Microwave coagulation for liver metastases

Abstract

Background

Liver metastases (i.e. secondary hepatic malignancies) are significantly more common than primary liver cancer. Long‐term survival after radical surgical treatment is approximately 50%. For people in whom resection for cure is not feasible, other treatments must be considered. One treatment option is microwave coagulation utilising electromagnetic waves. It involves placing an electrode into a lesion under ultrasound or computed tomography guidance.

Objectives

To evaluate the beneficial and harmful effects of microwave coagulation versus no intervention, other ablation methods, or systemic treatments in people with liver metastases regardless of the location of the primary tumour.

Search methods

We used standard, extensive Cochrane search methods. The latest date of search was 14 April 2023.

Selection criteria

Randomised clinical trials assessing beneficial or harmful effects of microwave coagulation and its comparators in people with liver metastases, irrespective of the location of the primary tumour. We included trials no matter the outcomes reported.

Data collection and analysis

We followed standard Cochrane methodological procedures. Our primary outcomes were: all‐cause mortality at the last follow‐up and time to mortality; health‐related quality of life (HRQoL); and any adverse events or complications. Our secondary outcomes were: cancer mortality; disease‐free survival; failure to clear liver metastases; recurrence of liver metastases; time to progression of liver metastases; and tumour response measures. We used risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI) to present the results. Two review authors independently extracted data and assessed the risk of bias using the Cochrane RoB 1 tool. We used GRADE methodology to assess the certainty of the evidence.

Main results

Three randomised clinical trials fulfilled the inclusion criteria. The control interventions differed in the three trials; therefore, meta‐analyses were not possible. The trials were at high risk of bias. The certainty of evidence of the assessed outcomes in the three comparisons was very low. Data on our prespecified outcomes were either missing or not reported.

Microwave coagulation plus conventional transarterial chemoembolisation (TACE) versus conventional TACE alone

One trial, conducted in China, randomised 50 participants (mean age 60 years, 76% males) with liver metastases from various primary sites. Authors reported that the follow‐up period was at least one month. The trial reported adverse events or complications in the experimental group only and for tumour response measures. There were no dropouts in the trial. The trial did not report on any other outcomes.

Microwave ablation versus conventional surgery

One trial, conducted in Japan, randomised 40 participants (mean age 61 years, 53% males) with multiple liver metastases of colorectal cancer. Ten participants were excluded after randomisation (six from the experimental and four from the control group); thus, the trial analyses included 30 participants. Follow‐up was three years. The reported number of deaths from all causes was 9/14 included participants in the microwave group versus 12/16 included participants in the conventional surgery group. The mean overall survival was 27 months in the microwave ablation and 25 months in the conventional surgery group. The three‐year overall survival was 14% with microwave ablation and 23% with conventional surgery, resulting in an HR of 0.91 (95% CI 0.39 to 2.15). The reported frequency of adverse events or complications was comparable between the two groups, except for the required blood transfusion, which was more common in the conventional surgery group. There was no intervention‐related mortality. Disease‐free survival was 11.3 months in the microwave ablationgroup and 13.3 months in the conventional surgery group. The trial did not report on HRQoL.

Microwave ablation versus radiofrequency ablation

One trial, conducted in Germany, randomised 50 participants (mean age 62.8 years, 46% males) who were followed for 24 months. Two‐year mortality showed an RR of 0.62 (95% CI 0.26 to 1.47). The trial reported that, by two years, 76.9% of participants in the microwave ablationgroup and 62.5% of participants in the radiofrequency ablation group survived (HR 0.63, 95% CI 0.23 to 1.73). The trial reported no deaths or major complications during the procedures in either group. There were two minor complications only in the radiofrequency ablation group (RR 0.19, 95% CI 0.01 to 3.67). The trial reported technical efficacy in 100% of procedures in both groups. Distant recurrence was reported for 10 participants in the microwave ablation group and nine participants in the radiofrequency ablation group (RR 1.03, 95% CI 0.50 to 2.08). No participant in the microwave ablation group demonstrated local progression at 12 months, while that occurred in two participants in the radiofrequency ablation group (RR 0.19, 95% CI 0.01 to 3.67). The trial did not report on HRQoL.

One trial reported partial support by Medicor (MMS Medicor Medical Supplies GmbH, Kerpen, Germany) for statistical analysis. The remaining two trials did not provide information on funding.

We identified four ongoing trials.

Authors' conclusions

The evidence is very uncertain about the effect of microwave ablation in addition to conventional TACE compared with conventional TACE alone on adverse events or complications. We do not know if microwave ablation compared with conventional surgery may have little to no effect on all‐cause mortality. We do not know the effect of microwave ablation compared with radiofrequency ablation on all‐cause mortality and adverse events or complications either.

Data on all‐cause mortality and time to mortality, HRQoL, adverse events or complications, cancer mortality, disease‐free survival, failure to clear liver metastases, recurrence of liver metastases, time to progression of liver metastases, and tumour response measures were either insufficient or were lacking.

In light of the current inconclusive evidence and the substantial gaps in data, the pursuit of additional good‐quality, large randomised clinical trials is not only justified but also essential to elucidate the efficacy and comparative benefits of microwave ablation in relation to various interventions for liver metastases.

The current version of the review, in comparison to the previous one, incorporates two new trials in two additional microwave ablation comparisons: 1. in addition to conventional TACE versus conventional TACE alone and 2. versus radiofrequency ablation.

Plain language summary

Microwave coagulation for liver metastases

Key messages

– We do not know whether microwave coagulation, added to another method of destroying cancer cells given directly to the liver (conventional transarterial chemoembolisation (TACE)), as compared with TACE alone, has benefit in terms of side effects or complications.

– We do not know whether microwave coagulation compared with conventional surgery or another method of destroying cancer cells (radiofrequency ablation) has benefit in terms of death, longer life, and side effects or complications.

What are liver metastases and microwave coagulation?

Liver metastases are new cancer sites that spread to other parts of the body. They commonly originate from cancers of the lung, stomach, colon (large intestine), rectum, and endometrium (lining of the womb). There are different ways to treat liver metastases in people in whom resection (surgical removal of the cancer) for cure is not feasible. One method, microwave ablation, requires placing a special electrode near the cancer site, which destroys surrounding cancer cells using electromagnetic waves.

What did we want to find out?

We wanted to find out if microwave ablation provides benefit over no intervention, other methods of destroying cancer cells given directly to the liver, or other types of treatments working throughout the whole body, when applied to people with liver metastases, regardless of the location of the primary cancer. We looked at the likelihood of death, how long people lived, whether it was possible to eliminate metastases, how often tumours returned, whether disease worsened, the quality of life in terms of health changes, and whether any side effects occurred.

What did we do?

We searched medical databases for randomised trials comparing microwave ablation with no intervention or other types of treatment of liver metastases. In a randomised trial, participants are allocated at random to the study treatments.

What did we find?

We found three trials, all conducted in upper‐middle and high‐income countries.

One study in China allocated 50 people to microwave ablation plus conventional TACE versus conventional TACE alone. In conventional TACE, a mixture of a drug toxic for cancer cells and a substance blocking blood vessels is injected directly to the artery feeding the tumour to destroy and close it. The study was very uncertain about the effect of microwave ablation plus conventional TACE on decreasing the size of the tumour. It reported side effects in the microwave ablation group only, such as fever, mild stomach pain, signs of mild liver inflammation or damaged, and mild fluid accumulation in the abdomen. Authors did not report how many people died, whether quality of life improved after treatment, whether people lived longer, whether metastases were eliminated, and whether cancer returned.

One study in Japan allocated 40 people to microwave ablation versus conventional surgery. The trial reported that the proportion of people surviving three years later was similar in both groups. People lived for similar periods of time (about 27 months with microwave ablation and 25 months with conventional surgery). The frequency of side effects or complications was similar between treatments, but people in the conventional surgery group more frequently required blood transfusion. The trial did not provide data on quality of life, whether metastases were eliminated, and whether cancer returned.

One study in Germany allocated 50 people to microwave ablation versus another method of destroying cancer cells (using radiofrequency waves called radiofrequency ablation). The study reported that the proportion of people dying was similar in both groups. Comparable numbers of people in both groups lived for one, two, and three years. There were two minor complications in the radiofrequency ablation group. In the microwave ablation group, cancer did not return to the same area after 12 months in any participants. However, in the radiofrequency ablation group, cancer returned to the same area in two people. Cancer appeared in a different area of the body in 10 people in the microwave ablation group and nine people in the radiofrequency ablation group. The trial did not report on quality of life, time to death, and whether metastases were eliminated.

Further randomised clinical trials are needed to strengthen the evidence on the effect of microwave ablation compared with treatments described above. We found no evidence for the comparison of microwave ablation with other methods of destroying cancer cells and treatments working throughout the whole body.

What are the limitations of the evidence?

Our confidence in the results is limited because none of the trials clearly reported their methods, or whether trial participants knew the treatment received. We still lack evidence on the effect of microwave ablation in addition to conventional TACE as compared with conventional TACE alone on death, quality of life, living longer, eliminating metastases, cancer returning, as well as on the effect of microwave ablation compared to conventional surgery and radiofrequency ablation on quality of life, eliminating metastases, and cancer returning.

How up to date is this evidence?

The evidence is up to date to 14 April 2023.

Summary of findings

Summary of findings 1. Microwave coagulation in addition to conventional transarterial chemoembolisation versus conventional transarterial chemoembolisation alone.

Microwave coagulation in addition to conventional transarterial chemoembolisation (TACE) versus conventional TACE alone
Patient or population: people with liver metastases Settings: hospitalised Intervention: microwave coagulation in addition to conventional TACE Comparison: conventional TACE alone
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional surgery	Microwave coagulation
All‐cause mortality	—		—	—	—	Outcome not reported
Time to mortality	—		—	—	—	Outcome not reported
Health‐related quality of life	—		—	—	—	Outcome not reported
Any adverse events or complications Follow‐up: ≥ 4 weeks	—		—	50 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	Adverse events or complications were provided for the experimental group only: fever (19 participants), mild right upper abdomen pain (9), mild serum transaminase elevation (8), reactive mild ascites (3), acute heart function failure (1), severe biliary infection (1), sepsis (1) It is unclear if there were no adverse events or complications in the control group or they were not reported.
Disease‐free survival	—		—	—	—	Outcome not reported
Failure to clear liver metastases	—		—	—	—	Outcome not reported
Recurrence of liver metastases	—		—	—	—	Outcome not reported
*The risk in the experimental group (corresponding risk and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised clinical trial; TACE: transarterial chemoembolisation.
GRADE Working Group grades of evidence 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 are very uncertain about the estimate: the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded two levels due to within‐study risk of bias: the trial did not describe randomisation, allocation concealment, or blinding; and provided insufficient information regarding selective outcome reporting.
^b Downgraded one level due to indirectness: most participants included in the trial represented only subgroups of people with liver metastases (i.e. cancers of gastrointestinal tract and lungs).
^c We could not assess imprecision according to CIs due to lack of information for the control group.

Summary of findings 2. Microwave coagulation versus conventional surgery.

Microwave coagulation versus conventional surgery
Patient or population: people with liver metastases Settings: hospitalised Intervention: microwave coagulation Comparison: conventional surgery
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional surgery	Microwave coagulation
All‐cause mortality Follow‐up: 3 years	—	—	—	40 (1 RCT)	—	Only Kaplan‐Meier estimated survival rates reported and numbers of deaths in participants followed.
Time to mortality (overall survival) Follow‐up: 3 years	23%	14%	HR 0.91 (95% CI 0.39 to 2.15)	30 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
Health‐related quality of life	—	—	—	—	—	Outcome not reported
Any adverse events or complications Follow‐up: 3 years	—	—	—	30 (1 RCT)	⊕⊝⊝⊝ Very lowa,d,e	The trial reported that the adverse events or complications frequency were similar between groups, except for the outcome 'required blood transfusion', which was more common in the conventional surgery group.
Disease‐free survival Follow‐up: 3 years	Mean 13.3 months*	2 months lower* (0 to 0 higher)		30 (1 RCT)	⊕⊝⊝⊝ Very lowa,e,f	Disease‐free survival as reported by trial authors – mean (SDs or CIs not reported)
Failure to clear liver metastases	—	—	—	—	—	Outcome not reported
Recurrence of liver metastases	—	—	—	—	—	Outcome not reported
*The risk in the experimental group (corresponding risk and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised clinical trial; SD: standard deviation.
GRADE Working Group grades of evidence 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 are very uncertain about the estimate: the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded one level due to within‐study risk of bias: the trial did not describe allocation concealment or blinding, and excluded 25% of participants after randomisation.
^b Downgraded two levels due to imprecision: CIs showed benefit, harm and no effect, ratio of upper to lower CI above 3 for HR, justifying downgrading two levels due to imprecision (GRADE guidance 34: Zeng 2022).
^c We also noted an issue of indirectness: the trial included only a subgroup of people with liver metastases (i.e. with colorectal cancer); however due to already very low rating, it was not possible to downgrade further.
^d Downgraded one level due to imprecision; the authors did not report the total number of participants with all types of adverse events or complications, we did not calculate CIs for each type of adverse event/complication, therefore we could not rate imprecision with respect to it. We followed the information provided in GRADE guidance 6 (Guyatt 2011), where the lowest number of events (100 events or fewer) with the highest relative risk ratio indicated it did not meet the optimal information size. The study reported a total of 16 events (unclear in how many participants in total).
^e Downgraded one level due to indirectness: the trial included only a subgroup of people with liver metastases (i.e. with colorectal cancer).
^f Downgraded one level due to imprecision; the authors did not report SDs or CIs for disease‐free survival; therefore, we cannot rate imprecision with respect to CIs. We followed the information provided in GRADE guidance 34 (Zeng 2022), where a sample size of at least 800 is suggested for the continuous outcomes, while the sample size of the participants analysed in the study was 30 (i.e. 4% of optimal information size indicated in the guidance).

Summary of findings 3. Microwave coagulation versus radiofrequency ablation.

Microwave coagulation versus radiofrequency ablation
Patient or population: people with liver metastases Settings: hospitalised Intervention: microwave coagulation Comparison: radiofrequency ablation
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Radiofrequency ablation	Microwave coagulation
All‐cause mortality follow‐up: 2 years	375 per 1000	232 per 1000 (98 to 551)	RR 0.62 (0.26 to 1.47)	50 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
Time to mortality (overall survival) follow‐up: 2 years	62.5%	76.9%	HR 0.63 (95% CI 0.23 to 1.73)	50 (1 RCT)	⊕⊝⊝⊝ Very lowa,c,d	—
Health‐related quality of life	—	—	—	—	—	Outcome not reported
Any adverse events or complications follow‐up: 12 months	—	—	RR 0.19 (0.01 to 3.67)	50 (1 RCT)	⊕⊝⊝⊝ Very lowb,c,e	2 participants in the radiofrequency ablation group had minor complications (small liver abscess not requiring treatment and low‐grade subcapsular bleeding). No such complications were reported for the microwave coagulation group. In both groups, no intervention‐ related deaths or any major complications were reported.
Disease‐free survival	—	—	—	—	—	Outcome not reported
Failure to clear liver metastases follow‐up: 12 months	0	0	Not estimable	50 (1 RCT)	See comment	The trial reported technical success and technical efficacy in 100% of procedures in both groups, i.e. no failure occurred.
Recurrence of liver metastases local progression follow‐up: 12 months	83 per 1000	16 per 1000 (1 to 306)	RR 0.19 (0.01 to 3.67)	50 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
Recurrence of liver metastases distant recurrence follow‐up: 12 months	375 per 1000	386 per 1000 (188 to 780)	RR 1.03 (0.50 to 2.08)	50 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
*The risk in the experimental group (corresponding risk and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised clinical trial; RR: risk ratio.
GRADE Working Group grades of evidence 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 are very uncertain about the estimate: the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded one level due to within‐study risk of bias: the trial did not describe allocation concealment.
^b Downgraded two levels due to imprecision: CIs showed benefit, harm, and no effect; ratio of upper to lower CI above 3 for RR, justifying downgrading two levels due to imprecision (GRADE guidance 34: Zeng 2022).
^c We also noted an issue of indirectness: the trial included only a subgroup of people with liver metastases (i.e. mainly with colorectal cancer and breast cancer metastases); however, due to the rating already being very low, it was not possible to downgrade further.
^d Downgraded two levels due to imprecision: CIs showed benefit, harm, and no effect; ratio of upper to lower CIs above 3 for HR, justifying downgrading two levels due to imprecision (GRADE guidance 34: Zeng 2022).
^e Downgraded one level due to the within‐study risk of bias: the trial did not describe allocation concealment or blinding.

Background

Description of the condition

The liver is affected by two of the most common groups of malignant tumours: primary liver cancers and liver metastases from colorectal carcinoma (Chakedis 2017; Ganesan 2023). Primary liver tumours arise from malignant cells within the liver, and hepatocellular carcinoma (HCC) represents the most common form of primary liver cancer (Ganesan 2023). Liver metastases are significantly more common than primary liver cancers (Bilchik 2000; Gavriilidis 2021). Long‐term survival reported for people after radical surgical treatment is approximately 50%. However, resection with a clear border (R0) is not feasible in most people (Nieuwenhuizen 2020; Nordlinger 2013). Liver metastases commonly originate from cancers of the lung, stomach, colon, rectum, and endometrium (Hugh 1997). In 25% to 35% of people with colorectal cancer, liver metastases are found on preoperative imaging, and 8% to 30% of the people will subsequently develop liver metastases (Bouvier 2021; Hugh 1997; Smith 2015). Colorectal cancer is the third most common cancer in Europe, and its prevalence is rising (GCO 2020). Globally, the age‐adjusted annual incidence for colorectal cancer is 23.4 per 100,000 men and 16.2 per 100,000 women (GCO 2020). There is a very high incidence in North America (age‐adjusted 29.4 per 100,000), Australia and New Zealand (age‐adjusted 37.4 per 100,000), Northern Europe (age‐adjusted 32.1 per 100,000), and Western Europe (age‐adjusted 28.8 per 100,000) (GCO 2020). There are lower incidences in Africa (age‐adjusted from 7.9 per 100,000 in Western Africa to 6.7 per 100,000 in Southern Africa) and South‐Central Asia (age‐adjusted 4.4 per 100,000). Globally, age‐adjusted mortality for colorectal cancer is 9 per 100,000; this rate is higher in countries with a higher incidence, and lower in countries with a lower incidence (GCO 2020). Globally, in 2017, approximately 414,000 men and 357,000 women died of colorectal cancer, making it the third leading cause of cancer death in men and the third in women (Global Burden of Disease Cancer Collaboration 2019). In the USA, approximately 52,550 people die of colorectal cancer each year, accounting for approximately 9% of all cancer deaths (Jemal 2022). In the USA, five‐year survival after diagnosis of colorectal cancer is 64.5% to 79.8% (Alyabsi 2021; Howlader 2018). In Europe, in 2007, the estimated survival rate was 55.8%, while in China, it was 56.9%; and the highest survival rates during 2010 to 2014 were observed in Canada at 70.8% for colon cancer and 70.9% for rectal cancer (Li 2021). In Europe, the relative survival for five years was 57% for colon cancer and 56% for rectal cancer (Holleczek 2015). However, the three‐year age‐ and sex‐standardised survival rate in people with metastatic colorectal cancer ranges from 16% to 38% in European countries (Bouvier 2021). Although improvement in long‐term survival has been reported since the 2000s, the CONCORD‐3 analysis shows significant disparities in colorectal cancer treatment outcomes worldwide (CONCORD‐3).

For people with liver metastases, surgical resection may cure the disease, but only a limited number of them qualify for resection (Bilchik 2000; Bipat 2007; Bouvier 2021). While hepatic resection proves highly favourable for people with colorectal liver metastases (Nordlinger 2013), its efficacy is comparatively limited for metastases of melanoma, oesophageal cancer, pancreatic ductal adenocarcinoma, and adrenocortical cancer (Gaujoux 2012; Gleisner 2007; Pawlik 2006). Possible options for people with unresectable liver metastases include chemotherapy delivered intra‐arterially (5‐fluorouracil), called 'regional chemotherapy'; systemic chemotherapy (5‐fluorouracil, irinotecan, oxaliplatin, leucovorin, capecitabine); or monoclonal antibodies (such as bevacizumab or cetuximab) (Riemsma 2009; Ye 2023). There are also several local tumour ablative techniques, one of which is microwave ablation (Riemsma 2009).

Description of the intervention

Microwave coagulation was developed in the late 1970s, and it has been used in surgery for coagulation of tumours (Criss 2023; Guan 2015; Hu 2020; Saldanha 2010; Shady 2018; Shibata 2000). The procedure involves placing an antenna into the tumour lesion under ultrasound or computed tomography guidance (Criss 2023; Guan 2015; Hu 2020; Saldanha 2010; Shady 2018). For the performance of microwave ablation, various interventional approaches (percutaneous, laparoscopic, or intraoperative) and methods of guidance (computed tomography, magnetic resonance imaging, and ultrasound) are available (Vogl 2017). Microwave coagulation can be applied with conscious sedation of the patient (Simon 2005; Vogl 2017). Indications for percutaneous microwave coagulation under ultrasound guidance reported in the literature include multinodular liver tumours, technically unresectable lesions, and patients unsuitable for surgery for other reasons (inadequate liver remnant, comorbidities, patient's decline) (Han 2022; Liang 2013). In such patients, microwave ablation is one of the options for relative non‐invasive treatment potentially associated with lower risk of complications (Han 2022; Liang 2013). The terms 'microwave ablation' and 'microwave coagulation' are used interchangeably in the literature on this procedure and are used interchangeably throughout the text.

How the intervention might work

Microwaves are electromagnetic waves with frequencies ranging from 900 MHz to 2450 MHz. Microwave irradiation interacts with water molecules in the liver lesion, which then start to vibrate at a high frequency (over 900 MHz). This vibration produces heat, leading to coagulative necrosis and reduction of tumour size (Ahmed 2011; Criss 2023; Guan 2015; Hu 2020; Saldanha 2010; Shady 2018).

Why it is important to do this review

In people with liver metastases, local or regional treatment methods can provide local control, but it is uncertain what long‐term outcomes can be anticipated with the use of some of these therapies. Systematic reviews may help to establish the effectiveness and the trade‐offs between benefits and harms associated with different non‐surgical ablation methods for the treatment of all forms of malignant liver tumours (primary and metastases). This Cochrane review aimed to compare microwave coagulation with no intervention, other ablation methods, or systemic treatments in people with liver metastases from any primary source. The protocol was published in 2012, followed by the review publication in 2013. We decided to update searches to check if further trials were published and to update the evidence and revise the review according to the updated reporting requirements.

Objectives

To evaluate the beneficial and harmful effects of microwave coagulation versus no intervention, other ablation methods, or systemic treatments in people with liver metastases regardless of the location of the primary tumour.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials assessing the beneficial and harmful effects of microwave coagulation and its comparators, irrespective of publication status, language, blinding, or outcomes reported. We are aware that our focus on randomised clinical trials puts more emphasis on potential benefits and may have resulted in overlooking late occurring or rare harms, which are often missed in randomised clinical trials (Storebø 2018). We considered quasi‐randomised and other controlled studies, identified with the search for randomised clinical trials, only for the reports of data on harms.

Types of participants

Participants at any age, with liver metastases regardless of the location of the primary tumour.

Types of interventions

Experimental intervention

Microwave coagulation

Control intervention

No intervention, other ablation methods (such as ablation with ethanol, radiofrequency, photocoagulation with laser, chemoembolisation, radioembolisation, and embolisation), or systemic treatments (such as chemotherapy, immunotherapy, radiotherapy).

Co‐interventions were allowed if provided equally to the experimental and control groups of an individual randomised trial.

We planned to conduct separate comparison analyses of microwave coagulation versus the above‐listed control interventions.

Types of outcome measures

Primary outcomes

• All‐cause mortality at the last follow‐up, and time to mortality (counted from the start of treatment)

• Health‐related quality of life, measured by means of validated scales

• Any adverse events or complications – the International Conference on Harmonisation (ICH) Guidelines defined adverse events as serious and non‐serious (ICH‐CPG 2016). A serious adverse event 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 is a congenital anomaly or birth defect. All other adverse events were adverse events considered as non‐serious.

Secondary outcomes

• Cancer mortality

• Disease‐free survival

• Failure to clear liver metastases

• Recurrence of liver metastases

• Time to progression of liver metastases

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

We extracted data on the outcomes at the end of treatment and at the longest follow‐up, whenever possible. We used the outcome data for the longest follow‐ups for our main analyses and conclusions. We included trials regardless of the outcomes reported.

Search methods for identification of studies

Electronic searches

The Cochrane Hepato‐Biliary Group (CHBG) Information Specialist searched the CHBG Controlled Trials Register via the Cochrane Register of Studies Web on 14 April 2023. We also searched the Cochrane Central Register of Controlled Trials(2023, Issue 4) inthe Cochrane Library, MEDLINE ALL Ovid (1946 to 14 April 2023); Embase Ovid (1974 to 14 April 2023); Science Citation Index Expanded (Web of Science; 1900 to 14 April 2023); Conference Proceedings Citation Index – Science (Web of Science; 1990 to 14 April 2023); Latin American Caribbean Health Sciences Literature (LILACS; VHL Regional Portal; 1982 to 14 April 2023), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL EBSCO; 1981 to 18 August 2023).

Up to 5 June 2017, searches for this review were part of a global search for a full review of non‐surgical ablation methods in people with liver metastases or primary malignant liver tumours (Riemsma 2009). These search strategies with the date range of the searches are given in Appendix 1. For the updates (28 June 2018, 3 September 2019, and 18 December 2020), we developed new, focused search strategies (Appendix 2; Appendix 3).

The most recent search strategies with the date range of the searches performed on 14 April 2023 (18 August 2023 for CINAHL) are given in Appendix 4.

Searching other resources

We searched ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/), EU Clinical Trials Register (www.clinicaltrialsregister.eu/), and ISRCTN registry (www.isrctn.com/) on 16 July 2023. We also searched all US Food and Drug Administration (FDA) approvals and investigational device exemptions, as found on www.fda.gov/, on 23 July 2023, and the European Medicines Agency website (EMA; www.ema.europa.eu/en/homepage) on 11 July 2023. We searched the following pharmaceutical company sources for ongoing or unpublished trials on 11 July 2023: AstraZeneca Clinical Trials website (www.astrazenecaclinicaltrials.com/), Bristol‐Myers Squibb Clinical Trial Registry (www.bms.com/researchers-and-partners/clinical-trials-and-research/clinical-trial-results.html), Eli Lilly and Company Clinical Trial Registry (www.lilly.com/clinical-research/clinical-trials), GlaxoSmithKline clinical trial register (www.gsk-studyregister.com/en/advanced-study-search/), and NovartisClinicalTrials.com (www.novartis.com/clinicaltrials). In addition, we searched for grey literature available on Google Scholar (scholar.google.com/) on 23 July 2023.

The most recent search strategies with the date of the search are given in Appendix 4.

We searched the reference lists of relevant reviews (such as Lopez 2006; Meijerink 2018; Nieuwenhuizen 2022; Schwartz 2004; Spiliotis 2021), Health Technology Assessment (HTA) reports (such as Marlow 2006), relevant Cochrane reviews, and all included trials. We also used PubMed's related articles search function for the included studies. We contacted authors of identified trials for additional information where needed.

We also checked MEDLINE and Embase for any relevant retraction statements and errata for the included studies as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2022).

Data collection and analysis

We performed this systematic review according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a). We used Review Manager to collect data and perform the analyses (RevMan 2023). We used Trial Sequential Analysis software to assess imprecision as a sensitivity analysis (Thorlund 2017; TSA 2021).

Selection of studies

For this update, review authors (DS, MJS, JWM, MP, RW, and MMB) screened the titles and abstracts of identified studies, working alone or in pairs. In the second round, the same review authors screened the full‐text reports, and differences in opinions in both rounds were resolved by discussion. NL selected and extracted data from a Chinese publication.

We recorded the selection process in sufficient detail to complete a PRISMA 2020 flow diagram (for updated systematic reviews which includes searches of databases, registers, and other sources) (Page 2021a; Page 2021b).

Data extraction and management

For trials included in the review, we extracted relevant data on participant characteristics, interventions, comparisons, trial outcome measures, time of follow‐up, trial designs, and methods. We used a data extraction form that was previously developed for another review on non‐surgical ablation methods (Riemsma 2009). We provided data for all trial groups in the Characteristics of included studies table, even if not used. For ongoing trials, we extracted basic information regarding methods, inclusion criteria, estimated enrolment of participants, interventions, outcomes, starting dates, and contact information using Review Manager tables as a template (RevMan 2023). One review author extracted data from the publications/ongoing studies retrieved, and a second author checked the extracted data. We resolved disagreements by discussion. For reports of the studies published in languages that we had no command of, we requested help from the CHBG Information Specialist. We attempted to contact the authors of the included trials to obtain required information on the trials, but only one author sent us some information (Vogl 2022) (see the Results section).

Assessment of risk of bias in included studies

We assessed the risk of bias in the included trials based on the domains described below (Gluud 2008; Higgins 2011; Hrobjartsson 2013; Hrobjartsson 2014a; Hrobjartsson 2014b; Kjaergard 2001; Moher 1998; Savović 2012a; Savović 2012b; Savović 2018; Schulz 1995; Wood 2008). Three review authors (DS, MJS, and MMB) independently assessed the risk of bias in two of the trials, while one Chinese‐speaking review author (NL) assessed the risk of bias in the third trial published in Chinese; this was checked on the basis of information obtained from the trial by another review author (MMB).

Allocation sequence generation

• Low risk of bias: study authors performed sequence generation using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if an independent person, not otherwise involved in the study, performed them.

• Unclear risk of bias: the study authors did not specify the method of sequence generation.

• High risk of bias: the sequence generation method was not random.

Allocation concealment

• Low risk of bias: participant allocation could not have been foreseen in advance of, or during, enrolment. A central and independent randomisation unit controlled allocation. Investigators were unaware of the allocation sequence (e.g. if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

• Unclear risk of bias: study authors did not describe the method used to conceal the allocation, so intervention allocations may have been foreseen before, or during, enrolment.

• High risk of bias: it is likely that investigators who assigned participants knew the allocation sequence. As such studies are quasi‐randomised studies, we excluded them when assessing beneficial effects.

Blinding of participants and personnel

• Low risk of bias: either of the following: no blinding or incomplete blinding, but review authors judged that the outcome was unlikely to have been influenced by lack of blinding; or blinding of participants and key study personnel ensured, and it was unlikely that the blinding could have been broken.

• Unclear risk of bias: either of the following: insufficient information to permit judgement of low risk or high risk; or the trial did not address this outcome.

• High risk of bias: either of the following: no blinding or incomplete blinding, and the outcome was likely to have been influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome was likely to have been influenced by lack of blinding.

Blinding of outcome assessment

• Low risk of bias: either of the following: no blinding of outcome assessment, but review authors judged that the outcome measurement was not likely to be influenced by lack of blinding; or blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

• Unclear risk of bias: either of the following: insufficient information to permit judgement of low risk or high risk; or the trial did not address this outcome.

• High risk of bias: either of the following: no blinding of outcome assessment, and the outcome measurement was likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. The study used sufficient methods, such as multiple imputation, to handle missing data.

• Unclear risk of bias: information was insufficient to assess whether missing data, in combination with the method used to handle missing data, were likely to induce bias in the results.

• High risk of bias: results were likely to be biased due to missing data.

Selective outcome reporting

• Low risk of bias: the trial reported the following predefined outcomes: all‐cause mortality, any adverse events or complications, and failure to clear liver metastases or recurrence of liver metastases. If the original trial protocol was available, the outcomes were those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.ClinicalTrials.gov), the outcomes sought should have been those enumerated in the original protocol, if the trial protocol was registered before or at the time the trial was begun. If the trial protocol was registered after the trial had begun, we would not consider those outcomes to be reliable.

• Unclear risk of bias: study authors did not report all predefined outcomes fully, or it was unclear whether study authors recorded data on these outcomes.

• High risk of bias: study authors did not report one or more predefined outcomes.

Other bias

• Low risk of bias: the trial appeared free of other factors that could have put it at risk of bias.

• Unclear risk of bias: the trial may or may not have been free of other factors that could have put it at risk of bias.

• High risk of bias: other factors in the trial could have put it at risk of bias.

Overall risk of bias

We judged a trial to be at low overall risk of bias if we assessed it at low risk of bias in all of the above domains. We judged a trial to be at high overall risk of bias if we assessed it as unclear or at high risk of bias in one or more of the above domains.

We present the bias risk assessment for each trial separately.

Measures of treatment effect

For dichotomous variables, we used a risk ratio (RR) with a 95% confidence interval (95% CI). For continuous variables, we planned to use the mean difference when outcomes were measured on the same scale or standardised mean difference for outcomes such as health‐related quality of life when different scales were used, with a 95% CI. For time to event outcomes, we planned to use hazard ratios (HR) using the methods described by Parmar and Tierney (Parmar 1998; Tierney 2007). We planned to extract information on, for example, HRs, P values, events ratios, curve data, and follow‐up, and enter them into a Microsoft Office Excel 2003 spreadsheet to calculate the log HRs and their standard errors (Tierney 2007).

Unit of analysis issues

The unit of analysis was participants in the individually randomised, parallel‐group randomised trials. For trials with more than two experimental groups, we planned to collect data for all experimental groups meeting the inclusion criteria of our protocol. If the control group was a common comparator in a comparison, we planned to divide the number of participants in the control group by the number of relevant experimental groups in order to avoid counting the same data multiple times. In the case of cross‐over trials, we planned to use data from the first trial period only (Higgins 2022b).

Dealing with missing data

We analysed the data using intention‐to‐treat when possible, and we also used available‐case analysis. Otherwise, in the protocol, we had planned to perform sensitivity analysis with worst‐best case scenario analysis and best‐worst case scenario analysis to assess how sensitive results were to reasonable changes in the assumptions that were made. The worst‐best scenario analysis assumes that all participants with missing data in the experimental group had a negative outcome and all participants with missing data in the comparison group did not have a negative outcome. The best‐worst scenario analysis assumes that all participants in the experimental group did not have a negative outcome and all participants in the comparison group had a negative outcome. However, because there was only one trial with missing data in a single comparison, these analyses were not considered necessary.

Assessment of heterogeneity

We planned to check if the included trials were clinically and methodologically similar enough to combine their results before commencing statistical analysis of the data. We planned to assess heterogeneity using Chi² and I² statistics (Deeks 2022). We planned to discuss any plausible causes of heterogeneity. We planned to use the random‐effects model in our main analysis (DerSimonian 1986), and the fixed‐effect model in a sensitivity analysis (Greenland 1985; Mantel 1959), to look for differences in results and potentially explain heterogeneity.

Assessment of reporting biases

We planned to use a funnel plot to explore reporting bias, had we identified at least 10 trials per analysis (Egger 1997; Macaskill 2001).

Data synthesis

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a) and used Review Manager for the analyses (RevMan 2023).

We planned to calculate RRs and HRs using the methods described by Parmar and Tierney (Parmar 1998; Tierney 2007). For outcomes such as HR for mortality, we planned to use the generic inverse variance method for the meta‐analysis. If we could not meta‐analyse the data, for example, in the case of extreme heterogeneity, we planned to present results in a forest plot, without the estimate, to show the variance of effects (Egger 1997).

We planned to group the trials by intervention, participant characteristics, and outcomes. We planned to present the data using forest plots, whenever possible, using the random‐effects model in our main analysis, and the fixed‐effect model in sensitivity analysis (DerSimonian 1986; Higgins 2011). As the included trials addressed different comparisons, the results could not be pooled for any of the outcomes. To summarise the data and to allow the reader to judge the results of the trials, based on differences and similarities of the included trials and their risk of bias, we also presented a narrative synthesis of the results, including text, tables, and figures, as appropriate. We described the most important characteristics of the trials, including a detailed review of the methodological shortcomings of the trials.

We planned to use funnel plots to identify possible small‐trial biases, such as publication bias (Egger 1997). Furthermore, we planned to discuss the possible implications of our findings if bias was present. None of this was possible due to lack of data.

We planned to examine the apparent significant beneficial and harmful intervention effects using Trial Sequential Analysis (Thorlund 2017; TSA 2021; Wetterslev 2017), in order to evaluate if these apparent effects could have been caused by random error ('play of chance') (Brok 2008; Brok 2009; Thorlund 2009; Thorlund 2010; Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). We did not carry out Trial Sequential Analysis, as we only included three small trials in three different comparison analyses (single trial per comparison).

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses, when possible, based on:

• prognostic indicators, such as age (by categorising the trials into a group with population at least 60 years old and population below 60 years old; Buisman 2022; Gomez 2010), sex, tumour size, location of primary tumour, and use of any co‐interventions;

• outcome data at the end of treatment and at the end of follow‐up;

• trials at low risk of bias compared to trials at high risk of bias, as defined in the Assessment of risk of bias in included studies section.

Sensitivity analysis

We could not perform sensitivity analyses as only one trial was identified for each comparison.

Summary of findings and assessment of the certainty of the evidence

We had planned to present, in the summary of findings tables, outcome results at the longest follow‐up for all three primary outcomes (all‐cause mortality at the last follow‐up and time to mortality; health‐related quality of life; any adverse events or complications) and three secondary outcomes (disease‐free survival; failure to clear liver metastases; recurrence of liver metastases). We constructed a summary of findings table for each available comparison. We considered within‐study risk of bias (study limitations) based on individual domains, as well as overall assessment, indirectness of evidence (population, intervention, control, outcomes), unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses), imprecision of effect estimate, and risk of publication bias. We used GRADE methods and GRADEpro GDT software to evaluate the certainty of evidence (GRADEpro GDT; Schünemann 2022a; Schünemann 2022b). The levels of certainty in the evidence were defined as high, moderate, low, or very low.

• 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

See the Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies tables.

Results of the search

Up to 5 June 2017, searches for this review were part of a global search for a full review of non‐surgical ablation methods in people with liver metastases or primary malignant liver tumours (Riemsma 2009). These search strategies with date range of the searches are given in Appendix 1; they produced 13,409 records. After excluding duplicates, we screened 13,382 records. Based on titles and abstracts, we found 13,047 records irrelevant for the current review, resulting in 335 full‐text papers being retrieved. From these, we found one trial that met the inclusion criteria for the present review (Shibata 2000). We excluded 334 records because they did not describe randomised clinical trials (149), they examined another intervention not relevant for this review (143), the population was not relevant for this review (30), and the comparison was not relevant for this review (12). By June 2017, we have identified no ongoing trials. We did not run separate searches for non‐randomised studies; we checked eligibility only if studies were identified during searches for randomised trials; none of these studies were eligible for inclusion. A summary of the searches is provided in Figure 1.

1.

Revised flow chart of identification of randomised trials for inclusion in the first published review version (Bala 2013). RCT: randomised clinical trial.

During the most recent search, we found 7804 new records through database searching, two additional records from handsearching, and five additional records from trial registries. We screened 2395 records after removal of duplicates. We excluded 2384 records based on title and abstract, and screened 11 full‐text publications. We included two additional trials in the qualitative synthesis (Vogl 2022; Xu 2012), excluded one study with an illegible population (mixed population of hepatocellular carcinoma and colorectal cancer liver metastases analysed together; Radosevic 2022), and excluded one study because it was not randomised (Correa‐Gallego 2014). However, from the excluded non‐randomised study by Correa‐Gallego 2014, we identified one additional reference in full text that provided data on harms. We identified five ongoing studies (COLLISION; COLLISION‐XL; JPRN‐UMIN000036206; NCT02820194; NCT03654131), and one published protocol of an already identified study was attached to its ClinicalTrials.gov record (COLLISION). The status of one of the studies previously listed as an ongoing trial was updated on 16 September 2022 because the study was terminated due to insufficient recruitment; therefore, we excluded the trial (NCT02820194). A summary of the updated searches is provided in Figure 2 (Page 2021a; Page 2021b).

2.

PRISMA flow diagram (Page 2021a; Page 2021b). Date of search 14 April 2023.

Included studies

We included three randomised clinical trials; one, conducted in China, comparing microwave coagulation in addition to conventional TACE versus conventional TACE alone (Xu 2012), one, conducted in Japan, comparing microwave coagulation versus conventional liver surgery (hepatectomy or liver resection) (Shibata 2000), and one, conducted in Germany, comparing microwave ablation versus radiofrequency ablation (Vogl 2022).

Microwave coagulation plus conventional transarterial chemoembolisation versus conventional transarterial chemoembolisation alone

Participants

The trial included 50 participants with liver metastases confirmed by clinical data and computed tomography/magnetic resonance imaging/biopsy (Xu 2012). The mean age of participants was 60 years and males constituted 76% of the trial participants. The primary sites of the metastatic tumours were the gastrointestinal tract (27 participants), lung (10 participants), pancreas (six participants), mammary gland (three participants), and other (four participants). The reported mean size of the liver tumour was 4.5 cm. In 23 participants, there were single liver metastases, and in 27 participants, there were multiple liver metastases.

Previous treatments

No previous treatment was reported.

Experimental intervention

Microwave coagulation in addition to TACE, which was performed following a conventional method (25 participants).

Control intervention

TACE was performed following a conventional method (25 participants).

Co‐interventions

No co‐interventions were reported.

Follow‐up

Participants were followed for at least one month (mean or median not reported).

Dropouts or withdrawals

There were no dropouts or withdrawals in the trial.

Intention‐to‐treat analysis

The trial did not report changes to the group's assignments after randomisation.

Funding

The trial did not report on funding.

Microwave coagulation versus conventional liver surgery

Participants

The trial included 40 participants with multiple liver metastases of colorectal cancer (fewer than 10) and with no evidence of extrahepatic disease, ascites, periportal or coeliac lymph node metastasis, liver cirrhosis, or chronic hepatitis (Shibata 2000). However, 10 participants (six from the experimental group and four from the control group) were excluded after randomisation because they did not meet the inclusion criteria of the trial, and so only 30 participants were analysed for the three‐year follow‐up. The 30 participants were 14 females and 16 males. The mean age of participants was 61 years. The diagnosis of participants with colorectal cancer (Stage IB to IIIC; T2N0 to T3N2) and liver metastases were confirmed by histological assessment. The tumours were resectable. The mean size of the liver tumour was 27 mm in participants in the experimental group and 34 mm in participants in the control group. The participants had two to nine metastases with a mean of 4.1 in the experimental group and 3.0 in the control group.

Previous treatments

Laparotomy in the experimental group.

Experimental intervention

Microwave coagulation (14 participants).

Control intervention

Conventional surgery. It involved lobectomy, segmentectomy, subsegmentectomy, with or without wedge resection (16 participants).

Co‐interventions

No co‐interventions were reported.

Follow‐up

Participants were followed for three years and up to 49 months (as shown on the Kaplan Meier curve).

Dropouts or withdrawals

About 25% of the included participants were excluded after randomisation as they did not meet the inclusion criteria of the trial.

Intention‐to‐treat analysis

Trial authors did not use the intention‐to‐treat principle for analysis of their data.

Funding

The trial did not report on funding.

Microwave coagulation versus radiofrequency ablation

Participants

The trial included 50 participants with liver metastases, which were confirmed by histology or radiology, or both (Vogl 2022). The mean age of the participants was 62.8 (standard deviation (SD) 11.8) years, and females constituted 54% of the sample. The primary sites of the metastatic tumours were colorectal cancer (27 participants), breast cancer (11 participants), pancreatic cancer (three participants), ovarian cancer (two participants), and other (seven participants). All participants had multiple metastases (information from the author). The mean size of the liver tumour was 17.2 (SD 8.1) mm in the microwave group and 15.3 (SD 6.1) mm in the radiofrequency group.

Previous treatments

Participants received previous treatment with surgical resection (45 participants), transarterial chemoembolisation (31 participants), systemic chemotherapy (16 participants in the radiofrequency group, none in the microwave group (information from the author)).

Experimental intervention

Microwave coagulation (26 participants).

Control intervention

Radiofrequency ablation (24 participants).

Both ablation procedures were performed using the dual ablation system (Amica; MMS Medicor Medical Supplies GmbH, Kerpen, Germany). Microwave and radiofrequency ablations were performed under the guidance of computer tomography.

Co‐interventions

The trial did not report co‐interventions.

Follow‐up

Participants were followed for 24 months.

Dropouts or withdrawals

There were no dropouts or withdrawals in the trial.

Intention‐to‐treat analysis

The trial reported no changes to the group's assignments after randomisation.

Funding

The trial was partially supported by Medicor (MMS Medicor Medical Supplies GmbH, Kerpen, Germany) for statistical analysis.

Excluded studies

We excluded three studies because they were not randomised clinical trials, did not fulfil the inclusion criteria of our review in terms of interventions or participants, or included mixed participants without providing results in separate for participants of interest (Correa‐Gallego 2014; Radosevic 2022). One study was excluded because it was terminated due to insufficient recruitment (NCT02820194). Only one excluded studies provided data on harms (Correa‐Gallego 2014).

Ongoing studies

We identified four ongoing studies focusing on participants with liver metastases from colorectal cancer. Two studies plan to compare microwave coagulation with stereotactic body radiotherapy (COLLISION‐XL; NCT03654131), one study plans to compare microwave coagulation with radiofrequency ablation (JPRN‐UMIN000036206), and one study plans to compare microwave coagulation or radiofrequency ablation with surgery (COLLISION). The planned enrolment is 68 to 618 participants. In addition to the four studies, we identified another planned study but as it was terminated because of insufficient recruitment on 16 September 2022, we recategorised it as excluded (NCT02820194). We contacted the authors regarding availability of any results but received no response.

We identified one non‐randomised study in the search result for randomised trials, and we considered it eligible for reporting of data on harm (Correa‐Gallego 2014).

Risk of bias in included studies

Overall, we assessed the risk of bias in all included trials as high for each of the assessed outcomes (Shibata 2000; Vogl 2022; Xu 2012). For an overview of the bias risk of the included trial, see Figure 3 and Figure 4.

3.

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

Blank cells mean that the outcome was not examined in the trial.

4.

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

Blank cells mean that the outcome was not examined in the trial.

Allocation

Generation of randomisation sequence

Xu 2012 did not describe the generation of randomisation sequence and was at unclear risk of bias. Shibata 2000 used a computer‐generated, 1:1 randomisation list, and Vogl 2022 assigned participants randomly to a 1:1 ratio. Thus, we judged the randomisation sequence generation at low risk of bias in these trials.

Allocation concealment

No trials reported allocation concealment. We have not received any additional information from the trial authors, so we judged them at unclear risk of bias (Shibata 2000; Vogl 2022; Xu 2012). In addition, Vogl 2022 used a permuted block design and there is no information on whether the researchers were aware of the block size. This lack of information raises the concern that researchers might have been able to predict which treatment group a particular individual was assigned last in the block.

Blinding

None of the three trials provided sufficient information to allow assessment of whether participants, physicians, or outcome assessors were properly blinded (Shibata 2000; Xu 2012; Vogl 2022). However, in the case of objective outcomes, such as all‐cause mortality or time to mortality, we believe that it is unlikely that lack of blinding would have influenced the outcomes. Therefore, we assessed Vogl 2022 at low risk for both performance and detection bias for those outcomes. Three outcomes (i.e. recurrence of liver metastases and failure to clear liver metastases in Vogl 2022, and tumour response in Shibata 2000), were clearly defined and objectively measured using magnetic resonance imaging (Vogl 2022), and by monitoring the levels of carcinoembryonic antigen (Shibata 2000). We believe it is unlikely that lack of blinding would have influenced the outcomes. Therefore, we assessed the risk for both performance and detection bias for those outcomes as low.

There were insufficient details about the measurement of adverse events or complications in Shibata 2000, Xu 2012, and Vogl 2022, and about the measurement of tumour response in Xu 2012. Therefore, the risk for both performance and detection bias for those outcomes was unclear in all trials.

Incomplete outcome data

In both Xu 2012 and Vogl 2022 (also confirmed by the authors of the latter trial) there were no withdrawals or dropouts reported. Thus, the risk of bias was low for both trials.

Shibata 2000 had a high dropout rate with 25% of the included participants excluded after randomisation. However, these participants were excluded because they did not meet the inclusion criteria of the trial. The exclusion after randomisation might have introduced bias (comparability between the two groups of treatment).

Selective reporting

None of the trials reported on or referred to a trial protocol (Shibata 2000; Vogl 2022; Xu 2012). We could not find the trial protocols of the three trials in the trial registries and in the publications searched. None of the trials provided information on all of our predefined outcomes in order to be judged at low risk of bias (see Assessment of risk of bias in included studies). Therefore, selective reporting was unclear in all three trials.

Other potential sources of bias

We could not assess if there were other possible sources of bias, based on the trial reports.

Effects of interventions

See: Table 1; Table 2; Table 3

See Table 1, Table 2, and Table 3. The data, presented in the results section, were obtained from the full‐text articles, summarising each of the included trials. There was only one trial per comparison.

Microwave coagulation plus conventional transarterial chemoembolisation versus conventional transarterial chemoembolisation alone

One trial compared microwave coagulation plus conventional TACE versus conventional TACE alone (Xu 2012).

Primary outcomes

All‐cause mortality at last follow‐up and time to mortality (counted from the start of treatment)

Xu 2012 did not report on all‐cause mortality and time to mortality.

Health‐related quality of life

Xu 2012 did not report on health‐related quality of life.

Any adverse events or complications

Xu 2012 reported adverse events or complications in the experimental group only: fever in 19 people, mild right upper abdomen pain in nine people, mild serum transaminase elevation in eight people, reactive mild ascites in three people, acute heart function failure in one person, severe biliary infection in one person, and sepsis in one person. As adverse events or complications in the control group were not mentioned in the full text of the trial, we do not know whether adverse events or complications occurred, or whether adverse events were not reported. Therefore, we have not analysed the data.

Secondary outcomes

Cancer mortality

Xu 2012 did not report on cancer mortality.

Disease‐free survival

Xu 2012 did not report on disease‐free survival.

Failure to clear liver metastases

Xu 2012 did not report on failure to clear liver metastases.

Recurrence of liver metastases

Xu 2012 did not report on recurrence of liver metastases.

Time to progression of liver metastases

Xu 2012 did not report on time to progression of liver metastases.

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

Xu 2012 reported this outcome as remission rates, according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for both groups during at least one‐month follow‐up. In the experimental group, there was complete response (remission) in seven people, partial response (remission) in 15 people, stable disease in two people, and progressive disease in one person, with a remission rate (complete or partial response) of 88%. In the control group, there was complete response (remission) in three people, partial response (remission) in 11 people, stable disease in six people, and progressive disease in five people, with a remission rate of 56%. The calculated RR was 1.57 (95% CI 1.08 to 2.29; 1 trial, 50 participants; Analysis 1.1; very low‐certainty evidence).

1.1. Analysis.

Comparison 1: Microwave ablation in addition to conventional transarterial chemoembolisation (TACE) versus conventional TACE alone, Outcome 1: Tumour response

Microwave coagulation versus conventional surgery

One trial compared microwave coagulation versus conventional liver surgery (hepatectomy or liver resection) (Shibata 2000).

Primary outcomes

All‐cause mortality at last follow‐up and time to mortality (counted from the start of treatment)

Shibata 2000 reported data for 30 participants out of 40 randomised. The reported number of deaths was 9/14 included participants in the microwave group versus 12/16 included participants in the conventional surgery group. Since the follow‐up periods differed amongst participants, and it was not reported how many of the participants who were censored died, we could not calculate mortality rates and RRs for this outcome.

The overall survival (reported by the authors as mean survival) during the 49‐month follow‐up (as shown on a Kaplan‐Meier curve) was 27 months in the microwave group versus 25 months in the conventional surgery group (as reported by authors P = 0.83) (very low‐certainty evidence).

Shibata 2000 reported estimated overall survival after one, two, and three years. In the microwave coagulation group, 71%, 57%, and 14% of the participants survived for one, two, and three years, and in the conventional surgery group, the percentages of participants who survived were 69%, 56%, and 23%, respectively. The HR calculated using the Parmar method from P = 0.83 and the number of people included in the analysis and the number of events reported in the paper was 0.91 (95% CI 0.39 to 2.15; very low‐certainty evidence) (Parmar 1998; Tierney 2007).

Health‐related quality of life

Shibata 2000 did not report on health‐related quality of life.

Any adverse events or complications

Shibata 2000 observed no intervention‐related mortality. They reported a similar frequency of adverse events or complications between the microwave coagulation and conventional surgery groups, except for the trial outcome 'required blood transfusion', which was more common in the conventional surgery group (very low‐certainty evidence). Table 4 presents other reported complications.

1. Adverse events or complications in people with liver metastases treated with microwave ablation or conventional surgery.

Shibata 2000	Microwave ablation group (14 participants)	Conventional surgery group (16 participants)
Any adverse events or complications excluding intervention‐related bleeding	2 (14%)	3 (19%)
Intervention‐related mortality	0	0
Wound infection	0	1 (6%)
Hepatic abscess	1 (7%)	0
Intestinal obstruction	0	1 (6%)
Required blood transfusion	0	6 (38%)
Bile duct fistula	1 (7%)	1 (6%)

Secondary outcomes

Cancer mortality

Shibata 2000 did not report on cancer mortality.

Disease‐free survival

Shibata 2000 reported disease‐free survival (as means) as 11.3 months in the microwave coagulation group versus 13.3 months in the conventional surgery group (as reported by authors P = 0.47) (very low‐certainty evidence).

Failure to clear liver metastases

Shibata 2000 did not report on failure to clear liver metastases.

Recurrence of liver metastases

Shibata 2000 did not report on recurrence of liver metastases.

Time to progression of liver metastases

Shibata 2000 did not report on time‐to‐progression of liver metastases.

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

Shibata 2000 measured the outcome only indirectly in terms of carcinoembryonic antigen level. After treatment, the carcinoembryonic antigen level decreased in both groups (microwave coagulation: from 18.5 (SD 21.6) ng/mL to 5.8 (SD 6.3) ng/mL; conventional surgery: from 13.5 (SD 11.4) ng/mL to 4.1 (SD 3.9) ng/mL).

Microwave coagulation versus other ablation methods

One trial compared microwave ablation versus radiofrequency ablation (Vogl 2022).

Primary outcomes

All‐cause mortality at last follow‐up and time to mortality (counted from the start of treatment)

Vogl 2022 reported data for all included participants. The reported two‐year mortality rate was 23.1% (6/26 participants) in the microwave coagulation group versus 37.5% (9/24 participants) in the radiofrequency group (RR 0.62, 95% CI 0.26 to 1.47; 1 trial, 50 participants; very low‐certainty evidence; Analysis 2.1).

2.1. Analysis.

Comparison 2: Microwave coagulation versus radiofrequency ablation, Outcome 1: All‐cause mortality at 2‐year follow‐up

Vogl 2022 estimated overall survival after one and two years. In the microwave coagulation group, 84.5% and 76.9% of participants survived for one and two years, and in the radiofrequency group, the percentages of participants who survived were 87.5% and 62.5%, respectively. The HR, calculated using the Parmar method from the number of participants included in the analysis and survival rates reported in the paper, was 0.63 (95% CI 0.23 to 1.73; very low‐certainty evidence) (Parmar 1998; Tierney 2007).

Health‐related quality of life

Vogl 2022 did not report on health‐related quality of life.

Any adverse events or complications

Vogl 2022 reported no intraprocedural deaths and no major complications during the procedures in both groups. Two participants in the radiofrequency ablation group had minor complications, such as small liver abscess not requiring treatment and low‐grade subcapsular bleeding (one participant each). No such complications were reported for the microwave coagulation group (RR 0.19, 95% CI 0.01 to 3.67; 1 trial, 50 participants; very low‐certainty evidence; Analysis 2.2).

2.2. Analysis.

Comparison 2: Microwave coagulation versus radiofrequency ablation, Outcome 2: Any adverse events or complications

Secondary outcomes

Cancer mortality

Vogl 2022 reported that all deaths were tumour‐related, and the authors confirmed that all people died of cancer. Therefore, the results reported for all‐cause mortality are repeated here.

Vogl 2022 reported data for all included participants. Two‐year mortality rate was 23.1% (6/26 participants) in the microwave group versus 37.5% (9/24 participants) in the radiofrequency group (RR 0.62, 95% CI 0.26 to 1.47; Analysis 2.1).

Disease‐free survival

Vogl 2022 did not report on disease‐free survival.

Failure to clear liver metastases

Vogl 2022 reported on technical success, defined as treatment delivered according to the protocol with ablation zone covering the whole index tumour in computer tomography at the end of ablation and technical efficacy, which was defined as ablation zone covering the whole index tumour in the first contrast‐enhanced magnetic resonance imaging performed 24 hours after ablation. The trial reported technical success and technical efficacy in 100% of procedures in both groups (i.e. no failure occurred).

Recurrence of liver metastases

Vogl 2022 reported on two types of recurrences: local tumour progression (tumour connected to the ablation zone which was previously effectively cleared) and distant recurrence (new lesion in the part of the liver not previously treated). No participant in the microwave coagulation group demonstrated local progression in 12 months, while there was local progression in two participants in the radiofrequency group (RR 0.19, 95% CI 0.01 to 3.67; 1 trial, 50 participants; very low‐certainty evidence; Analysis 2.3). There was distant recurrence for 10 participants in the microwave group and nine participants in the radiofrequency group (RR 1.03, 95% CI 0.50 to 2.08; 1 trial, 50 participants; Analysis 2.3; very low‐certainty evidence).

2.3. Analysis.

Comparison 2: Microwave coagulation versus radiofrequency ablation, Outcome 3: Recurrence of liver metastases

Time to progression of liver metastases

Vogl 2022 did not report on time to progression of liver metastases.

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

Vogl 2022 did not report on tumour response measures, such as complete response, partial response, stable disease, and disease progression.

Certainty of evidence

The certainty of the evidence for adverse events or complications for the 'microwave coagulation in addition to conventional TACE versus conventional TACE alone' comparison was downgraded to very low because of risk of bias (downgraded two levels for overall high risk of bias in the trial) and indirectness (downgraded one level because most trial participants had cancer of gastrointestinal tract or lungs (i.e. representing only a subset of participants with liver metastases)). We could not assess imprecision according to CIs due to lack of information about the control group. As there was only one trial, we could not assess inconsistency or publication bias (Table 1).

The certainty of evidence for the outcomes providing data for the comparison microwave coagulation versus conventional surgery was very low because of risk of bias (downgraded one level for overall high risk of bias in the trial), imprecision (the outcome 'overall survival' was downgraded two levels due to CIs showing benefit, harm, and no effect); and ratio of upper to lower CI for HR being above three (Zeng 2022); the outcome 'any adverse events or complications' was downgraded one level due to authors not reporting total number of participants with all types of adverse events/complications. However, the total number of events of 16 (well below 100 indicated as not meeting the optimal information size (Guyatt 2011)); outcome 'disease‐free survival' downgraded one level due to authors not reporting SDs or CIs for this outcome and study sample size not meeting the minimal required sample size, and indirectness (the trial included only a subset of participants with liver metastases, i.e. metastases from colorectal cancer adenocarcinoma). As there was only one trial, we could not assess inconsistency or publication bias (Table 2).

The certainty of evidence for the outcomes providing data for the comparison microwave coagulation versus other ablation methods was downgraded to very low because of risk of bias (downgraded one level for overall high risk of bias in the trial) and imprecision (downgraded two levels due to CIs showing benefit, harm, and no effect; ratio of upper to lower CIs being above three for RR or HR (Zeng 2022)), and indirectness (the trial included only a subset of participants with liver metastases, mainly with colorectal cancer and breast cancer metastases). As there was only one trial, we could not assess inconsistency or publication bias (Table 3).

Harm reported in non‐randomised studies retrieved through the searches for randomised clinical trials

The observational study reported complications after procedures in 27% of the people who received microwave ablation and 24% of the people receiving radiofrequency ablation (Correa‐Gallego 2014). Amongst the 118 people, in total, who received ablation with liver resection (no information was provided per group), there were the following complications: wound infection (16%), intra‐abdominal fluid collection (8%), and pleural effusions (4%). Amongst 16 participants who received ablation without liver resection, complications such as wound infections (two cases) and urethral leak associated with primary tumour resection (one case) occurred in three participants (two in the radiofrequency group and one in the microwave group).

Discussion

Summary of main results

Microwave coagulation plus conventional transarterial chemoembolisation versus conventional transarterial chemoembolisation alone

Only one small randomised clinical trial at high risk of bias provided some data on the short‐term effects of microwave coagulation in addition to TACE versus conventional TACE alone in people with liver metastases from various primary locations (mainly from gastrointestinal tract and lung) (Xu 2012). The trial reported higher complete or partial tumour response in the experimental group compared with the control group during at least one month follow‐up, but the evidence is very uncertain. Adverse events or complications were reported, but only in the experimental group.

Microwave coagulation versus conventional surgery

Only one small randomised clinical trial at high risk of bias provided some data on effects of microwave coagulation versus conventional surgery. Analyses showed no evidence of a difference in terms of time to mortality in people with liver metastases from colorectal cancer. The trial provided insufficient data to calculate the risk ratio for all‐cause mortality. The number of adverse events or complications was comparable in both groups, except for the blood transfusion requirement, which was more common in the hepatic resection group. The trial might have been underpowered to determine the difference in time to mortality between the two groups, as the number of participants required for the trial as calculated by the trial authors was 40, but the trial authors excluded 10 participants after randomisation, resulting in the final number of participants analysed being only 30. Also, because of the small sample size of the trial and its high risk of bias, we are very uncertain if there is a difference between observed time to mortality (Shibata 2000).

Microwave coagulation versus other ablation methods

Only one small randomised clinical trial at high risk of bias provided some data on effects of microwave coagulation versus radiofrequency ablation. Analyses showed no evidence of a difference in terms of all‐cause mortality or time to mortality (overall survival) in people with liver metastases from various primary sites (mainly colorectal cancer and breast cancer). Regarding adverse events, there were no major complications in either group. The minor complications, such as low‐grade subcapsular bleeding and a small liver abscess, were reported only for the radiofrequency ablation group. Due to the small sample size of the trial and its high risk of bias, we are very uncertain if there is a difference between observed all‐cause mortality and time to mortality (Vogl 2022).

Harms

In the search result of randomised clinical trials, we identified one non‐randomised study eligible for reporting of data on harm (Correa‐Gallego 2014).

We identified four ongoing trials.

We found no trials assessing microwave coagulation compared with other types of ablation or systemic treatments.

Overall completeness and applicability of evidence

The primary search strategy was broad, as it was designed for all non‐surgical ablation interventions. The update searches were developed specifically for the review question. Additionally, by searching through the reference lists of included trials and by checking identified review articles, we ensured that no relevant studies were overlooked. In addition, we checked registers of ongoing trials and information on the FDA and EMA websites.

Included trials enrolled participants with liver metastases from colorectal cancer only, or liver metastases from various primary locations, but mainly from gastrointestinal tract and lungs, or colorectal cancer and breast cancer. Therefore, the evidence may not be applicable to people with liver metastases from other primary locations, which was reflected in downgrading the certainty of evidence for indirectness. The included trials addressed a limited number of comparisons with limited sample sizes. However, the identified ongoing trials may bring additional evidence on the beneficial and harmful effects of microwave coagulation as compared with other types of ablative methods and systemic treatments.

The included trials lacked information on the effects of interventions on various outcomes prespecified in the review. All trials and all comparisons lacked evidence of the effect of microwave coagulation on health‐related quality of life, disease‐free survival rates, and time to progression of liver metastases, while the evidence was lacking for most outcomes from the comparison of microwave coagulation with no intervention (i.e. all‐cause mortality and time to mortality, cancer mortality, failure to clear liver metastases and recurrence of liver metastases). Other comparisons did not provide data on secondary outcomes, such as cancer mortality, failure to clear liver metastases, and recurrence of liver metastases.

Quality of the evidence

We assessed the trials as reported because we did not succeed in our attempt to explore the trustworthiness of the randomisation process when contacting the trial authors. We assessed each trial at an overall high risk of bias.

Shibata and colleagues did not report allocation concealment, did not provide a protocol, and excluded 25% of participants after randomisation (Shibata 2000). The trial also did not report whether blinding was applied, but we judged that in the case of objective outcomes, such as all‐cause mortality and time to mortality, and carcinoembryonic antigen level (as a measure of tumour response), lack of blinding would unlikely influence the outcomes.

In the trial by Xu and colleagues, there were problems with reporting of the randomisation methods, unclear risk of bias concerning blinding, and unclear risk of bias with respect to selective reporting due to lack of information about the protocol (Xu 2012). We had some doubts about the proper randomisation method used by Xu 2012, so it may be that it is not a randomised trial.

Vogl and colleagues did not report allocation concealment (Vogl 2022). The trial has no registered protocol. Information was insufficient to allow assessment of whether participants, physicians, or outcome assessors were properly blinded. However, the authors confirmed that outcome assessors were blinded, but without any further details. We judged that in the case of objective outcomes, such as all‐cause mortality and time to mortality, lack of blinding would have been unlikely to influence the outcomes. Therefore, the main limitation of this review was the certainty of the available evidence. We assessed the evidence at very low certainty for each comparison as we downgraded by one or two levels due to risk of bias (all trials were at high risk of bias and had single or numerous issues regarding risk of bias); one or two levels for imprecision (CIs showing benefit, harm and no effect, and ratio of upper to lower CIs being above three for HR or RR; authors not reporting total number of participants with events and total number of events not meeting optimal information size; authors not reporting SDs or CIs for outcomes and study sample sizes not meeting minimal required sample size); and one level for indirectness (the trials included subsets of participants with liver metastases and participants had a limited number of primary tumour locations). We could not assess inconsistency or publication bias.

Potential biases in the review process

The process of the review was rigorous; it included the publication of a protocol with all the methods for the review described and followed (Bala 2012). Trained and experienced review authors performed all the selection processes in duplicate to ensure reliability of the methods. The review included wide and comprehensive searches, also for unpublished studies, but publication bias might still be an issue. However, because we found only three trials, we may suspect publication bias, which we could not assess formally, because the minimum number for this is 10 trials (Boutron 2022; Higgins 2022a). A possible issue is also reporting bias because the identified and included trials seemed to lack protocols (Chan 2004). Randomised clinical trials often do not allow detection of adverse events or complications. Therefore, we considered quasi‐randomised and other studies, identified during searches for randomised trials, for data on harms. We did not specifically search for such studies. In our analyses of the trial with missing data, we used an intention‐to‐treat analysis with the assumption that all participants who were excluded after randomisation had a negative outcome, which may have introduced bias into the estimate of the treatment effect. Sensitivity analyses, using intention‐to‐treat analyses with the opposite assumption that all participants who were excluded after randomisation had a positive outcome as well as available‐case analysis, would not have changed the conclusion.

Agreements and disagreements with other studies or reviews

We found several reviews that assessed the efficacy of microwave coagulation in comparison with other ablation methods in various liver metastases.

National Institute for Health and Care Excellence (NICE) guidance based on the review of evidence (one randomised clinical trial that we identified and included (Shibata 2000) and several non‐randomised studies) has not identified major safety issues and showed adequate evidence for tumour ablation (NICE 2016). Therefore, the guidance recommends that microwave ablation be used in the treatment of liver metastases under standard arrangements regarding clinical governance, consent, and audit (NICE 2016).

The literature search identified four other reviews addressing the benefits and harms of microwave coagulation. One was limited to studies published in English with 30 or more participants with liver tumours treated with microwave ablation (Boutros 2010). The authors included mostly case series and two randomised trials (one included in our review (Shibata 2000)) and the other in participants with hepatocellular carcinoma. The authors concluded that microwave ablation might be useful in people with multiple lesions or requiring large necrosis size. The authors also indicated a need for further studies on this procedure. Another review aimed to assess the long‐term outcomes and complications of several types of ablative therapies used in the management of participants with liver metastases of colorectal cancer (Pathak 2011). It included 13 studies on microwave ablation, one of which was the randomised trial included in our review (Shibata 2000). However, the authors analysed data for the cohort of participants receiving microwave coagulation, without comparison with surgical resection. The meta‐analysis by Huo and colleagues compared the efficacy and safety of microwave ablation versus radiofrequency ablation (Huo 2015). They included 16 non‐randomised studies enroling participants with hepatocellular carcinoma or liver metastases. They concluded that both procedures had similar overall survival and safety profiles, but randomised clinical trials were warranted as the conclusions were based on cohort studies. Meijering and colleagues published one systematic review evaluating ablation with microwaves or radiofrequency as compared with systemic chemotherapy or partial resection in participants with colorectal cancer metastases to the liver (Meijerink 2018). They included all types of primary studies, systematic reviews, and guidelines, and they concluded that there was a need for randomised clinical trials. More recently, one review by Abdalla and colleagues compared microwave ablation with surgery and did not provide data on benefits with respect to safety or efficacy (Abdalla 2023). However, one review by Yang and colleagues found better three‐ and five‐year overall and disease‐free survival after microwave ablation in comparison to surgery (Yang 2020). Nevertheless, it included retrospective studies prone to high risk of selection bias. Nieuwenhuizen and colleagues compared microwave ablation, radiofrequency ablation, irreversible electroporation, or stereotactic ablative body radiotherapy and did not confirm any superiority for intermediate size unresectable colorectal liver metastases (Nieuwenhuizen 2022). This review included only one prospective non‐randomised study, and the remaining studies were retrospective. Moreover, the authors observed high heterogeneity in study populations, timing of interventions, and differences in chemotherapy regimens. This confirms that, without randomisation, the reliability of available evidence for any ablation technique or surgery is highly controversial.

Authors' conclusions

Implications for practice.

The evidence regarding the effectiveness of microwave coagulation in people with liver metastases is of very low certainty and is based on three small trials at high risk of bias. Our confidence in the results is limited due to the risk of bias, imprecision, and indirectness.

Only one trial compared microwave coagulation plus conventional transarterial chemoembolisation (TACE) versus conventional TACE alone. Therefore, the evidence is very uncertain about the effect of microwave coagulation on adverse events or complications. The trial lacked information on the effect of microwave coagulation with respect to all‐cause mortality and time to mortality, health‐related quality of life, cancer mortality, disease‐free survival, failure to clear liver metastases, recurrence of liver metastases, time to progression of liver metastases, and tumour response measures.

Only one trial compared microwave coagulation with conventional liver surgery. We conclude that the evidence is very uncertain about the effect of microwave coagulation on all‐cause mortality, disease‐free survival, and adverse events or complications. The trial did not report data on health‐related quality of life, cancer mortality, failure to clear liver metastases, recurrence of liver metastases, time to progression of liver metastases, and tumour response measures.

Only one trial compared microwave coagulation with other ablation methods. We conclude that the evidence is very uncertain about the effect of microwave coagulation on all‐cause mortality, overall survival, adverse events or complications, and recurrence of liver metastases. The trial did not report data on time to mortality, health‐related quality of life, disease‐free survival, time to progression of liver metastases, and tumour response measures.

Current evidence is inconclusive as we need more randomised clinical trials to strengthen the body of evidence and provide insight into the efficacy of microwave coagulation in comparison with no intervention, conventional surgery, and radiofrequency ablation. Due to ethical reasons, it may be unlikely that new trials comparing only microwave coagulation with no intervention will be conducted, but rather this comparison may be made in addition to providing the same treatment to both groups, as patients should receive care according to current guidelines. We did not identify evidence of microwave ablation compared with other types of ablative methods, or versus systemic treatments. We have identified four ongoing trials which may bring additional evidence on the beneficial and harmful effects of microwave coagulation as compared with other types of ablative methods and systemic treatments.

Implications for research.

Good‐quality, large, randomised clinical trials of microwave coagulation versus surgical resection, other ablation methods, or systemic treatments in participants with liver metastases in a wide variety of primary locations are needed. The trials must be designed and reported in accordance with SPIRIT (www.spirit-statement.org/) and CONSORT (www.consort-statement.org) statements, and report on outcomes that reflect the efficacy of the procedure, that is, mortality, overall survival, health‐related quality of life, as well as other patient‐important outcomes.

What's new

Date	Event	Description
27 March 2024	New search has been performed	Review text updated
27 March 2024	New citation required but conclusions have not changed	Despite the inclusion of two new trials identified by the latest literature searches, the conclusions about the uncertainty of results on clinically important outcomes remain unchanged. The two new trials required the addition of two new comparisons.

History

Protocol first published: Issue 10, 2012
Review first published: Issue 10, 2013

Appendices

Appendix 1. Primary search strategies ‐ searches on 5 June 2017

Database	Time span	Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register	29 September 2017	(((liver or hepatic or hepatocellular* or hepato‐cellular*) AND (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced) AND (liver or hepatic))) and (Ablati* OR (injection* and (ethanol or acetic acid)) or PEI or PAI)
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library	5 June 2017	(((liver or hepatic or hepatocellular* or hepato‐cellular*) AND (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced) AND (liver or hepatic))) and (rfta or radio‐frequ* or radiofrequ* or rfa or rf OR Ablati* OR (injection* and (ethanol or acetic acid)) or PEI or PAI OR Yttrium Radioisotopes OR selective internal radi* OR radioemboli* OR radio‐emboli* OR sir‐sphere* OR therasphere* OR ((yttrium* or 90y* or radiolabel*) AND microsphere*) OR Embolisation OR Embolisation OR ((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation OR lipiodol or HAI or arterial infusion or targeted chemotherapy OR ((transcatheter or transarterial) and chemoinfusion) OR Iodized Oil OR thermotherapy OR Hyperthermia OR Microwaves or coagulation OR cryosurgery)
MEDLINE Ovid	1950 to 5 June 2017	1 exp Carcinoma, Hepatocellular/ 2 exp Liver Neoplasms/ 3 hcc.mp. 4 ((liver or hepatic or hepatocellular$ or hepato‐cellular$) adj5 (cancer$ or neoplas$ or malign$ or carcinom$ or tumo$)).mp. 5 1 or 2 or 3 or 4 6 exp Neoplasm Metastasis/ 7 (metasta* or secondar* or spread or advanced).mp. 8 6 or 7 9 exp Neuroendocrine Tumors/ 10 exp Apudoma/ 11 exp Carcinoid Tumour/ 12 exp Adenoma, Islet Cell/ 13 exp Insulinoma/ 14 exp Carcinoma, Islet Cell/ 15 exp Gastrinoma/ 16 exp Glucagonoma/ 17 exp Somatostatinoma/ 18 exp Vipoma/ 19 exp Multiple Endocrine Neoplasia/ 20 exp Pancreatic Neoplasms/ 21 exp Malignant Carcinoid Syndrome/ 22 (neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids).mp. 23 (argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma).mp. 24 (nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses).mp. 25 (multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour).mp. 26 (diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours).mp. 27 (Pancreatic cholera or Verner‐Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome).mp. 28 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 29 exp Colorectal Neoplasms/ 30 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 neoplas$).tw,mp. 31 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 cancer$).tw,mp. 32 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 carcinoma$).tw,mp. 33 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 tumo$).tw,mp. 34 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 malignan$).tw,mp. 35 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 adenocarcinoma$).tw,mp. 36 29 or 30 or 31 or 32 or 33 or 34 or 35 37 exp Liver/ 38 (liver or hepatic).mp. 39 37 or 38 40 28 or 36 41 8 and 39 and 40 42 5 or 41 43 randomised controlled trial.pt. 44 controlled clinical trial.pt. 45 randomized.ab. 46 placebo.ab. 47 randomly.ab. 48 trial.ab. 49 groups.ab. 50 43 or 44 or 45 or 46 or 47 or 48 or 49 51 humans.sh. 52 50 and 51 53 (rfta or radio‐frequ$ or radiofrequ$ or rfa or rf).mp. 54 exp Catheter Ablation/ 55 53 or 54 56 percutaneous.mp. 57 (ablati* and (therap* or treatment* or radiofrequenc* or cryo*)).mp. 58 ((injection* and (ethanol or acetic acid)) or PEI or PAI).mp. 59 57 or 58 60 56 and 59 61 exp Yttrium Radioisotopes/ 62 selective internal radi$.tw,mp. 63 radioemboli$.tw,mp. 64 radio‐emboli$.tw,mp. 65 sir‐sphere$.tw,mp. 66 therasphere$.tw,mp. 67 ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$).tw,mp. 68 61 or 62 or 63 or 64 or 65 or 66 or 67 69 exp Chemoembolisation, Therapeutic/ 70 exp Embolisation, Therapeutic/ 71 (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation).mp. 72 exp Infusions, Intra‐Arterial/ 73 (lipiodol or HAI or arterial infusion or targeted chemotherapy).mp. 74 ((transcatheter or transarterial) and chemo‐infusion).mp. 75 exp Iodized Oil/ 76 69 or 70 or 71 or 72 or 73 or 74 or 75 77 thermotherapy.mp. or exp Hyperthermia, Induced/ 78 exp Microwaves/ or coagulation therapy.mp. or exp Electrocoagulation/ 79 exp Catheter Ablation/ or ablation.mp. 80 cryosurgery.mp. or exp Cryosurgery/ 81 55 or 60 or 68 or 76 or 77 or 78 or 79 or 80 82 42 and 52 and 81
Embase Ovid	1974 to 5 June 2017	1 Liver‐Cell‐Carcinoma# 2 Liver‐Tumour# 3 hcc AND CLINICAL‐TRIAL# AND HUMAN=YES 4 (liver OR hepatic OR hepatocellular$3 OR hepato‐cellular$3) NEAR (cancer$3 OR neoplas$3 OR malign$5 OR carcinom$3 OR tumo$3) AND CLINICAL‐TRIAL# AND HUMAN=YES 5 1 OR 2 OR 3 OR 4 6 Metastasis# 7 metasta$5 OR secondar$3 OR spread OR advanced 8 6 OR 7 9 Neuroendocrine‐Tumour# 10 Apudoma# 11 Carcinoid# 12 Pancreas‐Islet‐Cell‐Tumour# 13 Insulinoma# 14 Pancreas‐Islet‐Cell‐Carcinoma# 15 Gastrinoma# 16 Glucagonoma# 17 Somatostatinoma# 18 Vipoma# 19 Multiple‐Endocrine‐Neoplasia# 20 Pancreas‐Tumour# 21 Carcinoid‐Syndrome# 22 neuroendocrine ADJ tumour OR neuroendocrine ADJ tumours OR neuroendocrine ADJ tumour OR neuroendocrine ADJ tumours OR adenoma OR adenomas OR apudoma OR apudomas OR carcinoid OR carcinoids 23 argentaffinoma OR argentaffinomas OR somatostatinoma OR somatostatinomas OR islet ADJ cell ADJ tumour OR islet ADJ cell ADJ tumours OR island ADJ cell ADJ tumour OR island ADJ cell ADJ tumours OR nesidioblastoma 24 multiple ADJ endocrine ADJ adenomatosis OR familial ADJ endocrine ADJ adenomatoses OR familial ADJ endocrine ADJ adenomatosis OR multiple ADJ endocrine ADJ neoplasms OR vipoma OR vipomas OR diarrheogenic ADJ tumour 25 nesidioblastomas OR insulinoma OR insulinomas OR multiple ADJ endocrine ADJ neoplasia OR multiple ADJ endocrine ADJ adenopathy OR multiple ADJ endocrine ADJ adenopathies OR multiple ADJ endocrine ADJ adenomatoses 26 diarrheogenic ADJ tumours OR diarrheogenic ADJ tumour OR diarrheogenic ADJ tumours OR VIP ADJ secreting ADJ tumour OR VIP ADJ secreting ADJ tumours OR VIP ADJ secreting ADJ tumour OR VIP ADJ secreting ADJ tumours 27 Pancreatic ADJ cholera OR Verner‐Morrison ADJ syndrome OR Verner ADJ Morrison ADJ syndrome OR watery ADJ diarrhoea ADJ syndrome OR watery ADJ diarrhoea ADJ syndrome OR WDHA OR WDHH OR neuroendocrine ADJ carcinoma OR neuroendocrine ADJ carcinomas OR carcinoid ADJ syndrome 28 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 29 Colorectal‐Tumour# 30 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR neoplas$5 31 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR cancer$3 32 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR carcinoma$5 33 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR tumo$5 34 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR malignan$5 35 (colon$5 OR rect$5 OR colorect$3 OR bowel OR large ADJ intestin$5) NEAR adenocarcinoma$5 36 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35 37 Liver# 38 liver OR hepatic 39 37 OR 38 40 28 OR 36 41 8 AND 39 AND 40 42 5 OR 41 43 random$7 OR factorial$3 OR crossover$3 OR cross ADJ over$3 OR placebo$3 OR doubl$3 ADJ blind$5 OR singl$3 ADJ blind$5 OR assign$7 OR allocat$5 OR volunteer$3 44 Crossover‐Procedure# 45 Double‐Blind‐Procedure# 46 Randomized‐Controlled‐Trial# 47 Single‐Blind‐Procedure# 48 43 OR 44 OR 45 OR 46 OR 47 49 rfta OR radio‐frequ$7 OR radiofrequ$7 OR rfa OR rf 50 Catheter‐Ablation# 51 49 OR 50 52 percutaneous 53 ablati$5 AND (therap$5 OR treatment$3 OR radiofrequenc$3 OR cryo$7) 54 injection$3 AND (ethanol OR acetic ADJ acid) OR PEI OR PAI 55 53 OR 54 56 52 AND 55 57 Yttrium# 58 selective ADJ internal ADJ radi$7 OR radioemboli$7 OR radio‐emboli$7 OR sir‐sphere$5 OR therasphere$5 59 (yttrium$7 OR 90y$7 OR radiolabel$7) NEAR microsphere$3 60 57 OR 58 OR 59 61 Chemoembolisation# 62 Artificial‐Embolism# 63 (transcatheter OR transarterial) AND (emboli$5 OR chemoemboli$5) OR TAE OR TACE OR lipiodolisation OR lipiodol ADJ embolisation 64 Intraarterial‐Drug‐Administration#.DE. 65 lipiodol OR HAI OR arterial ADJ infusion OR targeted ADJ chemotherapy 66 (transcatheter OR transarterial) AND chemo‐infusion 67 (transcatheter OR transarterial) AND chemo ADJ infusion 68 Iodinated‐Poppyseed‐Oil#.DE. 69 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68 70 Hyperthermic‐Therapy 71 thermotherapy 72 Microwave‐Radiation# 73 Cryocoagulation# OR Electrocoagulation# OR Laser‐Coagulation# 74 coagulation ADJ therapy 75 Catheter‐Ablation# 76 ablation 77 Cryosurgery#.W..DE. 78 70 OR 71 OR 72 OR 73 OR 74 OR 75 OR 76 OR 77 79 51 OR 56 OR 60 OR 69 OR 78 80 42 AND 48 AND 79 81 HUMAN=YES 82 80 AND 81 83 CLINICAL‐TRIAL# 84 82 AND 83
LILACS (Bireme)	1982 to 5 June 2017	(Pt RANDOMIZED CONTROLLED TRIAL OR Pt CONTROLLED CLINICAL TRIAL OR Mh RANDOMIZED CONTROLLED TRIALS OR Mh RANDOM ALLOCATION OR Mh DOUBLE‐BLIND METHOD OR Mh SINGLE‐BLIND METHOD OR Pt MULTICENTER STUDY) OR ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw clinic$)) AND NOT ((CT ANIMALS OR MH ANIMALS OR CT RABBITS OR CT MICE OR MH RATS OR MH PRIMATES OR MH DOGS OR MH RABBITS OR MH SWINE) AND NOT (CT HUMAN AND CT ANIMALS)) [Palavras] and (liver or hepatic) [Palavras]
Science Citation Index Expanded (Web of Science)	1970 to 5 June 2017	# 70 #69 AND #37 AND #30 # 69 #68 OR #67 OR #66 OR #65 OR #64 OR #54 OR #45 OR #40 # 68 TS=(cryosurgery OR cryo‐surgery) # 67 TS=(ablation*) # 66 TS=(Microwaves* or Microwave‐Radiation* OR coagulation therapy or Electrocoagulation* or Electro‐coagulation* or Cryocoagulation* OR Laser‐Coagulation* OR Cryo‐coagulation* ) # 65 TS= (thermotherapy or Induced Hyperthermia or Hyperthermic Therapy) # 64 #63 OR #62 OR #61 OR #60 OR #59 OR #58 OR #57 OR #56 OR #55 # 63 TS=Iodinated Poppyseed Oil # 62 TS=Intra‐arterial Drug Administration # 61 TS=Artificial‐Embolism # 60 TS=Iodized Oil* # 59 TS=((transcatheter or transarterial) and chemo‐infusion) # 58 TS=(lipiodol or HAI or arterial infusion or targeted chemotherapy) # 57 TS=Intra‐Arterial Infusion* # 56 TS=(((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation) # 55 TS=Embolisation # 54 #53 OR #52 OR #51 OR #50 OR #49 OR #48 OR #47 OR #46 # 53 TS=Yttrium # 52 TS=((yttrium* and microsphere*) or (90y* and microsphere*) or (radiolabel* and microsphere*)) # 51 TS=therasphere* # 50 TS=sir‐sphere* # 49 TS=radio‐emboli* # 48 TS=radioemboli* # 47 TS=selective internal radi* # 46 TS=Yttrium Radioisotopes # 45 #44 AND #41 # 44 #43 OR #42 # 43 TS=((injection* and (ethanol or acetic acid)) or PEI or PAI) # 42 TS=(ablati* and (therap* or treatment* or radiofrequenc* or cryo*)) # 41 TS=percutaneous # 40 #39 OR #38 # 39 TS=Catheter Ablation # 38 TS=(rfta or radio‐frequ* or radiofrequ* or rfa or rf) # 37 #36 AND #35 # 36 TS=human* # 35 #34 OR #33 OR #32 OR #31 # 34 TS=trial* # 33 TS=random* # 32 TS=groups # 31 TS=placebo # 30 #29 OR #10 # 29 #28 AND #27 AND #11 # 28 #26 OR #19 # 27 TS=(liver or hepatic) # 26 #25 OR #24 OR #23 OR #22 OR #21 OR #20 # 25 TS=(colon* adenocarcinoma* or rect* adenocarcinoma* or colorect* adenocarcinoma* or bowel adenocarcinoma* or large intestin* adenocarcinoma*) # 24 TS=(colon* malignan* or rect* malignan* or colorect* malignan* or bowel malignan* or large intestin* malignan*) # 23 TS=(colon* tumo* or rect* tumo* or colorect* tumo* or bowel tumo* or large intestin* tumo*) # 22 TS=(colon* carcinoma* or rect* carcinoma* or colorect* carcinoma* or bowel carcinoma* or large intestin* carcinoma*) # 21 TS=(colon* cancer* or rect* cancer* or colorect* cancer* or bowel cancer* or large intestin* cancer*) # 20 TS=(colon* neoplas* or rect* neoplas* or colorect* neoplas* or bowel neoplas* or large intestin* neoplas*) # 19 #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 # 18 TS=(Gastrinoma or Glucagonoma or Somatostatinoma or Pancreatic Neoplasm*) # 17 TS=(Pancreatic cholera or Verner‐Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome) # 16 TS=(diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours) # 15 TS=(multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour) # 14 TS=(nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses) # 13 TS=(argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma) # 12 TS=(neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids) # 11 TS=(Neoplasm Metastasis or metasta* or secondar* or spread or advanced) # 10 #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1 # 9 TS=(Liver‐Cell‐Carcinoma or Liver Cell Carcinoma) # 8 TS=(liver malign* or hepatic malign* or hepatocellular* malign* or hepato‐cellular* malign*) # 7 TS=(liver tumo* or hepatic tumo* or hepatocellular* tumo* or hepato‐cellular* tumo*) # 6 TS=(liver carcinom* or hepatic carcinom* or hepatocellular* carcinom* or hepato‐cellular* carcinom*) # 5 TS=(liver neoplas* or hepatic neoplas* or hepatocellular* neoplas* or hepato‐cellular* neoplas*) # 4 TS=(liver cancer* or hepatic cancer* or hepatocellular* cancer* or hepato‐cellular* cancer*) # 3 TS=hcc # 2 TS=Liver Neoplasms # 1 TS=Hepatocellular Carcinoma
CINAHL (EBSCO)	1982 to 5 June 2017	1 exp Carcinoma, Hepatocellular/ 2 exp Liver Neoplasms/ 3 hcc.mp. 4 ((liver or hepatic or hepatocellular$ or hepato‐cellular$) adj5 (cancer$ or neoplas$ or malign$ or carcinom$ or tumo$)).mp. 5 1 or 2 or 3 or 4 6 exp Neoplasm Metastasis/ 7 (metasta* or secondar* or spread or advanced).mp. 8 6 or 7 9 exp Neuroendocrine Tumors/ 10 Apudoma.mp. 11 exp Carcinoid Tumour/ 12 exp Adenoma, Islet Cell/ 13 exp INSULINOMA/ 14 exp Carcinoma, Islet Cell/ 15 exp GASTRINOMA/ 16 Glucagonoma.mp. or exp Glucagon/ 17 Somatostatinoma.mp. 18 Vipoma.mp. 19 exp Endocrine Gland Neoplasms/ or Multiple Endocrine Neoplasia.mp. 20 exp Pancreatic Neoplasms/ 21 Malignant Carcinoid Syndrome.mp. or exp Gastrointestinal Neoplasms/ 22 (neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids).mp. 23 (argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma).mp. 24 (nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses).mp. 25 (multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour).mp. 26 (diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours).mp. 27 (Pancreatic cholera or Verner‐Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome).mp. 28 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 29 exp Colorectal Neoplasms/ 30 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 neoplas$).tw,mp. 31 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 cancer$).tw,mp. 32 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 carcinoma$).tw,mp. 33 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 tumo$).tw,mp. 34 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 malignan$).tw,mp. 35 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 adenocarcinoma$).tw,mp. 36 29 or 30 or 31 or 32 or 33 or 34 or 35 37 exp LIVER/ 38 (liver or hepatic).mp. 39 37 or 38 40 28 or 36 41 8 and 39 and 40 42 5 or 41 43 randomised controlled trial.pt. 44 controlled clinical trial.pt. 45 randomized.ab. 46 placebo.ab. 47 randomly.ab. 48 trial.ab. 49 groups.ab. 50 43 or 44 or 45 or 46 or 47 or 48 or 49 51 (rfta or radio‐frequ$ or radiofrequ$ or rfa or rf).mp. 52 exp Catheter Ablation/ 53 51 or 52 54 percutaneous.mp. 55 (ablati* and (therap* or treatment* or radiofrequenc* or cryo*)).mp. 56 ((injection* and (ethanol or acetic acid)) or PEI or PAI).mp. 57 55 or 56 58 54 and 57 59 Yttrium Radioisotopes.mp. 60 selective internal radi$.tw,mp. 61 radioemboli$.tw,mp. 62 radio‐emboli$.tw,mp. 63 sir‐sphere$.tw,mp. 64 therasphere$.tw,mp. 65 ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$).tw,mp. 66 59 or 60 or 61 or 62 or 63 or 64 or 65 67 exp Chemoembolisation, Therapeutic/ 68 exp Embolisation, Therapeutic/ 69 (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation).mp. 70 exp Infusions, Intraarterial/ 71 (lipiodol or HAI or arterial infusion or targeted chemotherapy).mp. 72 ((transcatheter or transarterial) and chemo‐infusion).mp. 73 Iodized Oil.mp. 74 67 or 68 or 69 or 70 or 71 or 72 or 73 75 exp Hyperthermia, Induced/ 76 thermotherapy.mp. 77 exp MICROWAVES/ 78 Electrocoagulation.mp. 79 coagulation therapy.mp. 80 exp Catheter Ablation/ 81 ablation.mp. 82 cryosurgery.mp. or exp CRYOSURGERY/ 83 53 or 58 or 66 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 84 42 and 52 and 83

Appendix 2. Search strategies for the updated searches on 28 June 2018 and 3 September 2019

Database	Time span	Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register	3 September 2019	(((microwave* or thermal or necrosis or therap* or electro*) and coagulat*) or ((microwave and (irradiat* or radiat*)) or electrocoagulat*)) AND (((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced) and (liver or hepatic)))
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library	2019, Issue 9	#1 MeSH descriptor: [Microwaves] explode all trees #2 MeSH descriptor: [Electrocoagulation] explode all trees #3 (microwave* or thermal or necrosis or therap* or electro*) and coagulat* #4 (microwave and (irradiat* or radiat*)) or electrocoagulat* #5 #1 or #2 or #3 or #4 #6 MeSH descriptor: [Carcinoma, Hepatocellular] explode all trees #7 MeSH descriptor: [Liver Neoplasms] explode all trees #8 ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #9 #6 or #7 or #8 #10 MeSH descriptor: [Neoplasm Metastasis] explode all trees #11 MeSH descriptor: [Liver] explode all trees #12 ((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #13 (#10 and #11) or #12 #14 #5 and (#9 or #13)
MEDLINE Ovid	1946 to 3 September 2019	1. exp MICROWAVES/ 2. exp ELECTROCOAGULATION/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 5. 1 or 2 or 3 or 4 6. exp Carcinoma, Hepatocellular/ 7. exp Liver Neoplasms/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 9. 6 or 7 or 8 10. exp Neoplasm Metastasis/ 11. exp LIVER/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 16. 14 and 15
Embase Ovid	1974 to 3 September 2019	1. exp microwave radiation/ 2. exp electrocoagulation/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 5. 1 or 2 or 3 or 4 6. exp liver cell carcinoma/ 7. exp liver tumor/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 9. 6 or 7 or 8 10. exp metastasis/ 11. exp liver/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 16. 14 and 15
LILACS (Bireme)	1982 to 3 September 2019	(((microwave$ or thermal or necrosis or therap$ or electro$) and coagulat$) or ((microwave and (irradiat$ or radiat$)) or electrocoagulat$)) [Words] and (((liver or hepatic or hepatocellular$ or hepato‐cellular$) and (cancer$ or neoplasm$ or malign$ or carcinoma$ or tumo$)) or ((metasta$ or secondar$ or spread or advanced) and (liver or hepatic))) [Words]
Science Citation Index Expanded (Web of Science)	1900 to 3 September 2019	#8 #7 AND #6 #7 TS=(random* or blind* or placebo* or meta‐analys*) #6 #3 and (#4 or #5) #5 TS=((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #4 TS=((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #3 #2 OR #1 #2 TS=((microwave and (irradiat* or radiat*)) or electrocoagulat*) #1 TS=((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
Conference Proceedings Citation Index – Science (Web of Science)	1900 to 3 September 2019	#8 #7 AND #6 #7 TS=(random* or blind* or placebo* or meta‐analys*) #6 #3 and (#4 or #5) #5 TS=((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #4 TS=((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #3 #2 OR #1 #2 TS=((microwave and (irradiat* or radiat*)) or electrocoagulat*) #1 TS=((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
CINAHL (EBSCO)	1982 to 3 September 2019	1 exp Carcinoma, Hepatocellular/ 2 exp Liver Neoplasms/ 3 hcc.mp. 4 ((liver or hepatic or hepatocellular$ or hepato‐cellular$) adj5 (cancer$ or neoplas$ or malign$ or carcinom$ or tumo$)).mp. 5 1 or 2 or 3 or 4 6 exp Neoplasm Metastasis/ 7 (metasta* or secondar* or spread or advanced).mp. 8 6 or 7 9 exp Neuroendocrine Tumors/ 10 Apudoma.mp. 11 exp Carcinoid Tumour/ 12 exp Adenoma, Islet Cell/ 13 exp INSULINOMA/ 14 exp Carcinoma, Islet Cell/ 15 exp GASTRINOMA/ 16 Glucagonoma.mp. or exp Glucagon/ 17 Somatostatinoma.mp. 18 Vipoma.mp. 19 exp Endocrine Gland Neoplasms/ or Multiple Endocrine Neoplasia.mp. 20 exp Pancreatic Neoplasms/ 21 Malignant Carcinoid Syndrome.mp. or exp Gastrointestinal Neoplasms/ 22 (neuroendocrine tumour or neuroendocrine tumours or neuroendocrine tumour or neuroendocrine tumours or adenoma or adenomas or apudoma or apudomas or carcinoid or carcinoids).mp. 23 (argentaffinoma or argentaffinomas or somatostatinoma or somatostatinomas or islet cell tumour or islet cell tumours or island cell tumour or island cell tumours or nesidioblastoma).mp. 24 (nesidioblastomas or insulinoma or insulinomas or multiple endocrine neoplasia or multiple endocrine adenopathy or multiple endocrine adenopathies or multiple endocrine adenomatoses).mp. 25 (multiple endocrine adenomatosis or familial endocrine adenomatoses or familial endocrine adenomatosis or multiple endocrine neoplasms or vipoma or vipomas or diarrheogenic tumour).mp. 26 (diarrheogenic tumours or diarrheogenic tumour or diarrheogenic tumours or VIP secreting tumour or VIP secreting tumours or VIP secreting tumour or VIP secreting tumours).mp. 27 (Pancreatic cholera or Verner‐Morrison syndrome or Verner Morrison syndrome or watery diarrhoea syndrome or watery diarrhoea syndrome or WDHA or WDHH or neuroendocrine carcinoma or neuroendocrine carcinomas or carcinoid syndrome).mp. 28 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 29 exp Colorectal Neoplasms/ 30 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 neoplas$).tw,mp. 31 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 cancer$).tw,mp. 32 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 carcinoma$).tw,mp. 33 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 tumo$).tw,mp. 34 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 malignan$).tw,mp. 35 ((colon$ or rect$ or colorect$ or bowel or large intestin$) adj5 adenocarcinoma$).tw,mp. 36 29 or 30 or 31 or 32 or 33 or 34 or 35 37 exp LIVER/ 38 (liver or hepatic).mp. 39 37 or 38 40 28 or 36 41 8 and 39 and 40 42 5 or 41 43 randomised controlled trial.pt. 44 controlled clinical trial.pt. 45 randomized.ab. 46 placebo.ab. 47 randomly.ab. 48 trial.ab. 49 groups.ab. 50 43 or 44 or 45 or 46 or 47 or 48 or 49 51 (rfta or radio‐frequ$ or radiofrequ$ or rfa or rf).mp. 52 exp Catheter Ablation/ 53 51 or 52 54 percutaneous.mp. 55 (ablati* and (therap* or treatment* or radiofrequenc* or cryo*)).mp. 56 ((injection* and (ethanol or acetic acid)) or PEI or PAI).mp. 57 55 or 56 58 54 and 57 59 Yttrium Radioisotopes.mp. 60 selective internal radi$.tw,mp. 61 radioemboli$.tw,mp. 62 radio‐emboli$.tw,mp. 63 sir‐sphere$.tw,mp. 64 therasphere$.tw,mp. 65 ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$).tw,mp. 66 59 or 60 or 61 or 62 or 63 or 64 or 65 67 exp Chemoembolisation, Therapeutic/ 68 exp Embolisation, Therapeutic/ 69 (((transcatheter or transarterial) and (emboli* or chemoemboli*)) or TAE or TACE or lipiodolisation or lipiodol embolisation).mp. 70 exp Infusions, Intraarterial/ 71 (lipiodol or HAI or arterial infusion or targeted chemotherapy).mp. 72 ((transcatheter or transarterial) and chemo‐infusion).mp. 73 Iodized Oil.mp. 74 67 or 68 or 69 or 70 or 71 or 72 or 73 75 exp Hyperthermia, Induced/ 76 thermotherapy.mp. 77 exp MICROWAVES/ 78 Electrocoagulation.mp. 79 coagulation therapy.mp. 80 exp Catheter Ablation/ 81 ablation.mp. 82 cryosurgery.mp. or exp CRYOSURGERY/ 83 53 or 58 or 66 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 84 42 and 52 and 83

Appendix 3. Search strategies for the updated searches on 18 December 2020

Database	Time span	Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register	18 December 2020	(((microwave* or thermal or necrosis or therap* or electro*) and coagulat*) or ((microwave and (irradiat* or radiat*)) or electrocoagulat*)) AND (((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced) and (liver or hepatic)))
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library	2020, Issue 12	#1 MeSH descriptor: [Microwaves] explode all trees #2 MeSH descriptor: [Electrocoagulation] explode all trees #3 (microwave* or thermal or necrosis or therap* or electro*) and coagulat* #4 (microwave and (irradiat* or radiat*)) or electrocoagulat* #5 #1 or #2 or #3 or #4 #6 MeSH descriptor: [Carcinoma, Hepatocellular] explode all trees #7 MeSH descriptor: [Liver Neoplasms] explode all trees #8 ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #9 #6 or #7 or #8 #10 MeSH descriptor: [Neoplasm Metastasis] explode all trees #11 MeSH descriptor: [Liver] explode all trees #12 ((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #13 (#10 and #11) or #12 #14 #5 and (#9 or #13)
MEDLINE Ovid	1946 to 18 December 2020	1. exp MICROWAVES/ 2. exp ELECTROCOAGULATION/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 5. 1 or 2 or 3 or 4 6. exp Carcinoma, Hepatocellular/ 7. exp Liver Neoplasms/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 9. 6 or 7 or 8 10. exp Neoplasm Metastasis/ 11. exp LIVER/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. (randomized controlled trial or controlled clinical trial).pt. or clinical trials as topic.sh. or trial.ti. 16. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 17. 14 and (15 or 16)
Embase Ovid	1974 to 18 December 2020	1. exp microwave radiation/ 2. exp electrocoagulation/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 5. 1 or 2 or 3 or 4 6. exp liver cell carcinoma/ 7. exp liver tumor/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 9. 6 or 7 or 8 10. exp metastasis/ 11. exp liver/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. Randomized controlled trial/ or Controlled clinical study/ or trial.ti. 16. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 17. 14 and (15 or 16)
LILACS (Bireme)	1982 to 18 December 2020	(((microwave$ or thermal or necrosis or therap$ or electro$) and coagulat$) or ((microwave and (irradiat$ or radiat$)) or electrocoagulat$)) [Words] and (((liver or hepatic or hepatocellular$ or hepato‐cellular$) and (cancer$ or neoplasm$ or malign$ or carcinoma$ or tumo$)) or ((metasta$ or secondar$ or spread or advanced) and (liver or hepatic))) [Words]
Science Citation Index Expanded and Conference Proceedings Citation Index – Science (Web of Science)	1900 to 18 December 2020	#8 #7 AND #6 #7 TI=(random* or blind* or placebo* or meta‐analys* or trial*) OR TS=(random* or blind* or placebo* or meta‐analys*) #6 #3 and (#4 or #5) #5 TS=((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #4 TS=((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #3 #2 OR #1 #2 TS=((microwave and (irradiat* or radiat*)) or electrocoagulat*) #1 TS=((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
CINAHL (EBSCO)	1982 to 18 December 2020	S38 S36 AND S37 Limiters ‐ Exclude MEDLINE records S37 TX (random* OR placebo* OR blind* OR trial* OR group*) S36 S3 AND S6 AND S28 AND S35 S35 S29 OR S30 OR S31 OR S32 OR S33 OR S34 S34 TX radiat* S33 TX irradiat* S32 TX electrocoagulat* S31 TX hyperthermia* S30 TX thermotherap* S29 TX Microwave* S28 S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 S27 TX ((colon* OR rect* OR colorect* OR bowel OR large intestin*) AND (neoplas* OR cancer* OR carcinoma* OR tumo?r* OR malignan* OR adenocarcinoma*)) S26 MM colorectal neoplasms S25 TX (Pancreatic cholera OR Verner‐Morrison syndrome OR Verner Morrison syndrome OR watery diarrhoea syndrome OR WDHA OR WDHH OR neuroendocrine carcinoma*) S24 TX VIP secreting tumo?r* S23 TX (familial endocrine adenomatos* OR diarrheogenic tumo?r*) S22 TX (insulinoma* OR (multiple endocrine AND (neoplasia OR adenopath* OR adenomatos* OR neoplasm*))) S21 TX (argentaffinoma* OR somatostatinoma* OR islet cell tumo?r* OR island cell tumo?r* OR nesidioblastoma*) S20 TX ((neuroendocrine AND tumo?r*) OR (adenoma* OR apudoma* OR carcinoid*)) S19 TX malignant carcinoid syndrome Search modes S18 TX (apudoma* OR glucagonoma* OR somatostatinoma* OR vipoma*) S17 MM (apudoma OR glucagonoma OR somatostatinoma) S16 MM glucagon S15 MM gastrointestinal neoplasms S14 MM endocrine gland neoplasms S13 MM pancreatic neoplasms S12 MM gastrinoma S11 MM insulinoma S10 MM carcinoma, islet cell S9 MM adenoma, islet cell S8 MM carcinoid tumor S7 MM neuroendocrine tumors S6 S4 OR S5 S5 TX (metasta* OR secondar* OR spread OR advanced) S4 MM neoplasm metastasis S3 S1 OR S2 S2 MM (liver OR hepatic) S1 MM liver

Appendix 4. Search strategies for the updated searches on 14 April 2023

Database	Date range	Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register (via the Cochrane Register of Studies Web)	14 April 2023	(((microwave* or thermal or necrosis or therap* or electro*) and coagulat*) or ((microwave and (irradiat* or radiat*)) or electrocoagulat*)) AND (((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) OR ((metasta* or secondar* or spread or advanced) and (liver or hepatic)))
Cochrane Central Register of Controlled Trials in the Cochrane Library	2023, Issue 4	#1 MeSH descriptor: [Microwaves] explode all trees #2 MeSH descriptor: [Electrocoagulation] explode all trees #3 (microwave* or thermal or necrosis or therap* or electro*) and coagulat* #4 (microwave and (irradiat* or radiat*)) or electrocoagulat* #5 #1 or #2 or #3 or #4 #6 MeSH descriptor: [Carcinoma, Hepatocellular] explode all trees #7 MeSH descriptor: [Liver Neoplasms] explode all trees #8 ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #9 #6 or #7 or #8 #10 MeSH descriptor: [Neoplasm Metastasis] explode all trees #11 MeSH descriptor: [Liver] explode all trees #12 ((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #13 (#10 and #11) or #12 #14 #5 and (#9 or #13)
MEDLINE ALL Ovid	1946 to 14 April 2023	1. exp MICROWAVES/ 2. exp ELECTROCOAGULATION/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms, population supplementary concept word, anatomy supplementary concept word] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms, population supplementary concept word, anatomy supplementary concept word] 5. 1 or 2 or 3 or 4 6. exp Carcinoma, Hepatocellular/ 7. exp Liver Neoplasms/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms, population supplementary concept word, anatomy supplementary concept word] 9. 6 or 7 or 8 10. exp Neoplasm Metastasis/ 11. exp LIVER/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms, population supplementary concept word, anatomy supplementary concept word] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. (randomized controlled trial or controlled clinical trial or retracted publication or retraction of publication).pt. 16. clinical trials as topic.sh. 17. (random* or placebo*).ab. or trial.ti. 18. 15 or 16 or 17 19. exp animals/ not humans.sh. 20. 18 not 19 21. 14 and 20
Embase Ovid	1974 to 14 April 2023	1. exp microwave radiation/ 2. exp electrocoagulation/ 3. ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword heading word, floating subheading word, candidate term word] 4. ((microwave and (irradiat* or radiat*)) or electrocoagulat*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword heading word, floating subheading word, candidate term word] 5. 1 or 2 or 3 or 4 6. exp liver cell carcinoma/ 7. exp liver tumor/ 8. ((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword heading word, floating subheading word, candidate term word] 9. 6 or 7 or 8 10. exp metastasis/ 11. exp liver/ 12. ((metasta* or secondar* or spread or advanced) and (liver or hepatic)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword heading word, floating subheading word, candidate term word] 13. (10 and 11) or 12 14. 5 and (9 or 13) 15. Randomized controlled trial/ or Controlled clinical study/ or randomization/ or intermethod comparison/ or double blind procedure/ or human experiment/ or retracted article/ 16. (random$ or placebo or parallel group$1 or crossover or cross over or assigned or allocated or volunteer or volunteers).ti,ab. 17. (compare or compared or comparison or trial).ti. 18. ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. 19. (open adj label).ti,ab. 20. ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 21. ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. 22. (controlled adj7 (study or design or trial)).ti,ab. 23. (erratum or tombstone).pt. or yes.ne. 24. or/15‐23 25. (random$ adj sampl$ adj7 ('cross section$' or questionnaire$ or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.) 26. Cross‐sectional study/ not (randomized controlled trial/ or controlled clinical study/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.) 27. (((case adj control$) and random$) not randomi?ed controlled).ti,ab. 28. (Systematic review not (trial or study)).ti. 29. (nonrandom$ not random$).ti,ab. 30. 'Random field$'.ti,ab. 31. (random cluster adj3 sampl$).ti,ab. 32. (review.ab. and review.pt.) not trial.ti. 33. 'we searched'.ab. and (review.ti. or review.pt.) 34. 'update review'.ab. 35. (databases adj4 searched).ab. 36. (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/ 37. Animal experiment/ not (human experiment/ or human/) 38. or/25‐37 39. 24 not 38 40. 14 and 39
Science Citation Index Expanded (Web of Science)	1900 to 14 April 2023	#8 #7 AND #6 #7 TI=(random* or blind* or placebo* or meta‐analys* or trial*) OR TS=(random* or blind* or placebo* or meta‐analys*) #6 #3 and (#4 or #5) #5 TS=((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #4 TS=((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #3 #2 OR #1 #2 TS=((microwave and (irradiat* or radiat*)) or electrocoagulat*) #1 TS=((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
Conference Proceedings Citation Index – Science (Web of Science)	1990 to 14 April 2023	#8 #7 AND #6 #7 TI=(random* or blind* or placebo* or meta‐analys* or trial*) OR TS=(random* or blind* or placebo* or meta‐analys*) #6 #3 and (#4 or #5) #5 TS=((metasta* or secondar* or spread or advanced) and (liver or hepatic)) #4 TS=((liver or hepatic or hepatocellular* or hepato‐cellular*) and (cancer* or neoplasm* or malign* or carcinoma* or tumo*)) #3 #2 OR #1 #2 TS=((microwave and (irradiat* or radiat*)) or electrocoagulat*) #1 TS=((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
LILACS (VHL Regional Portal)	1982 to 14 April 2023	((((microwave* OR thermal OR necrosis OR therap* OR electro*) AND coagulat*) OR ((microwave AND (irradiat* OR radiat*)) OR electrocoagulat*))) AND ((((liver OR hepatic OR hepatocellular* OR hepato‐cellular*) AND (cancer* OR neoplasm* OR malign* OR carcinoma* OR tumo*)) OR ((metasta* OR secondar* OR spread OR advanced) AND (liver OR hepatic)))) AND ( db:("LILACS"))
CINAHL (EBSCO)	1 October 2020 to 18 August 2023	S38 S36 AND S37 Limiters ‐ Exclude MEDLINE records S37 TX (random* OR placebo* OR blind* OR trial* OR group*) S36 S3 AND S6 AND S28 AND S35 S35 S29 OR S30 OR S31 OR S32 OR S33 OR S34 S34 TX radiat* S33 TX irradiat* S32 TX electrocoagulat* S31 TX hyperthermia* S30 TX thermotherap* S29 TX Microwave* S28 S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 S27 TX ((colon* OR rect* OR colorect* OR bowel OR large intestin*) AND (neoplas* OR cancer* OR carcinoma* OR tumo?r* OR malignan* OR adenocarcinoma*)) S26 MM colorectal neoplasms S25 TX (Pancreatic cholera OR Verner‐Morrison syndrome OR Verner Morrison syndrome OR watery diarrhoea syndrome OR WDHA OR WDHH OR neuroendocrine carcinoma*) S24 TX VIP secreting tumo?r* S23 TX (familial endocrine adenomatos* OR diarrheogenic tumo?r*) S22 TX (insulinoma* OR (multiple endocrine AND (neoplasia OR adenopath* OR adenomatos* OR neoplasm*))) S21 TX (argentaffinoma* OR somatostatinoma* OR islet cell tumo?r* OR island cell tumo?r* OR nesidioblastoma*) S20 TX ((neuroendocrine AND tumo?r*) OR (adenoma* OR apudoma* OR carcinoid*)) S19 TX malignant carcinoid syndrome Search modes S18 TX (apudoma* OR glucagonoma* OR somatostatinoma* OR vipoma*) S17 MM (apudoma OR glucagonoma OR somatostatinoma) S16 MM glucagon S15 MM gastrointestinal neoplasms S14 MM endocrine gland neoplasms S13 MM pancreatic neoplasms S12 MM gastrinoma S11 MM insulinoma S10 MM carcinoma, islet cell S9 MM adenoma, islet cell S8 MM carcinoid tumor S7 MM neuroendocrine tumors S6 S4 OR S5 S5 TX (metasta* OR secondar* OR spread OR advanced) S4 MM neoplasm metastasis S3 S1 OR S2 S2 MM (liver OR hepatic) S1 MM liver
ClinicalTrial.gov (clinicaltrials.gov/)	16 July 2023	Condition or disease: Liver metastases Intervention: Microwave
World Health Organization International Clinical Trial Registry Platform (www.who.int/ictrp)	16 July 2023	Liver AND metastases AND microwave
EU Clinical Trials Register (www.clinicaltrialsregister.eu/)	16 July 2023	Liver AND metastases AND microwave
ISRCTN registry (www.isrctn.com/)	16 July 2023	Liver AND microwave
European Medicines Agency (EMA; www.ema.europa.eu/ema/)	11 July 2023	1) (microwave and (irradiat* or radiat*)) or electrocoagulat* OR microwaves 2) ((microwave* or thermal or necrosis or therap* or electro*) and coagulat*)
Food and Drug Administration (FDA; www.fda.gov)	23 July 2023	1. Liver metastases 2. microwave
Pharmaceutical company sources for ongoing or unpublished trials: AstraZeneca Clinical Trials website: www.astrazenecaclinicaltrials.com/ Bristol‐Myers Squibb Clinical Trial Registry: www.bms.com/researchers-and-partners/clinical-trials-and-research/clinical-trial-results.html Eli Lilly and Company Clinical Trial Registry www.lilly.com/clinical-research/clinical-trials GlaxoSmithKline clinical trial register: www.gsk-studyregister.com/en/advanced-study-search/ NovartisClinicalTrials.com: www.novartis.com/clinicaltrials	11 July 2023	1) electrocoagulat* OR microwaves 2) oncology: liver or hepat* 3) liver cancer:metastas* 4) electrocoagulation OR microwaves 5) electrocoagulation OR microwaves
Google Scholar (scholar.google.com/)	23 July 2023	1) allintitle: microwave liver metastases randomized 2) allintitle: microwave liver metastases randomised 3) allintitle: microwave liver metastases rct

Data and analyses

Comparison 1. Microwave ablation in addition to conventional transarterial chemoembolisation (TACE) versus conventional TACE alone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Tumour response	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Microwave coagulation versus radiofrequency ablation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality at 2‐year follow‐up	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.2 Any adverse events or complications	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3 Recurrence of liver metastases	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.3.1 Local progression	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 3.67]
2.3.2 Distant recurrence	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.50, 2.08]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Shibata 2000.

Study characteristics
Methods	Study type: randomised clinical trial Location: Japan, single centre, hospital Time frame of the study: 1990–1997 Inclusion criteria: histological confirmation of colorectal adenocarcinoma, multiple but < 10 metastatic tumours in the liver, histological assessment by core needle biopsy of ≥ 1 of those tumours, dimension of the largest tumour < 80 mm (measured in computed tomography with contrast), no metastases to periportal region, coeliac lymph node or extrahepatic (confirmed by computed tomography and ultrasonography), no ascites (confirmed by computed tomography and ultrasonography), no liver cirrhosis or chronic hepatitis Follow‐up: 3 years (Kaplan‐Meier curve shown up to 49 months)
Participants	Total number of participants: 40 randomly assigned, 30 analysed (10 excluded after randomisation: 6 from intervention and 4 from control group for not meeting inclusion criteria) Primary sites: resectable; colorectal cancer, Stage IB to IIIC (T2N0‐T3N2) Mean size of the liver tumour: mean 27 mm in experimental group and 34 mm in control group Number of tumours: range 2–9, mean 4.1 in experimental group, mean 3.0 in control group Mean age: 61 (SD 10) years Males: 57% in experimental group, 38% in control group
Interventions	2 treatment groups Group 1: microwave coagulation therapy (14 participants included in the analysis of the trial out of 20 randomised) – applied after surgery (laparotomy) using microwave tissue coagulator (HSD‐20M by Azwell, Osaka, Japan) at an output of 60–100 W for 2–20 minutes under the guidance of ultrasonography. Group 2: conventional surgery (16 participants included in the analysis of the trial out of 20 randomised) – involved lobectomy, segmentectomy, subsegmentectomy, wedge resection, or combinations of these.
Outcomes	Number of deaths at the end of follow‐up; 1‐, 2‐, 3‐year overall survival; disease‐free interval; tumour response measures; adverse events or complications
Notes	Letters to authors sent on 3 July 2018 and 13 Oct 2020 to enquire about trial methods and other missing information for the conductance of the review analysis. No reply received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Enroled participants were assigned to the groups randomly with the use of a computer‐generated, 1:1 randomisation list, no stratification used.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All‐cause mortality and time to mortality	Low risk	Not reported; however, in case of objective outcomes, such as all‐cause mortality and time to mortality, lack of blinding will be unlikely to influence the outcomes.
Blinding of participants and personnel (performance bias) Adverse events or complications	Unclear risk	Not reported; insufficient details were provided about the measurement of this outcome; therefore, the influence of the lack of blinding is unclear.
Blinding of participants and personnel (performance bias) Tumour response measures	Low risk	Not reported; measured in an objective way – level of carcinoembryonic antigen level, so lack of blinding unlikely to have influenced the outcomes.
Blinding of outcome assessment (detection bias) All‐cause mortality and time to mortality	Low risk	Not reported; however, in case of objective outcomes, such as all‐cause mortality and time to mortality, lack of blinding unlikely to have influenced the outcomes.
Blinding of outcome assessment (detection bias) Adverse events or complications	Unclear risk	Not reported; insufficient details were provided about the measurement of this outcome; therefore, the influence of the lack of blinding was unclear.
Blinding of outcome assessment (detection bias) Tumour response measures	Low risk	Not reported; measured in an objective way – level of carcinoembryonic antigen level, lack of blinding unlikely to have influenced the outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	High dropout rate; 10 participants excluded after randomisation (during surgery) 6/20 participants in microwave group (reasons: metastases in the periportal or coeliac lymph nodes (or both) (1 participant); ≥ 10 metastatic tumours in the liver (determined using intraoperative ultrasonography directly on the liver) (3 participants); peritoneal dissemination of the tumour (2 participants)) 4/20 participants in control group (metastases in the periportal or coeliac lymph nodes (or both) (2 participants); ≥ 10 metastatic tumours in the liver (determined using intraoperative ultrasonography directly on the liver) (2 participants))
Selective reporting (reporting bias)	Unclear risk	No protocol reported or available, but all‐cause mortality and overall survival information given with P value and curve; not clear if any other clinically important outcomes were planned to be assessed.
Other bias	Unclear risk	Insufficient information.

Vogl 2022.

Study characteristics
Methods	Study type: randomised clinical trial Location: Germany, single centre, hospital Time frame of the study: January 2014 to April 2016 Inclusion criteria: diagnosis of liver metastases confirmed histologically or radiologically (or both), lesions' axial diameter < 5 cm, maximum of 5 lesions, magnetic resonance imaging examination using 1.5 Tesla (T) or 3 T, thermal ablation as therapy option, consent (written and verbal), aged > 18 years, good general condition, therapy planned clinically with decision made by a multidisciplinary tumour board Follow‐up: 2 years for survival, 12 months for recurrence of tumour disease
Participants	50 participants with liver metastases (27 females, 23 males, mean age: 62.8 (SD 11.8) years, age range: 40–91 years) Total number of participants: 50 randomly assigned (1 participant was assigned to the MWA group instead of the RFA group by mistake, so final number was 26 participants in MWA group and 24 participants in the RFA group), 50 participants were analysed. Primary sites: colorectal carcinoma 54% (13 in MWA and 14 in RFA), breast cancer 22% (6 in MWA and 5 in RFA), pancreatic carcinoma 6.0% (3 in MWA and 0 in RFA), ovarian carcinoma 4% (2 in MWA and 0 in RFA), cholangiocarcinoma 6% (1 in MWA and 2 in RFA), neuroendocrine tumour 2% (1 in MWA), oesophageal cancer 2% (1 in RFA), uveal melanoma 2% (1 in RFA), oropharyngeal cancer 2% (1 in RFA). Mean size of the liver tumour: MWA: 17.2 (SD 8.1) mm (range: 6.3–37.1 mm), RFA: 15.3 (SD 6.1) mm (range: 7.6–34.4 mm) Number of tumours: all participants had multiple metastases (information from the author). Mean age: MWA: 62.7 (SD 11.8) years; RFA: 63.3 (SD 11.8) years Males: MWA: 14/26 (53.8%) participants, RFA: 13/24 (54.2%) participants Previous treatment: in the RFA group 22/24 (91.6%) participants underwent surgical resection before ablative therapy, 17/24 (70.8%) were treated with TACE, and 16/24 (66.6%) participants were treated with systemic chemotherapy before trial inclusion. In the MWA group, 23/26 (88.5%) participants underwent previous surgery and 14/26 (53.8%) underwent TACE before the trial commencement and 0 participants in this group received systemic chemotherapy (information from the author).
Interventions	2 treatment groups Group 1: MWA performed with a single electrode device in 3 steps, starting with output power of 45–60 W for 1 minute, followed by increased output power of 65–80 W for 1 minute, and finally 85–100 W for 5–10 minutes. Output frequencies were 2450 MHz and a maximum output power was 140 W. Group 2: RFA performed with a single electrode device with an output power of 200 W. Output frequencies were 450 kHz and procedure lasted 10–20 minutes. Both procedures were performed under the guidance of computer tomography.
Outcomes	Mortality rate at 12, 24 months; local recurrence rate (local tumour progression) within 12 months; development of malignant formations (distant intrahepatic recurrence) within 12 months; serious and non‐serious complications
Notes	Trial partially supported by Medicor (MMS Medicor Medical Supplies GmbH, Kerpen, Germany) for statistical analysis. Letters to authors sent on 16 and 18 August 2023 to enquire about trial methods, protocol, and other missing information for the conductance of the review analysis. We received partial replies to the questions, but not all information was fully provided.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned in a 1:1 ratio.
Allocation concealment (selection bias)	Unclear risk	Not reported; the trial used a permuted block design and there was no information on whether the researchers are aware of the block size. This lack of information raises the concern that the researchers might be able to predict which treatment group a particular individual was assigned last in the block. Authors replied that no external body was involved in randomisation process but did not provide information on how the process.
Blinding of participants and personnel (performance bias) All‐cause mortality and time to mortality	Low risk	Not reported; however, in case of objective outcomes, such as all‐cause mortality and time to mortality, lack of blinding unlikely to have influenced the outcomes.
Blinding of participants and personnel (performance bias) Adverse events or complications	Unclear risk	Not reported; insufficient details were provided about the measurement of this outcome; therefore, the influence of the lack of blinding was unclear.
Blinding of participants and personnel (performance bias) Recurrence of liver metastases and failure to clear liver metastases	Low risk	The outcome was clearly defined and measured using objective methods – magnetic resonance imaging.
Blinding of outcome assessment (detection bias) All‐cause mortality and time to mortality	Low risk	Not reported; however, in case of objective outcomes, such as all‐cause mortality and time to mortality, lack of blinding unlikely to have influenced the outcomes.
Blinding of outcome assessment (detection bias) Adverse events or complications	Unclear risk	Not reported; insufficient details were provided about the measurement of this outcome; therefore, the influence of the lack of blinding was unclear.
Blinding of outcome assessment (detection bias) Recurrence of liver metastases and failure to clear liver metastases	Low risk	The outcome was clearly defined and measured using objective methods – magnetic resonance imaging.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data, no withdrawals; also confirmed by trial authors.
Selective reporting (reporting bias)	Unclear risk	No protocol found and not provided by trial authors.
Other bias	Unclear risk	Insufficient information.

Xu 2012.

Study characteristics
Methods	Study type: randomised clinical trial Location: China, single centre, hospital Time frame of the study: March 2008 to February 2012 Inclusion criteria: liver metastases confirmed with clinical data and computed tomography/magnetic resonance imaging/biopsy Follow‐up: ≥ 1 month
Participants	Total number of participants: 50 randomly assigned and analysed Primary sites: gastrointestinal tract (27 participants), mammary gland (3 participants), lung (10 participants), pancreas (6 participants), other sites (4 participants) Mean size of the liver tumour: 4.5 cm Number of tumours: single liver metastases (23 participants), multiple liver metastases (27 participants) Mean age: 60 years Males: 76%
Interventions	2 treatment groups Group 1: microwave coagulation therapy in addition to conventional TACE (25 participants) Group 2: conventional TACE alone (25 participants) Postmortem computed tomography (an output of 30–50/60 W); the microwave coagulation time was determined by the lesion size and hepatoma echo under the guidance of contrast‐enhanced grey‐scale ultrasonography Co‐intervention: conventional TACE treatment (femoral artery puncture (Seldinger technique), hepatic artery cannulation, conventional angiography, TACE (tetrahydropalmatine 30–60 mg, superliquified lipiodol 10–20 mL), transhepatic arterial infusion (oxaliplatin 50–100 mg, hydroxycamptothecin 20 mg))
Outcomes	Tumour response (reported by the authors as remission according to mRECIST criteria); adverse events (fever, abdomen pain, serum transaminase elevation, ascites, function failure, biliary infection, sepsis); levels of T‐cells
Notes	Letters to authors sent on 7 July and 14 October 2020 in order to enquire about trial methods and other missing information for the analysis. No reply received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were randomised, but randomisation method not reported so we could not judge whether they used an appropriate method.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) Adverse events or complications	Unclear risk	The design of combination therapy versus single therapy makes it difficult to blind participants and practitioners. As no information was provided about blinding, we could not judge whether participants and personnel were blinded.
Blinding of participants and personnel (performance bias) Tumour response measures	Unclear risk	The design of combination therapy versus single therapy makes it difficult to blind participants and practitioners. As no information was provided about blinding, we cannot judge whether the participants and personnel were blinded or not.
Blinding of outcome assessment (detection bias) Adverse events or complications	Unclear risk	The design of combination therapy versus single therapy makes it difficult to blind participants and practitioners. As no information was provided about blinding, we cannot judge whether the participants and personnel were blinded or not.
Blinding of outcome assessment (detection bias) Tumour response measures	Unclear risk	The design of combination therapy versus single therapy makes it difficult to blind participants and practitioners. As no information was provided about blinding, we cannot judge whether the participants and personnel were blinded or not.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals or dropouts
Selective reporting (reporting bias)	Unclear risk	Insufficient information, protocol not reported and not available.
Other bias	Unclear risk	Insufficient information.

MWA: microwave ablation; RFA: radiofrequency ablation; SD: standard deviation; TACE: transarterial chemoembolisation.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Correa‐Gallego 2014	Non‐randomised study. The study provided data on harms from the experimental and control interventions.
NCT02820194	Terminated study: as of 1 August 2023. Information was updated on Clinical Trials.gov on 16 September 2022 that the study was terminated due to insufficient recruitment. E‐mail sent to Dr Scorsetii, listed as contact person, on 3 August 2023 and repeated 14 August 2023. No reply received.
Radosevic 2022	Patient population irrelevant to review question.

Characteristics of ongoing studies [ordered by study ID]

COLLISION.

Study name	Colorectal Liver metastases: surgery vs thermal ablation (COLLISION)
Methods	Study type: randomised, single‐blind, non‐inferiority clinical trial Location: the Netherlands, university medical centre Time frame of the study: from July 2017 to December 2022 Inclusion criteria Age ≥ 18 years ≥ 1 colorectal cancer liver metastases up to 3 cm of size suitable for surgery or ablation Additional lesion suitable for resection or ablation Up to 10 metastases in total Clinical risk score of 0–2 Confirmed suitability for resection or ablation during surgery Follow‐up: 5 years
Participants	Estimated enrolment 618
Interventions	Thermal ablation (radiofrequency ablation or microwave ablation) vs surgical resection
Outcomes	Overall survival (primary), disease‐free survival, time to progression (secondary)
Starting date	July 2017
Contact information	Contacts: RS Puijk, MD; MR Meijerink, MD, PhD
Notes

COLLISION‐XL.

Study name	Unresectable colorectal liver metastases (3–5 cm): stereotactic body radiotherapy vs. microwave ablation (COLLISION‐XL)
Methods	Study type: prospective, open‐label, multicentre phase II randomised clinical trial Location: the Netherlands, University Medical Centre Time frame of the study: from 15 September 2019 to 15 January 2025 Inclusion criteria Up to 3 unresectable liver metastases from colorectal cancer of 3–5 cm of size, eligible for both interventions (microwave ablation and stereotactic body radiotherapy) – target lesions verified by a panel including ≥ 2 interventional radiologists, hepatobiliary surgeons, radiation oncologists Additional lesions allowed if suitable for surgery or ablation and up to 3 cm No extrahepatic lesions or limited to 1 lesion if not positive para‐aortal lymph nodes, coeliac lymph nodes, adrenal metastases, pleural carcinomatosis, or peritoneal carcinomatosis Up to 10 lesions in total for participants with lesion only in the liver, and up to 5 lesions for participants with extrahepatic lesion Participants with previous focal treatment applied to the liver are eligible Participants without previous focal treatment applied to the liver only if not suitable for first‐line chemotherapy or with progression during or after such treatment Participants with lesions recurring after focal treatment if not suitable for systemic therapy
Participants	Estimated enrolment: 68
Interventions	Stereotactic body radiotherapy vs microwave ablation
Outcomes	Primary endpoints: 1‐year local tumour progression‐free survival Secondary endpoints: local tumour progression‐free survival time, overall survival, disease‐free survival, time to progression, procedural morbidity/toxicity and mortality, assessment of pain and quality of life and cost‐effectiveness ratio
Starting date	15 September 2019
Contact information	Contact: Nieuwenhuizen S, MD; Meijerink MR, MD, PhD
Notes

JPRN‐UMIN000036206.

Study name	The safety and efficacy of microwave ablation and radiofrequency ablation for colorectal cancer liver metastasis: a randomised controlled clinical trial
Methods	Study type: parallel, open‐label, randomised clinical trial Location: Japan, University hospital Time frame of the study: from 15 February 2019 to 31 May 2020 Inclusion criteria Age of 20–100 years Colorectal carcinoma confirmed histopathologically or with imaging features characteristic for liver metastasis from colorectal cancer Not resectable tumours or no consent for surgery Up to 3 tumours, up to 3 cm in diameter, or a solitary lesion up to 5 cm in diameter (allowed primary and recurrent tumours, but not with local progression) No extrahepatic lesions No vascular invasion
Participants	Estimated enrolment: 104
Interventions	Microwave ablation vs radiofrequency ablation
Outcomes	Primary endpoints: modified Response Evaluation Criteria in Solid Tumors (mRECIST; evaluated using computed tomography scan taken after the first session of treatment) Secondary endpoints: complete ablation of tumours after the final session of treatment, number of sessions required to complete the treatment, and adverse events
Starting date	15 February 2019
Contact information	Contact: Shiina Shuichiro
Notes	Funding: self‐funding Question about the study sent to the main author; contact person 1 August 2023 and again 14 August 2023.

NCT03654131.

Study name	Stereotactic body radiation therapy vs. percutaneous microwave ablation for colorectal cancer patients with metastatic disease in the liver
Methods	Study type: randomised, open‐label, phase II trial Location: Denmark, single centre, hospital Time frame of the study: July 2018 to July 2021 Inclusion criteria Age > 18 years Colorectal cancer with up to 3 liver metastases (diameter up to 4.0 cm) not suitable for resection Lesions suitable for both types of treatment
Participants	Estimated enrolment: 100
Interventions	Microwave ablation vs stereotactic body radiotherapy
Outcomes	Primary endpoint: freedom from local lesion progression (participant level) Secondary endpoints: overall survival, freedom from local lesion progression (tumour level), toxicity ≥ grade 3 potentially associated with the treatment, toxicity profile, quality of life using European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ‐C30)
Starting date	25 July 2018
Contact information	Contact: Signe Normann Risum, MD, PhD; tel: +45 35453545; E‐mail: rigshospital.rigshospitalet@regionh.dk
Notes	Estimated primary completion date: 25 July 2023 for primary outcome, 25 July 2026 for all outcomes

Differences between protocol and review

We made the following changes from the protocol (Bala 2012).

We divided the outcome, proportion of participants with failure to clear liver metastases or with recurrence of liver metastases, into two outcomes.

• Proportion of participants with failure to clear liver metastases

• Proportion of participants with recurrence of liver metastases

We reclassified the outcome 'One‐year survival, three‐year survival, and disease‐free survival' into two outcomes: 'overall survival', which was included under time to mortality and 'disease‐free survival,' which was classified as a secondary outcome, as we consider this division is more clinically relevant.

The searches in the protocol were planned to be performed for all reviews on non‐surgical ablation methods together, but since 5 June 2017 the searches were developed and performed for each review separately.

Dealing with missing data: two trials reported no missing data (Vogl 2022; Xu 2012), and one trial excluded 25% of participants after randomisation (Shibata 2000). Therefore, for the comparison including Shibata 2000, we performed available‐case analysis and intention‐to‐treat analysis, including participants as originally randomised. We did not perform a sensitivity analysis assuming that all participants with missing data were either treatment failures or successes.

Contributions of authors

Study inclusion and data extraction: DS, MJS, JWM, MP, NL, RW, and MMB.

Analyses: DS, MJS, RW, and MMB.

Review writing: DS, MJS, JWM, MP, NL, RW, and MMB.

All authors agreed on the final version of the review.

Sources of support

Internal sources

• Kleijnen Systematic Reviews (KSR) Ltd, UK

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

• Jagiellonian University Medical College (JUMC), Poland

  DS, MJS, MMB, JWM, and MP are either employed by JUMC or are students at JUMC and worked on the review within their research activities.

External sources

• The Dutch Health Care Insurance Board, Netherlands

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

• Cochrane Hepato‐Biliary Group, Denmark

  Provided help with the review preparation until publication, including the peer review process.

Declarations of interest

DS: none.

MJS: none.

JWM: none.

Michał Pędziwiatr received speaking honoraria and travel grants from Johnson&Johnson, Baxter, Storz, Medtronic, Olympus; he is not aware of any direct conflict of interest.

NL: none.

RW declares that the company they work for does work for a number of pharmaceutical companies in unrelated indications, and that they are not aware of any direct conflict of interest.

MMB: none.

These authors contributed equally to this work.

New search for studies and content updated (no change to conclusions)