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UNASSIGNED: A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function.
UNASSIGNED: To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm).
UNASSIGNED: Systematic review and network meta-analysis.
UNASSIGNED: Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews.
UNASSIGNED: Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research.
UNASSIGNED: Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials.
UNASSIGNED: Many studies were small and of poor quality. No comparative studies were found for some therapies.
UNASSIGNED: The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection.
UNASSIGNED: PROSPERO CRD42020221357.
UNASSIGNED: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.
Hepatocellular carcinoma is the most common type of primary liver cancer. There are a range of different treatments available for patients with early hepatocellular carcinoma. We looked for clinical trials in patients with small tumours (up to 3 cm) that compared different treatments. We brought together and analysed the results of these trials to see which treatments were most effective in terms of survival, progression, side effects and quality of life. Overall, the evidence has limitations; many trials had few patients and were of poor quality. Most were from China or Japan, where the common causes of liver disease and treatments available differ from those in the United Kingdom. The results of our analyses were very uncertain so we cannot be sure which treatment is the best overall. We did find that three treatments – radiofrequency ablation, microwave ablation and surgery – were generally more effective than percutaneous ethanol injection and percutaneous acid injection. There was not enough evidence to be certain which treatment was better when radiofrequency ablation was compared with laser ablation, microwave ablation, proton beam therapy or surgery. We found only poor-quality, non-randomised trials on high-intensity focused ultrasound, cryoablation and irreversible electroporation. There was very little evidence on treatments that combined radiofrequency ablation with other therapies. We found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative radiotherapy or wider radiotherapy techniques with other treatments. Only two studies reported data on quality of life or patient satisfaction. We discussed the findings with patients and clinical experts. Stereotactic ablative radiotherapy was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients. Feasibility studies could inform future clinical trials by exploring issues such as whether patients are willing to take part in a trial or find the treatments acceptable.

BACKGROUND: Percutaneous ethanol injection (PEI) has been shown to be a valuable treatment for thyroid nodular pathology and metastatic cervical adenopathies.
OBJECTIVE: To evaluate the effectiveness, safety, and cost-effectiveness of PEI in thyroid nodular pathology and metastatic cervical adenopathies.
METHODS: A systematic review (SR) using meta-analysis was conducted on the effectiveness and safety of PEI. A SR on cost-effectiveness was also performed. The SRs were conducted according to the methodology developed by the Cochrane Collaboration with reporting in accordance with the PRISMA statement. A cost-minimization analysis was carried out using a decision tree model. Assuming equal effectiveness between two minimally invasive techniques (PEI and radiofrequency ablation (RFA)), the model compared the costs of the alternatives with a horizon of six months and from the perspective of the Spanish National Health System.
RESULTS: The search identified three RCTs (n=157) that evaluated PEI versus RFA in patients diagnosed with benign thyroid nodules: ninety-six patients with predominantly cystic nodules and sixty-one patients with solid nodules. No evidence was found on other techniques or thyroid nodular pathology. No statistically significant differences were observed between PEI and RFA in volume reduction (%), symptom score, cosmetic score, therapeutic success and major complications. No economic evaluations were identified. The cost-minimization analysis estimated the cost per patient of the PEI procedure at €326 compared to €4781 for RFA, which means an incremental difference of -€4455.
CONCLUSIONS: There are no differences between PEI and RFA regarding their safety and effectiveness, but the economic evaluation determined that the former option is cheaper.

Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC.
Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤3 cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence.
Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n = 17) or Japan (n = 7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons.
It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake.

The most common sites of extrahepatic metastases from hepatocellular carcinoma (HCC) are the lungs, intra-abdominal lymph nodes, bones, and adrenal glands, in that order. Although systemic therapies are a common treatment for patients with extrahepatic metastases, local ablative therapies for the extrahepatic metastatic lesions can be performed in selected patients. In this article, the literature on image-guided thermal ablation for metastasis to each organ was reviewed to summarize the current evidence. Radiofrequency ablation was the most commonly evaluated technique, and microwave ablation, cryoablation, and percutaneous ethanol injection were also utilized. The local control rate of thermal ablation therapy was relatively favorable, at approximately 70-90% in various organs. The survival outcomes varied among the studies, and several studies reported that the absence of viable intrahepatic lesions was associated with improved survival rates. Since only retrospective data from relatively small studies has been available thus far, more robust studies with prospective designs and larger cohorts are desired to prove the usefulness of thermal ablation for extrahepatic metastases from HCC.

Tumor ablation has been widely applied in Asia, accounting for 44.65% of clinical studies worldwide. We reviewed 5853 clinical studies to provide insight on the advance of tumor ablation in Asia chronologically and geographically among different techniques and organs. Since 1998, tumor ablation application has dramatically evolved in Asia. All kinds of ablation techniques, including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation (LA), cryoablation (CA), high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE), have been applied, with the first application of PEI and the most popular application of RFA. Twenty-five countries and one district in Asia have applied tumor ablation in various organs, including liver, lung, uterus, thyroid, kidney, pancreas, bone, prostate, breast, adrenal gland, lymph node parathyroid, esophagus, etc. Due to the high incidence of tumors as well as advanced economy and technology, East Asia accounted for 93.87% of studies, led by China (45.00%), Japan (32.72%), South Korea (12.10%), and Taiwan (4.03%). With the enrichment of evidence from large-scale multicenter and randomized control studies, China and South Korea have issued several guidelines on tumor ablation for liver, lung, and thyroid, which provided recommendations for global standardization of tumor ablation techniques. Therefore, Asia has made active contribution to global tumor ablation therapy.KeypointsKey point 1: Asia accounted for 44.65% of clinical studies worldwide on tumor ablation.Key point 2: Twenty-five countries and one district in Asia have used tumor ablation in various organs, and East Asia accounted for 93.87% of studies, led by China (45.00%), Japan (32.72%), South Korea (12.10%), and Taiwan (4.03%).Key point 3: China and South Korea have issued several guidelines on tumor ablation for liver, lung, and thyroid, which provided recommendations for global standardization of tumor ablation techniques.

Percutaneous ethanol injection (PEI) is used for the treatment of benign cystic thyroid nodules. This systematic review and meta-analysis aimed to obtain strong evidence of its long-term efficacy and safety.
PubMed, CENTRAL, Scopus and Web of Science databases were searched until November 2020 for studies reporting data on volume reduction rate (VRR), compressive symptoms and cosmetic concerns. Associated complications were assessed. A random-effects model was designed to pool the data.
Out of 385 papers, nine studies evaluating 1667 nodules were finally included. Overall, VRR at 6, 12, 24, 36, 60 and 120 months was 77%, 81%, 72%, 68%, 74% and 69%, respectively. Significant reductions in the compressive symptoms and cosmetic concerns were observed. No permanent complications were observed.
The present meta-analysis showed that PEI could significantly reduce the volume of benign cystic thyroid nodules. This reduction was already effective at 6 months post-treatment, and the effect was stable over time.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. We conducted network meta-regression within a Bayesian framework to compare and rank different treatment strategies for HCC through direct and indirect evidence from international studies.
We pooled the OR for 1-year, 3-year and 5-year overall survival, based on lesions of size ˂ 3 cm, 3-5 cm and ≤5 cm, using five therapeutic options including resection (RES), radiofrequency ablation (RFA), microwave ablation (MWA), transcatheter arterial chemoembolisation (TACE) plus RFA (TR) and percutaneous ethanol injection (PEI).
We identified 74 studies, including 26 944 patients. After adjustment for study design, and in the full sample of studies, the treatments were ranked in order of greatest to least benefit as follows for 5 year survival: (1) RES, (2) TR, (3) RFA, (4) MWA and (5) PEI. The ranks were similar for 1- and 3-year survival, with RES and TR being the highest ranking treatments. In both smaller (<3 cm) and larger tumours (3-5 cm), RES and TR were also the two highest ranking treatments. There was little evidence of inconsistency between direct and indirect evidence.
The comparison of different treatment strategies for HCC indicated that RES is associated with longer survival. However, many of the between-treatment comparisons were not statistically significant and, for now, selection of strategies for treatment will depend on patient and disease characteristics. Additionally, much of the evidence was provided by non-randomised studies and knowledge gaps still exist. More head-to-head comparisons between both RES and TR, or other approaches, will be necessary to confirm these findings.

BACKGROUND: Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) are important treatments for patients with hepatocellular carcinoma (HCC) who are not eligible for resection and liver transplantation. Therefore, it is important to establish comparisons between RFA, PEI and the two therapies in combination.
OBJECTIVE: To evaluate the clinical efficacy and safety of combined RFA-PEI versus monotherapy with either RFA or PEI for HCC to provide references for clinical practice and further research.
METHODS: We searched all eligible studies published before September 2015 in the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases, such as CBM, CNKI, VIP and WanFang and also retrieved papers from other sources. All relevant controlled trials were collected. Meta-analyses were performed using RevMan version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).
RESULTS: Thirteen trials with 1621 patients were identified. Compared with PEI, RFA was associated with significant improvement in overall survival (OS) rate at 1, 2, 3 and 4 years, cancer-free survival (CFS) rate at 1, 2 and 3 years and complete tumour necrosis. RFA was associated with a significant reduction in the local recurrence rate at 1, 2 and 3 years. However, RFA was also associated with a higher total risk of complications. Compared with RFA alone, combined RFA-PEI was associated with a significant improvement in the OS rate at 1.5, 2 and 3 years and a significant reduction in the local recurrence rate. However, combined RFA-PEI was also associated with a higher risk of fever.
CONCLUSIONS: The combination of RFA and PEI appears to be the optimal treatment strategy when considering combined RFA-PEI or either RFA or PEI alone. Combined RFA-PEI significantly improves OS and reduces the risk of local recurrence without increasing major complications. Further large-scale studies are needed to assess economic outcomes and quality of life.

Local ablative techniques-percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation (RFA)-have been developed to treat unresectable hepatocellular carcinoma (HCC). The success rate of percutaneous ablation therapy for HCC depends on correct targeting of the tumor via an imaging technique. However, probe insertion often is not completely accurate for small HCC nodules, which are poorly defined on conventional B-mode ultrasound (US) alone. Thus, multiple sessions of ablation therapy are frequently required in difficult cases. By means of two breakthroughs in US technology, harmonic imaging and the development of second-generation contrast agents, dynamic contrast-enhanced harmonic US imaging with an intravenous contrast agent can depict tumor vascularity sensitively and accurately, and is able to evaluate small hypervascular HCCs even when B-mode US cannot adequately characterize the tumors. Therefore, dynamic contrast-enhanced US can facilitate RFA electrode placement in hypervascular HCC, which is poorly depicted by B-mode US. The use of dynamic contrast-enhanced US guidance in ablation therapy for liver cancer is an efficient approach. Here, we present an overview of the current status of dynamic contrast-enhanced US-guided ablation therapy, and summarize the current indications and outcomes of reported clinical use in comparison with that of other modalities.