Hyperthermia ablation combined with transarterial chemoembolization versus monotherapy for hepatocellular carcinoma: A systematic review and meta‐analysis

Abstract Background and aims The existing evidence has indicated that hyperthermia ablation (HA) and HA combined with transarterial chemoembolization (HATACE) are the optimal alternative to surgical resection for patients with hepatocellular carcinoma (HCC) in the COVID‐19 crisis. However, the evidence for decision‐making is lacking in terms of comparison between HA and HATACE. Herein, a comprehensive evaluation was performed to compare the efficacy and safety of HATACE with monotherapy. Materials and Methods Worldwide studies were collected to evaluate the HATACE regimen for HCC due to the practical need for global extrapolation of applicative population. Meta‐analyses were performed using the RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Results Thirty‐six studies involving a large sample of 5036 patients were included finally. Compared with HA alone, HATACE produced the advantage of 5‐year overall survival (OS) rate (OR:1.90; 95%CI:1.46,2.46; p < 0.05) without increasing toxicity (p ≥ 0.05). Compared with TACE alone, HATACE was associated with superior 5‐year OS rate (OR:3.54; 95%CI:1.96,6.37; p < 0.05) and significantly reduced the incidences of severe liver damage (OR:0.32; 95%CI:0.11,0.96; p < 0.05) and ascites (OR:0.42; 95%CI:0.20,0.88; p < 0.05). Subgroup analysis results of small (≤3 cm) HCC revealed that there were no significant differences between the HATACE group and HA monotherapy group in regard to the OS rates (p ≥ 0.05). Conclusions Compared with TACE alone, HATACE was more effective and safe for HCC. Compared with HA alone, HATACE was more effective for non‐small‐sized (>3 cm) HCC with comparable safety. However, the survival benefit of adjuvant TACE in HATACE regimen was not found for the patients with small (≤3 cm) HCC.


| MATERIALS & METHODS
A pre-retrieval procedure was implemented to ensure that the best results of literature retrieval could be obtained, which started on 11 March 2020. A preliminary and rapid systematic review was conducted before this study to ascertain how to design this study scientifically and accurately. Systematic review and meta-analysis were identified as the preferred research method for this study due to the actual need of comprehensive and worldwide data for global extrapolation of applicative population. No ethical approval or patient consent was required for the systematic review and meta-analysis as the data originated from previously published studies.

| Inclusion and exclusion criteria of study selection
Studies were included if they matched the following criteria based on the pilot study of systematic review and meta-analysis. (i) Participants: Patients were diagnosed with primary HCC by histopathology and imageological examination, while the patients with metastatic liver cancer were excluded. (ii) Intervention and comparison: HA modalities included radiofrequency ablation (RFA) and microwave ablation (MWA) in this article. Studies for HATACE should compare HATACE with monotherapy of HA (RFA/MWA) or TACE. (iii) Outcomes: Outcomes of evaluation were including overall survival (OS), adverse effects, and complications. The primary endpoint was OS as conventional assessment criteria, which is defined of adjuvant TACE in HATACE regimen was not found for the patients with small (≤3 cm) HCC.

K E Y W O R D S
COVID-19, hepatocellular carcinoma, hyperthermia ablation, meta-analysis, SARS-CoV-2, transarterial chemoembolization as the time from random assignment to the last followup or death. (iv) Study type: Studies with control group were included to compare HATACE with monotherapy of HA or TACE for HCC, such as randomized controlled trial (RCT), controlled clinical trial (CCT), and propensity score matching study (PSMS). Different criteria of study type were performed for general meta-analysis and sensitivity analysis due to different aims.
Publications were excluded if they were (i) retraction by published journals; (ii) duplicate publications; (iii) clinical research without control group; and (iv) inappropriate article type including cellular or animal experiments, letters, editorials, commentaries, protocols, reviews, systematic reviews or meta-analyses.

| Search strategy and study screening
The pre-retrieval was performed on 11 March 2020, and the comprehensive retrieval was started on 15 April 2020, following the pilot systematic review. The retrieval was updated every month during the research process in order to acquire the latest data of reports. The final retrieval time was 15 May 2021. We searched five international databases including the Cochrane Library, Web of Science, PubMed, Embase, and Scopus. We also searched other supplementary resources, such as the Google Scholar, Medical Matrix, reference lists of relevant reviews and included papers, COVID-19 Open Research Dataset Challenge (CORD-19), COVID-19 Research Database (WHO), and WHO International Clinical Trials Registry Platform. No restrictions were set for study language, publication date, and publication status. Additionally, we also communicated with some colleagues to identify the potential unpublished trials for avoiding publication bias. Studies were selected according to the inclusion and exclusion criteria through two stages: the first stage was evaluation of titles and abstracts, followed by full text review as the second stage.

| Data extraction and data analysis
Data were extracted from each included article using standardized forms. Meta-analysis should not count overlapping populations in any outcome synthesis to avoid the bias of data double counting. Therefore, when multiple publications from the same institution were identified as duplicates (e.g., studies reporting the same series of patients at different phases or different perspectives), we chose the most recent updated papers with the largest sample size or longest follow-up duration for the quantitative synthesis of the meta-analyses.
The meta-analyses were performed with the RevMan version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration) provided by the Cochrane organization. Odds ratios (ORs) and 95% confidence intervals (CIs) were used as the summary statistics for dichotomous data, which were calculated using the statistical method of Mantel-Haenszel and the analysis model of fixed-effect or random-effects according to the estimate of heterogeneity. The two-sided level of statistical significance was denoted as the two-tailed p value below the threshold of 0.05. The statistical heterogeneity (or consistency) among studies was measured with the Cochran's Q χ² test and I² test. A p value of up to 0.10 was considered significant heterogeneity in the Cochran's Q χ² test. An I² value of 0% indicates the optimal consistency (or no observed heterogeneity), and larger values indicate the increasing heterogeneity (or decreasing consistency). I² statistic ≤50% was considered indicative of low heterogeneity with the fixedeffect model, and >50% was considered indicative of high heterogeneity with the random-effects model.

| Sensitivity analysis and subgroup analysis
Randomized controlled trials (RCTs) and systematic reviews of RCTs could provide the most reliable evidence about the effects of healthcare interventions. 38 Therefore, we chose RCTs for sensitivity analysis to test the robustness of our findings from the meta-analyses. Only RCTs were included in the sensitivity analysis in order to avoid potential biases associated with case ascertainment or others from non-RCT studies. Risk ratios (RRs, instead of ORs) and 95% CIs were used as the summary statistics for dichotomous data in the sensitivity analyses of RCTs, while the others were the same as above. The risk of bias in RCTs was assessed in both table and figure formats according to the Cochrane Collaboration's tool for randomized trials. 38 There is conflicting debate as to whether it is necessary to implement additional TACE of combination therapy for small (≤3 cm) HCC. Accordingly, HCC was classified into two grades according to tumor size: small-sized HCC (diameter of 3 cm or less) and non-small-sized HCC (diameter greater than 3 cm). Subgroup analysis was implemented on the basis of the size classification.

| Results of the systematic review and meta-analysis
Identification flow of the studies is exhibited as Figure 1 and Data S1. A total of 36 eligible studies 39-74 involving a large sample amount of 5036 patients were included finally for the systematic review and meta-analysis ( Figure 1, Table 1, Data S1). All of the included studies  were published in SCI journals and included in the Web of Science with good quality of reports. The main features of the included trials  are detailedly presented in Table 1 and Data S1.

Age (years) M/F (n) Child-Pugh A/B/C (n) Diameter (cm)
THA  The meta-analyses results showed that compared with HA alone, HATACE was associated with a significant improvement in the OS rate at 1 year (OR = 2.  Table 2).
The results demonstrated that the OS rates were significantly higher with HATACE than TACE alone at 1, 2, 3, 4, and 5 years. Compared with TACE alone, HATACE was associated with significant reduction in the incidences of severe liver damage (OR = 0.41, 95% CI = 0.18-0.98, p = 0.04) and ascites (OR = 0.54, 95% CI = 0.30-0.98, p = 0.04). No significant differences were observed between HATACE group and TACE alone group with respect to the incidences of abdominal infection, abdominal pain, bleeding, pleural effusion, fever, and nausea and vomiting ( Table 2).

| Results of the sensitivity analysis with RCTs
The sensitivity analysis of RCTs was performed to test the robustness of our findings derived from the meta-analyses above. A total of 10 RCTs 40 Figure 3 and Figure 4). The sensitivity analysis for HATACE versus HA was completed with a total of eight RCTs. 40 Table 4). The findings of HATACE versus HA were identified as reliable and stable on the basis of the results of sensitivity meta-analyses with RCTs ( Figure 5 and Table 4).
The sensitivity analysis for HATACE versus TACE was completed with a total of four RCTs. 40,52,55,71 We could not finish the sensitivity meta-analysis of RCTs because of the limited studies and insufficient data, so qualitative synthetic evaluation was carried out for the sensitivity analysis of HATACE versus TACE. The

Age (years) M/F (n) Child-Pugh A/B/C (n) Diameter (cm)
TR synthetic results of the four RCTs 40,52,55,71 revealed that compared with TACE alone, HATACE was associated with significant improvement in the efficacy and significant reduction in the incidences of adverse reaction and complication, which is in conformity with the meta-analyses results of HATACE versus TACE above.

| Results of the subgroup analysis for small HCC
The subgroup analyses results for small HCC demonstrated that there were no significant differences between the HATACE group and HA alone group with respect to the OS rates at 1, 2, 3, 4, and 5 years (p ≥ 0.05; Table 5).

| DISCUSSION
The statistics showed that liver cancer was the third leading cause of cancer death worldwide in 2020, with about 906,000 new cases and 830,000 deaths annually. 75,76 In addition, there were approximately half cases and deaths of the total number worldwide distributed in China. 75,76 There is some debate that compared with the monotherapy of HA (or TACE) for treating HCC, whether HATACE could improve the efficacy meanwhile without increasing (or even reducing) toxicity and complications. This question should be definitively answered by the comprehensive systematic review and meta-analysis results.
The synergistic effects of combined HA and TACE may overcome their own limitations and improve the therapeutic outcomes. 35 The results of meta-analyses demonstrated that the oncologic outcomes of HATACE were markedly superior to those of HA or TACE alone: (i) Compared with HA monotherapy, HATACE could significantly improve the OS rates of 1, 2, 3, 4, and 5 years, what is more, without increasing the incidences of adverse effects and complications. The robustness of the results was tested by the meta-analysis of RCTs, and the results of sensitivity meta-analysis confirmed that all of the measurement outcomes are reliable evidence. Therefore, the results of HATACE versus HA manifested that adjuvant TACE is necessary and complementary in the HA-based integrated therapy. (ii) Compared with TACE monotherapy, HATACE could significantly improve the OS rates without increasing the incidences of abdominal infection, abdominal pain, bleeding, pleural effusion, fever, and nausea and vomiting; more importantly, HATACE was associated with significant reduction in the incidences of severe liver damage and ascites. These findings are in conformity with the sensitivity analysis results of qualitative synthetic evaluation with the data of RCTs. Therefore, the results of HATACE versus TACE manifested that HA plays a significant synergistic role in HATACE; most important of all, HA is confirmed to be effective in reducing the toxicity of TACE and protecting liver function to some extent.
There are two sides as coins in the relation between TACE and HCC patients' systemic function status (including immunity). (i) Although systemic chemotherapy leads to immunosuppression, minimally invasive TACE controls it to a minimum via its substantively limited dose and focally delivered administration 35,77 ; (ii) TACE is beneficial to improve patient's holistic status (including immunity) because cancerous damage to the body (including immunosuppression caused by cancer) is ameliorated after reducing the cancer quantity [77][78][79][80] ; and (iii) The synthetical risk-benefit result of TACE, depending on the balance of the two aspects above, is superior to majority of the therapies for HCC, especially when the synergistic advantages were unlocked with HA combination. 35,81 It is also in line with the meta-analysis results that HATACE was associated with significant improvement in the OS rates and significant reduction in the incidences of severe liver damage and ascites.
HATACE has a broad clinical applications for different stages of HCC based on the studies for systematic review, including early or very early stage 39 39,56,63,64,68,69,73 in regard to the survival benefit from HATACE compared with HA monotherapy for small (≤3 cm) HCC. To explore the potential different benefits associated with the different size classification of HCC, subgroup analyses were carried out for small HCC to compare HATACE with HA alone. The results revealed that the survival benefit of additional TACE is very limited without statistical significance for the patients with small HCC. Therefore, HATACE is more effective and befitting for non-small-sized (>3 cm) HCC than HA monotherapy.
Verna et al. 82 indicated that all non-essential studies were halted when the COVID-19 pandemic started, and COVID-19 should become the preferred research subject during this unprecedented pandemic for rescuing patients in disaster. Mancilla-Galindo et al. 26 presented a novel idea of mild hyperthermia (thermotherapy) as a potential therapy for patients with mild-to-moderate COVID-19 to prevent disease progression. Hyperthermia  therapy (including HA) could improve the immunity of cancer patients, [23][24][25][26][27][28][29][30][31][32][33]83,84 which should be given adequate attention to for the anticancer treatment in the context of COVID-19 crisis. [8][9][10][11][12][13][14]26 The need of minimal invasion has already become a crucial consideration for therapeutic decision-making in the SAUCCC. [8][9][10][11][12][13][14] Accordingly, HA and HATACE possess unique superiorities among multifarious therapies for appropriate HCC patients in the SAUCCC, [17][18][19][20][22][23][24][25][26][27][28][29][30][31][32][33][85][86][87][88] which is fully exhibited in the Data S1. COVID-19 throughout the world has caused unprecedented social turmoil on a global level, triggering  [99][100][101] To our knowledge, this article is the first systematic review and meta-analysis to evaluate HATACE for HCC, regarding ablation modalities including both RFA and MWA. Additionally, it addresses not only the largest sample size of 5036 patients from 36 included studies in this subject, 102 but also a total of 10 RCTs for sensitivity analyses. Therefore, the present study could provide more comprehensive and reliable evidence for decision-makings than other congeneric research. 102 However, there are some limitations in our study indeed. The robustness of the HATACE versus HA results was demonstrated by the sensitivity metaanalysis of RCTs with adequate qualification, but the sensitivity meta-analysis of RCTs for HATACE versus TACE was not implemented finally because of the insufficient studies and data. So the evidential strength grade of HATACE versus TACE should be judged to be lower than that of HATACE versus HA. Nevertheless, it is very circumscribed and impractical to investigate the adverse reactions of therapies only relying on RCTs in this topic. Non-RCT clinical studies are necessary and important for assessing the safety; therefore, the adverse reactions evaluation of HATACE, which is a key consideration for clinical decision-making during the COVID-19 pandemic, is relatively independent on the test strategy of meta-analysis with RCTs. Hence, the conclusions on the safety of HATACE, including that HA significantly reduces the toxicity of TACE and preserves the liver function to some extent, could be considered adequately reliable.
In this study, we have demonstrated that HATACE for HCC is superior to TACE monotherapy with respect to either efficacy or safety. HATACE is more effective than HA monotherapy with comparable safety for non-small-sized (>3 cm) HCC. Compared with HATACE, HA monotherapy could provide comparable survival benefit for the patients with small (≤3 cm) HCC. Namely, adjuvant TACE is not necessary for HA therapy in treating small HCC. Although there are some deficiencies as discussed in limitations above, this research could provide a comprehensive reference for clinical decision-making on the base of the 36 included studies and the adequately large sample size of 5036 patients. In addition, we should pay more attention to HA and HATACE due to their superiorities in the SAUCCC.