able to find these studies in any trial registry. Fifthly, there seemed to be inappropriate inclusion of participants based on cancer stage and severity of liver disease, that contravenes guidelines from learned societies (Omata 2010; EASL‐EORTC 2012; Heimbach 2018). This could have resulted in significant harm for participants and raised important ethical issues. TACE should not be offered in patients with Child Pugh B8/B9 or Child Pugh C due to significant risk of deterioration of liver function and death (EASL‐EORTC 2012;Granito 2017). TACE should also not be first‐line treatment in patients with tumours greater than 3 cm, where therapies with curative intent such as resection, ablation, or liver transplantation are recommended. All these recommendations are clearly stated in the Asian Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), and AASLD guidelines (Omata 2010; EASL‐EORTC 2012; Heimbach 2018). In the studies awaiting classification, 6% to 23% of included patients had Child Pugh C cirrhosis, and there was no information on Child Pugh B8/B9 (apart from the fact that up to 50% of patients had Child Pugh B). Moreover, 25% of patients had TNM stage I (and should, therefore, have received a curative treatment, not TACE which is a palliative treatment (Sirivatanauksorn 2011)). Therefore, there are significant concerns on the selection of patients.

If our decision to list all 114 studies in studies awaiting classification is not considered appropriate in any way, we hereby invite trialists or journal editors to send us information that can prove or disprove that these studies were indeed randomised clinical trials. We wrote to the journals that published the 114 studies, and we did not hear back with useful information.

Overall completeness and applicability of evidence

We designed comprehensive and scientific search strategies. We searched in English, Spanish, and Chinese databases.

Quality of the evidence

We found no eligible randomised clinical trials evaluating the beneficial or harmful effects, or both, of the combination of TACE plus thermal ablation versus TACE alone, thus we cannot analyse the certainty (quality) of evidence.

Potential biases in the review process

The systematic review has been conducted following the corresponding protocol (Liu 2019a). The process of preparing this review was rigorous. We did a comprehensive search for eligible trials.

Agreements and disagreements with other studies or reviews

We found 15 meta‐analyses (Fan 2009; Fan 2011; Sun 2011; Lei 2013; Zhao 2013; Cao 2014; Gu 2014; Hu 2015; Wang 2016b; Katsanos 2017; Yang 2017; Zhao 2017; Liu 2018a; Xiong 2018a; Xiong 2018b) comparing the efficacy and safety of TACE plus radiofrequency ablation versus TACE alone. These 15 meta‐analyses were based on the same studies that we have identified during our trial selection. We have not included these studies in our review for the reasons listed above.

Authors' conclusions

Implications for practice.

No eligible randomised clinical trials assessing the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone were included into this review. Therefore, our results did not show or reject the efficiency of any treatment strategy for hepatocellular carcinoma.

Implications for research.

Large prospectively registered trials with rigorous methods comparing the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone in hepatocellular carcinoma are needed. Such randomised clinical trials should be designed according to the SPIRIT statement (Chan 2013); registered in a WHO data register; with obtained full ethical approval; and reported according to the CONSORT statement (Schulz 2010). Such trials should be conducted in people who are not eligible for treatments with curative intent (liver transplantation, ablation surgical resection), who have sufficient liver reserve as assessed by the Child Pugh score, and do not have extrahepatic metastases. Therefore, future trial participants must be classified at Barcelona Clinic Liver Cancer Stage B (intermediate stage) (BCLC‐B) or an equivalent, with other staging systems.

In view of the large number of studies we have identified as potentially problematic, there is an urgent need for validated tools to assist systematic review teams in identifying problematic studies. Our approach to assessing the 114 studies identified through electronic searching reinforces the importance of systematic review teams carefully appraising the studies they identify in order to reduce the impact of potentially problematic studies on evidence used to inform healthcare decision‐making.

History

Protocol first published: Issue 5, 2019

Acknowledgements

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, the Capital Region, Rigshospitalet, Copenhagen, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

Authors' Disclaimer: The presented information within this review covers the current status of published studies on the topic, as assessed by our review team. We welcome journals or authors of the studies to help us in further classification of the studies, and on basis of this to decide whether to retract the studies or not.

Peer reviewers: Karl Heinz Weiss, Germany; Vanja Giljaca, UK Contact editors: Stefano Trastulli, Italy; Luit Penninga, Denmark Sign‐off editor: Christian Gluud, Denmark Methodological Editor: Theresa Moore, UK Methods Support Unit Lead and Statistical Editor: Kerry Dwan, UK Cochrane Abdomen and Endocrine Network Editor: Rachel Richardson, UK

Appendices

Appendix 1. Search Strategies

Database	Time span	Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register (through the Cochrane Library)	2020, Issue 12	(((hepat* or liver) and (carcinom* or cancer* or neoplasm* or malign* or tumo)) or hepatocellular caricoma or HCC) AND (((thermal or (radiofrequenc or radio‐frequenc* or radio frequenc) or microwave or laser or high intensity focused ultrasound or cryo) AND (ablati or therap* or treat* or suger* or coag)) OR cryoablati or cryosuger* or RFA or RFTA or RFT or RFCA or MWA or HIFU) AND (((transcatheter or transarterial) and chemoemboli*) or TACE)
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library	2020, Issue 12	#1 MeSH descriptor: [Carcinoma, Hepatocellular] explode all trees #2 MeSH descriptor: [Liver Neoplasms] explode all trees #3 (((hepat* or liver) and (carcinom* or cancer* or neoplasm* or malign* or tumo)) or hepatocellular caricoma or HCC) #4 #1 or #2 or #3 #5 MeSH descriptor: [Catheter Ablation] explode all trees #6 MeSH descriptor: [Ablation Techniques ] explode all trees #7 MeSH descriptor: [Cryosurgery] explode all trees #8 MeSH descriptor: [Laser Therapy ] explode all trees #9 MeSH descriptor: [High‐Intensity Focused Ultrasound Ablation] explode all trees #10 ((thermal or (radiofrequenc or radio‐frequenc* or radio frequenc) or microwave or laser or high intensity focused ultrasound or cryo) AND (ablati or therap* or treat* or suger* or coag)) OR cryoablati or cryosuger* or RFA or RFTA or RFT or RFCA or MWA or HIFU #11 #5 or #6 or #7or #8 or #9 or #10 #12 MeSH descriptor [Embolization, Therapeutic] explode all trees #13 ((transcatheter or transarterial) and chemoemboli*) orTACE #14 #12 or #13 #15 #4 and #11 and #14 in trials
MEDLINE (PubMed)	1946 to December 2020	((((hepatocellular OR hepato‐cellular OR hepatic OR liver) and (carcinom* OR cancer OR neoplasm* OR malign* OR tumor)) OR hepatocellular carcinoma OR HCC) OR Carcinoma, Hepatocellular[MeSH] OR Liver Neoplasms[MeSH]) and ((((thermal OR (radiofrequenc* OR radio‐frequenc* OR radio frequenc) OR microwave OR laser OR high intensity focused ultrasound) AND (ablati OR therapy OR therapies OR treat* OR suger* OR coag)) OR cryoablati OR RFA OR rfta OR RFT OR rfca OR MWA OR hifu) OR Catheter Ablation[MeSH] OR Ablation Techniques[MeSH] OR Cryosurgery[MeSH] OR Laser Therapy[MeSH] OR High Intensity Focused Ultrasound Ablation[MeSH]) and ((((transcatheter OR transarterial) and chemoemboli*) OR TACE) OR Chemoembolization, Therapeutic[MeSH]) and ((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR clinical trials as topic[mesh:noexp] OR randomly[tiab] OR trial[ti]) NOT (animals[mh] NOT humans[mh]))
Embase (www.embase.com)	1974 to December 2020	#1 'liver cell carcinoma'/exp #2 ((hepat* or liver) and (carcinom* or cancer* or neoplasm* or malign* or tumo)) or ‘hepatocellular caricoma’ or HCC #3 #1 or #2 #4 'radiofrequency ablation'/exp #5 'catheter ablation'/exp #6 'microwave thermotherapy'/exp #7 'cryoablation'/exp #8 'laser surgery'/exp #9 'high intensity focused ultrasound'/exp #10 thermal or (radiofrequenc or radio‐frequenc* or radio frequenc) or microwave or laser or ‘high intensity focused ultrasound’ or cryo* #11 ablation* or therap* or treat* or suger* or coag* #12 #10 and #11 #13 cryoablati* or cryosuger* or RFA or RFTA or RFT or RFCA or MWA or HIFU #14 #4 or #5 or #6 or #7 or #8 or #9 or #12 or #13 #15 'chemoembolization'/exp #16 ((transcatheter or transarterial) and chemoemboli) or TACE #17 #15 or #16 #18 #3 and #14 and #17 #19 random or blind* or placebo* or 'meta‐analysis' #20 #18 and #19
LILACS (Bireme)	1982 to December 2020	(((hepat$ or liver) and (carcinom$ or cancer$ or neoplasm$ or malign$ or tumo$)) or hepatocellular caricoma or HCC) AND (((thermal or (radiofrequenc$ or radio‐frequenc$ or radio frequenc$) or microwave or laser$ or high intensity focused ultrasound or cryo$) [Words] and (ablati$ or therap$ or treat$ or suger$ or coag$)) OR cryoablati$ or cryosuger$ or RFA or RFTA or RFT or RFCA or MWA or HIFU) [Words] and (((transcatheter or transarterial) and chemoemboli$) or TACE) [Words]
Science Citation Index Expanded (Web of Science)	1900 to December 2020	#1 TS=(((hepat* or liver) and (carcinom* or cancer* or neoplasm* or malign* or tumo)) or hepatocellular caricoma or HCC) #2 TS=(thermal or (radiofrequenc or radio‐frequenc* or radio frequenc) or microwave or laser or high intensity focused ultrasound or cryo) #3 TS=(ablati or therap* or treat* or suger* or coag) #4 #2 AND #3 #5 TS=(cryoablati or cryosuger* or RFA or RFTA or RFT or RFCA or MWA or HIFU) #6 #4 OR #5 #7 TS=(((transcatheter or transarterial) and chemoemboli) or TACE) #8 TS=(random OR blind* OR placebo* OR meta‐analysis) #9 #1 AND #6 AND #7 AND #8
Conference Proceedings Citation Index–Science (Web of Science)	1990 to December 2020	#1 TS=(((hepat* or liver) and (carcinom* or cancer* or neoplasm* or malign* or tumo)) or hepatocellular caricoma or HCC) #2 TS=(thermal or (radiofrequenc or radio‐frequenc* or radio frequenc) or microwave or laser or high intensity focused ultrasound or cryo) #3 TS=(ablati or therap* or treat* or suger* or coag) #4 #2 AND #3 #5 TS=(cryoablati or cryosuger* or RFA or RFTA or RFT or RFCA or MWA or HIFU) #6 #4 OR #5 #7 TS=(((transcatheter or transarterial) and chemoemboli) or TACE) #8 TS=(random OR blind* OR placebo* OR meta‐analysis) #9 #1 AND #6 AND #7 AND #8
China National Knowledge Infrastructure	1994 to December 2020	TI=('TACE' + '肝动脉化疗栓塞' + '栓塞') AND TI=('热消融' + '消融' + '射频消融' + 'RFA' + '微波消融' + 'MWA' + '氩氦刀消融' + '冷冻消融' + 'HIFU' + '高强度聚焦超声' + '超声消融' + '激光消融') AND TI=('肝癌' + '肝细胞癌') AND (AB=('随机' + '随机对照') OR FT=('随机' + '随机对照'))
Wanfang	1998 to December 2020	主题: (TACE + "肝动脉栓塞" + "肝动脉化疗栓塞") * ("热消融" + "射频消融" + RFA + "微波消融" + MWA + "氩氦刀消融" + "冷冻消融" + HIFU + "高强度聚焦超声" + "超声消融" + "激光消融") * ("肝癌" + "肝细胞癌") * ("随机" + "随机对照")

Study	Reason for exclusion
Chen 2014	Intervention not of interest to our review
Chen 2015	Not an RCT
Hou 2017	Intervention not of interest to our review
Hu 2010	Intervention not of interest to our review
Huang 2015b	Intervention not of interest to our review
Kong 2015	Intervention not of interest to our review
Li 2013a	Not an RCT
Li 2013b	Intervention not of interest to our review
Li 2015b	Intervention not of interest to our review
Liu 2007	Intervention not of interest to our review
Liu 2015	Intervention not of interest to our review
Liu 2016b	Intervention not of interest to our review
Lu 2015	Intervention not of interest to our review
Sha 2012	Intervention not of interest to our review
Wang 2011	Intervention not of interest to our review
Wang 2016a	Intervention not of interest to our review
Wu 2006	Not a RCT
Wu 2011a	Not an RCT
Wu 2017a	Intervention not of interest to our review
Xiang 2007	Intervention not of interest to our review
Yang 2016	Intervention not of interest to our review

Methods	Study design: randomised clinical trial Study duration: July 2010 to June 2012 Setting: hospital
Participants	Number of participants: 70 Inclusion criteria: diagnosed as HCC; BCLC B stage Age (mean ± SD, range ): TACE + RFA: 56.97 ± 7.41 years, 21‐73 years; TACE alone: 56.58 ± 8.66 years, 21‐74 years Male (n/total): TACE + RFA: 30/35; TACE alone: 29/35
Interventions	TACE + RFA group (n = 35): TACE: TACE comprised of hepatic arterial infusion chemotherapy and hepatic artery embolisation Chemotherapeutic drugs: theprubicin and oxaliplatin RFA: CT‐guided Control group (n = 35): TACE comprised of hepatic arterial infusion chemotherapy and hepatic artery embolisation Chemotherapeutic drugs: theprubicin and oxaliplatin
Outcomes	Tumour response: measured by contrast‐enhanced CT at 1 month after treatment Survival rates: measured at 1 year after treatment Adverse events Liver function: blood testing
Notes	Country of study: China Source of funding: none There was insufficient information available to satisfactorily determine the method of randomisation and the study data could not be verified. We have attempted to contact the study authors for more information, but so far, we have not been successful in doing this.

Study name	Transarterial chemoembolization (TACE) with or without sequential cryoablation in hepatocellular carcinoma of BCLC B: a multicentral randomised controlled trial
Methods	Interventional study
Participants	Inclusion criteria: 1. CT, MRI, and AFP combined with clinical or pathological diagnosis of hepatocellular carcinoma 2. Prior informed consent; be able to follow the visit/treatment rules according to the research programmes 3. Generally in good condition, adequate bone marrow, liver and renal function 4. ECOG Performance Status of 0‐2 5. Advanced stage HCC/BCLC B stage 6. Hepatitis B history or HBsAg positive 7. Patients without previous surgery, local‐regional therapies (radiofrequency ablation, etc.), or liver transplantation 8. Aged 18 to 65 years 9. Child Pugh class A/B (=< 7) 10. Baseline laboratory tests meeting the following criteria: platelet count >= 100 * 10 ^ 9/L; ALT and AST < 3 * upper limit of normal; BUN and creatinine < 1.5 * upper limit of normal; INR < 1.5, or PT < 4 seconds above control. ALB >= 30g/L; total bilirubin =< 34 mmol/L Exclusion criteria： 1. Pregnant or lactating women 2. Extrahepatic metastasis, or tumour thrombosis invasive venous system 3. Any contraindications for hepatic embolisation procedures (known renal failure/insufficiency requiring hemo‐or peritoneal dialysis) 4. Patients with prior malignancy were ineligible for the study, with the exception of those who had been disease‐free for longer than 5 years 5. Patients with liver transplantation
Interventions	Group A: Transarterial chemoembolisation Group B: Transarterial chemoembolisation (TACE) with sequential cryoablation
Outcomes	3‐year overall survival rate Postoperative complication Time to progression Distant metastasis rate
Starting date	2016‐04‐01
Contact information
Notes

Study name	Treatment of BCLC medium‐term hepatocellular carcinoma (HCC) of randomised controlled study of conventional TACE sequential microwave ablation (MWA) and conventional TACE alone
Methods	Parallel study
Participants	Subjects who meet the following criteria can be included in this study: 1. Gender, age 18‐70 (inclusive) 2. HCC meets the clinical diagnostic criteria of AASLD or EASL 3. Subjects were not willing to have surgical excision 4. BCLC medium liver cancer, numbers of tumours less than 5, maximum diameter is less than 10 cm 5. Good liver reserve function (Child‐Pugh A level) 6. The ECOG score is 0. Exclusion criteria: 1. Waiting for surgical resection or liver transplantation 2. Visible portal vein, hepatic vein, bile duct invasion 3. Extrahepatic metastasis 4. History of liver cancer treatment (transplantation, excision, TACE, ablation, radiotherapy) 5. Uncorrected clotting disorder (platelet count 50 x 109/L or thrombin activity < 50%) 6. Normal blood flow results in normal range 7. Unstable coronary artery disease or recent myocardial infarction (within 1 year) 8. Echocardiography of left ventricular ejection fraction < 50% 9. Active infection requiring antibiotic treatment 10. Current anticoagulation therapy or have known haemorrhagic disease 11. Renal insufficiency (serum creatinine > 176.8 mu mol/L) 12. AST and/or ALT > 3 times normal limit 13. Pregnant or lactating subjects, women of childbearing age receiving a serum pregnancy test within 72 hours of the start of treatment 14. Allergy to known iodine contrast agents
Interventions	Experimental group: TACE + MWA Control group: TACE
Outcomes	Safety and efficacy
Starting date	2017‐12‐06
Contact information	zhengjiasheng6@163.com
Notes

Study name	Combine TACE and RFA versus TACE alone for HCC with PVTT (CORTT)
Methods	Interventional (clinical trial)
Participants	Inclusion Criteria: HCC with portal vein tumour thrombus in the first or second branch Refused sorafenib or could not tolerate the adverse effect of sorafenib A solitary HCC ≤ 5.0 cm in diameter, or multiple HCC ≤ 3 lesions, each ≤ 5.0 cm in diameter Eastern Cooperative Oncology Group Performance Status 0‐1 Child‐Pugh Score ≤ 8 Platelet counts of > 60,000/mm³, haemoglobin > 8.5 g/dL, prothrombin time prolonged < 6s Albumin > 2.8 g/dL, total bilirubin < 51.3 umol/L; alanine aminotransferase (ALT) and aspartate transaminase（AST) < 5 times of upper limit Signed informed consent Exclusion Criteria: Presence of extrahepatic metastasis except lymph node metastasis The blood supply of tumour lesions is absolutely poor or arterial‐venous shunt that TACE can not be performed Uncontrolled or refractory ascites, ongoing variceal bleeding or encephalopathy Severe heart, brain or kidney diseases Previous or concurrent cancer that is distinct in primary site or histology from HCC Pregnant women or lactating women
Interventions	Experimental: TACE‐RFA 2 sessions of TACE first, RFA for residual viable tumours and PVTT within 1 month Active Comparator: TACE alone Repeated TACE and 1 to 2 months interval between two sessions of TACE
Outcomes	Primary outcome measures: Overall survival rates [time frame: 1 year] Secondary outcome measures: Progression‐free survival rates [time frame: 6 months] Response rate of PVTT [time frame: 6 months] Number of participants with adverse events [time frame: 1 month]
Starting date	October 2014
Contact information	Ming Zhao, doctor +86 020 87343272zhaoming@sysucc.org.cn
Notes

Study name	TACE + RFA versus TACE alone for intermediate‐stage hepatocellular carcinoma
Methods	Experimental: TACE‐RFA 1‐2 sessions of TACE treatment, then followed by RFA treatment
Participants	Inclusion Criteria: Multiple HCC (2‐3 lesions), largest lesion 3‐7 cm in diameter, or multiple HCC (4‐10 lesions), each ≤ 7 cm in diameter No vascular invasion or extrahepatic metastases Eastern Cooperative Oncology Group Performance Status 0‐1 Child‐Pugh Stage A or B Treatment‐naive Exclusion Criteria: Platelet counts of < 40 × 109/L，prothrombin time activity < 40% Albumin > 2.8 g/dL, total bilirubin < 51.3 umol/L; alanine aminotransferase (ALT) and aspartate transaminase（AST）< 5 times of upper limit No evaluable target lesions Uncontrolled or refractory ascites, ongoing variceal bleeding or encephalopathy Severe heart, brain or kidney diseases Previous or concurrent cancer that is distinct in primary site or histology from HCC Pregnant women or lactating women Be allergic to adriamycin, lobaplatin, mitomycin and iodised oil
Interventions	Experimental: TACE‐RFA 1‐2 sessions of TACE treatment, then followed by RFA treatment Active Comparator: TACE alone TACE treatment several times until tumour progresses to advanced stage
Outcomes	Primary outcome measures: Overall survival rate [time frame: 3 years] Secondary outcome measures : Tumour progression rate [time frame: 2 years] Tumour progress to advanced‐stage rate [time frame: 2 years] Hepatic dysfunction rate [time frame: 2 years] Adverse event rate [time frame: 3 years]
Starting date	April 2015
Contact information	Contact: Ming Zhao, doctor +86 020 87343272, zhaoming@sysucc.org.cn Contact: Tao Pan, doctor +862087343271, pantao0909@hotmail.com
Notes

Study name	Single session combined locoregional therapies for hepatocellular carcinoma
Methods	Allocation: Randomised Intervention model: Parallel assignment Masking: None (open‐label)
Participants	Inclusion Criteria: Child classification A or B Serum albumin ≥ 3 gm/L Serum bilirubin < 2.5 mg/dL Platelet count ≥ 70,000 mm³ INR ≤ 1.6 Serum creatinine < 2 mg/dL Tumour size more than 4 cm and confined to one lobe of the liver Exclusion Criteria: Patients with portal vein thrombosis A technically inaccessible hepatic artery Metastatic HCC More than three lesions Lesions in close proximity to the portal vein, inferior vena cava, or gallbladder were excluded from the study.
Interventions	(1) Active comparator: Transarterial chemoembolisation (TACE) (2) Experimental: Radiofrequency ablation with TACE (3) Experimental: Microwave ablation combined with TACE
Outcomes	Number of patients with successful ablation [time frame: 3 months]
Starting date	January 2015
Contact information	Sherief Abd‐Elsalam 00201000040794, mailto:Sherif_tropical%40yahoo.com?subject=NCT02646137, Combined TACE and RF, Single Session Combined Locoregional Therapies for Hepatocellular Carcinoma
Notes	None

PERMALINK

The combination of transcatheter arterial chemoembolisation (TACE) and thermal ablation versus TACE alone for hepatocellular carcinoma

BoZhi Liu

YongChao Zhang

Hui Chen

Wei Li

Emmanuel Tsochatzis

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Experimental intervention

Control intervention

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Overall risk of bias

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Meta‐analysis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Trial Sequential Analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

Effects of interventions

Discussion

Summary of main results

Overall completeness and applicability of evidence

Quality of the evidence

Potential biases in the review process

Agreements and disagreements with other studies or reviews

Authors' conclusions

Implications for practice.

Implications for research.

History

Acknowledgements

Appendices

Appendix 1. Search Strategies

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting classification [ordered by study ID]

Ai 2019.

An 2017.

Bao 2020.

Bian 2020.

Chen 2020.