Assessment of Radiofrequency Ablation for Papillary Microcarcinoma of the Thyroid A Systematic Review and Meta-analysis

IMPORTANCE Papillary microcarcinomas of the thyroid (mPTCs) account for an increasing proportion of thyroid cancers in past decades. The use of radiofrequency ablation (RFA) has been investigated as an alternative to surgery. The effectiveness and safety of RFA has yet to be determined.


P
][5] Patients with a diagnosis of mPTC have a disease-specific survival of more than 99% after 10 years of follow-up. 6,7ost guidelines concerning thyroid cancer care recommend a lobectomy as the first-line treatment strategy for lowrisk unifocal mPTC. 8,91][12][13][14][15] To de-escalate the treatment of mPTC and reduce surgery-related morbidity, lessaggressive treatment strategies such as active surveillance 16 and thermal ablation 17 for patients with low-risk mPTC have been proposed.
Thermal ablation primarily includes 3 techniques: microwave ablation, laser ablation, and radiofrequency ablation (RFA).Radiofrequency ablation is a nonsurgical, minimally invasive technique that relies on alternating electromagnetic current to cause molecular frictional heating to control tissue mass. 18Although RFA is currently used mostly in patients with benign nodules, recurrent PTC, and inoperable disease, [19][20][21][22] recent evidence suggests that RFA could be an efficient treatment for patients with low-risk mPTC and has been shown to be more effective than microwave ablation or laser ablation. 17n this systematic review and meta-analysis of current literature, the primary goal is to analyze the effectiveness and safety of RFA for low-risk mPTC in a large number of patients.

Literature Search and Patient Selection
A systematic literature search was performed using the databases Embase, MEDLINE via Ovid, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and the top 100 references of Google Scholar.The search strategy is illustrated in the eTable in the Supplement.The search strategy was created by a qualified librarian of the University Medical Center Rotterdam (S.T.G.G.).Two reviewers (S.P.J.v.D. and H.I.C.) independently screened titles and abstracts of articles published until May 28, 2021.In cases of disagreement in the selection of articles, a third reviewer (T.M.v.G.) was consulted to make the final decision.Studies were included if they involved patients who had a primary mPTC and were treated with RFA for the first time.Exclusion criteria were: (1) case reports, case series of less than 5 patients, letters, conference abstracts, (systematic) reviews, meta-analyses, guidelines, study protocols, statements, or non-English articles; (2) patients with preablation lymph node or distant metastases, recurrence, or extrathyroidal extension; and (3) patients treated with other thermal ablation techniques such as laser, ethanol, or microwave ablation.This meta-analysis of scientific literature was conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. 23

Data Extraction and Outcomes
The following data were extracted: author names, year of publication, type of study, study period, total number of patients, total number of tumors, patient age, patient sex, total and mean number of RFA sessions, largest tumor diameter, volume of tumor, volume reduction rate, complications, and tumor progression.The primary outcome of this meta-analysis was the complete disappearance rate of mPTCs.Secondary outcomes were tumor progression and complications.Complete disappearance rate was defined by the percentage of patients with a completely absorbed tumor volume on results of ultrasonography after RFA.Incomplete ablation was defined as incompletely absorbed tumor volume on results of ultrasonography after RFA with benign fine-needle aspiration (FNA) results.Tumor progression was defined as cytologically or histologically confirmed residual mPTC in the ablation area, newly found mPTC elsewhere in the thyroid, or lymph node or distant metastases.
Complications were assessed using the reporting standards of the Society of Interventional Radiology. 24Cardiac events and/or arrhythmias, surgical intervention owing to bleeding after RFA, and voice changes (lasting >1 month) were considered major complications.Pain, hematoma, skin burn, temporary voice changes (lasting ≤1 month), hypoparathyroidism, fever, and neck swelling were considered minor complications.Volume reduction rate was calculated and defined in the included studies as following: volume reduction rate (%) = (initial volume -final volume)/initial volume ×100%.

Statistical Analysis
Descriptive statistics were presented as counts (numbers and percentages) and means with SDs.Medians were used as approximations of the mean in case of skewed variables.Metaanalysis of proportions and means was performed with 95% CIs.Between-study heterogeneity was calculated by the Higgins inconsistency index I 2 .If there was no statistical proof for heterogeneity (P ≥ .05), the assumption of homogeneity was deemed valid and a fixed-effect model was applied.Otherwise, a random-effect model was used.The risk of publication bias of the included studies was analyzed by using visual checking of symmetry in funnel plots and the Egger regression test.Meta-analysis was performed using metafor for R,

Key Points
Question What is the role of radiofrequency ablation in the treatment of low-risk papillary microcarcinoma of the thyroid?Findings In this systematic review and meta-analysis that included 15 studies comprising 1770 patients with 1822 tumors treated with radiofrequency ablation, the pooled proportion of complete tumor disappearance was 79%.
Meaning This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid.

Other Effect Measures Volume Reduction Ratio
31][32]34,37,41 The pooled proportion of the mean tumor volume reduction ratio after 12 months was 92.1% (95% CI, 85.0%-99.2%).There was high heterogeneity between the studies (I 2 = 99.8%;P < .001).,33,36,41 In most studies, tumor volume increased immediately after ablation and decreased gradually between 1 and 6 months of follow-up.Tumor volume reduction over time can be seen in eFigure 3 in the Supplement.The weighted pooled proportion of the mean tumor volume reduction was 95.0 mm 3 (95% CI, 83.2-106.8mm 3 ), with evidence of high heterogeneity between the studies (I 2 = 87.7%;P < .001).The mean (SD) follow-up was 29.8 (17.7) months.Publication Bias Asymmetrical distribution in the funnel plots, suggestive of publication bias, was found for overall tumor progression, major complications, and total complications.Evidence of publication bias was found by the Egger test (   sion rates (z score, 2.22; P = .03),total complications (z score, 42.1; P < .001),and major complications (z score, 42.1; P < .001).Funnel plots can be found in eFigure 4 in the Supplement.

Discussion
In this study, the effectiveness and safety of RFA as a treatment for mPTC in 1770 patients was analyzed.This study demonstrates that 79% of all patients with mPTC who underwent RFA had complete disappearance of tumor tissue on results of ultrasonography after RFA.Although complete disappearance of the tumor was not achieved in 21% of the patients undergoing RFA, only 7 patients (0.4%) received a diagnosis of FNA-confirmed residual mPTC cells.This finding emphasizes that the assessment of tumor response in patients with mPTC after RFA is complicated.Most studies applied ultrasonography and FNA of the residual tumor volume and, if no cancer cells were seen on cytologic examination, patients generally received follow-up.The diagnostic accuracy of FNA after RFA has shown to be reduced because of insufficient cellularity in the ablation area. 42,43Core needle biopsy is thought to have a higher diagnostic accuracy for detecting residual cancer cells and could be valuable in increasing the certainty of "complete mPTC disappearance" in case of residual tumor volume on ultrasonography after RFA. 25 To assess the oncologic acceptability of RFA as a treatment option, complete tumor response after RFA has to be clearly defined, as no criterion standard exists yet.
The overall complication rate due to RFA was low (48 [2.7%]) and 3 (0.2%) major complications occurred.All complications, minor and major, resolved spontaneously within 3 months.Twenty-two patients (1.2%) experienced FNAconfirmed residual mPTC or new mPTC, which all were permanently removed by additional ablations.Surgical complications such as permanent hypothyroidism and recurrent laryngeal nerve damage occur in 30% and 1% to 2% of patients, respectively, after unilateral thyroid lobectomy. 12,44,45 the current study, less-severe complications in patients treated with RFA, such as pain, hematoma, skin burn, and temporary voice hoarseness, occurred in 2.5% of patients.
All included studies were conducted in China and Korea, where thyroid cancer guidelines differ significantly from guidelines in Europe.][53] However, this treatment strategy has also been shown to have low potential in countries in which restrictive diagnostic workup strategies are applied. 54In these countries, the number of patients with mPTC are limited and, when encountered, the mPTC is often further progressed (ie, lymph node metastases or extrathyroidal extension), resulting in a high level of reluctance among thyroid specialists to use active surveillance. 54The effectiveness and safety of RFA in a population with a restrictive diagnostic workup strategy is unknown.With a 79% complete disappearance rate of tumor tissue, RFA could also be a valuable treatment option for patients with low-risk mPTC in these countries.The question whether RFA can aid in preventing lymph node metastases remains to be investigated.
Although this study suggests that RFA is a safe and efficient method to treat low-risk mPTCs, there is no evidence that treatment of low-risk mPTC is associated with any clinical benefit.Especially in populations with less-restrictive diagnostic workup protocols, patients with low-risk mPTC should generally receive active surveillance.However, in case of local tumor growth under active surveillance or in case of patient anxiety about active surveillance, RFA could be a valuable minimally invasive strategy in the management of low-risk mPTC.Different studied treatment options for mPTC and its advantages and disadvantages are described in Table 4. 52,[55][56][57][58]

Limitations
This study has some limitations, the most important of which is the inclusion of mostly retrospective case series with small sample sizes that use several RFA techniques (eg, ablation energy, time of ablation, electrode tip diameter) and follow-up schedules.These studies have a higher risk of bias and low certainty. 39,40n addition, the likelihood of patient selection bias is increased in the included studies (eg, smaller tumors, healthier patients).
There were 11 studies with potential overlapping patient cohorts based on author names, inclusion periods, and affiliations.Finally, owing to the only recent developments in the field of thermal ablation techniques for patients with mPTC, follow-up periods of the patients included in the analyzed studies were relatively short (mean [SD], 33.0 [11.4] months).Despite these limitations, this review managed to illustrate the available evidence on the effectiveness and safety of RFA in patients with mPTC.
The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions.Future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.To properly assess and compare oncologic outcomes with surgery and/or active surveillance in populations with restrictive diagnostic workup strategies, prospective trials or registration studies with longterm follow-up should be conducted.Although 3 Chinese studies showed that RFA was less expensive than surgery in patients with mPTC, 34,35,41 future research may also focus on evaluating the long-term cost-effectiveness of RFA in other national health care environments.

Conclusions
The findings of this systematic review and meta-analysis suggest that RFA is a safe and efficient method to treat low-risk mPTC, with 79% complete disappearance rates of tumor tissue.Future research may focus on determining what role RFA could play in the treatment of mPTC, especially in countries with restrictive diagnostic workup protocols.Radiofrequency ablation could be envisioned as step-up treatment after local tumor growth under active surveillance or initial treatment in patients with anxiety about active surveillance and wishing to avoid surgery.
Abbreviations: mPTC, papillary microcarcinoma of the thyroid; NS, not specified; RFA, radiofrequency ablation; VRR, volume reduction rate.a Found in other place than ablated area.

Table 1 .
Characteristics of Included Studies Abbreviations: NS, not specified; PLA, People's Liberation Army; RFA, radiofrequency ablation.a Case series.b Cohort studies.

Table 2 .
Effectiveness and Safety of RFA in Patients With mPTC

Table 3 .
Meta-analysis of RFA in Patients With mPTC