Clinical outcomes of radiofrequency ablation for solitary T1aN0M0 versus T1bN0M0 papillary thyroid carcinoma: a propensity-matched cohort study

Abstract Objective To conduct a cohort study comparing the treatment outcomes of radiofrequency ablation (RFA) therapy for solitary T1aN0M0 (T1a) versus T1bN0M0 (T1b) papillary thyroid carcinoma (PTC). Methods This retrospective analysis comprised 310 patients with low-risk PTC undergoing RFA classified into T1a (n = 272) and T1b (n = 38) groups according to the tumor size. A comparative analysis between the two groups was conducted for the volume reduction ratio (VRR), volume, local tumor progression (LTP), and recurrence-free survival (RFS) before and after 1:2 propensity score matching (PSM). Cox analysis was conducted to examine the influence of several variables, including T1b, on recurrence following RFA for PTC. Results The total VRR was 99.99 ± 0.11% throughout the median follow-up duration of 26 months, and the overall incidence of LTP was 2.58% (8/310). No irrecoverable complications occurred after RFA. The variations between the T1a and T1b groups following PSM were insignificant in terms of volume (p = 0.574), VRR (p = 0.574), complete disappearance rate (p = 0.210), LTP incidence (p = 1.000), and RFS rate (p = 0.610). The correlation between T1b and LTP continued to be insignificant (p = 0.686). No distant metastasis or delayed surgery occurred. Conclusions The presence of T1b did not influence the patients’ prognoses following RFA for T1N0M0 PTC. After appropriate patient selection and adequate preoperative assessment, RFA has the potential to serve as an effective therapy for individuals with T1a and T1b PTC.


Introduction
Papillary thyroid carcinoma (PTC) is the most prevalent subtype of thyroid cancer.Papillary thyroid microcarcinoma (PTMC) is a subtype of PTC that contains lesions measuring less than 10 mm in diameter [1].The prognosis for patients with PTMCs is favorable since these tumors are typically regarded as indolent [2].In a study involving 1235 patients diagnosed with low-risk PTMC, Ito et al. [3] found that throughout the active surveillance (AS) duration (which spanned from 1.5 to 19 years), no patients developed distant metastases or died due to PTMC.In cases of patients with PTC who cannot undergo surgery, the 2017 guidelines from the Korean Society of Thyroid Radiology recommend thermal ablations as an alternative treatment option [4].Recently, radiofrequency ablation (RFA) [5][6][7][8][9][10], microwave ablation [11][12][13][14], and laser ablation [15,16] have increasingly been applied to patients with PTMCs, leading to good clinical outcomes [17].However, these findings focused primarily on the tumors known as PTMCs and did not account for the low-risk small PTCs that measured < 2 cm but were > 1 cm.T1 Thyroid cancers are classified as T1a (tumor size � 1 cm) and T1b (tumor size > 1 cm but � 2 cm) according to their size as per the American Joint Committee on Cancer (AJCC) TNM classification [18].No significant variation was identified in lymph node metastasis (LNM) and tumor growth between T1aN0M0 and T1bN0M0 PTC in a prospective study with long-term AS (average follow-up duration of 7.4 years) [19].T1a and T1b thyroid cancer patients undergoing either complete thyroidectomy or lobectomy showed similar overall and disease-specific survival rates, according to large-sample database research [20].The incidence of PTCs has increased in patients who refuse surgery or are ineligible for surgery due to age or other factors [21].The effectiveness and safety of thermal ablation in treating T1bN0M0 PTC have been described in recent studies [22][23][24][25][26].Moreover, T1N0M0 PTC patients undergoing either surgery or thermal ablation showed similar disease-free survival rates [27][28][29].However, little research has compared the efficacy and safety of T1a and T1b PTC treated with RFA.Thus, this retrospective study aimed to examine the clinical outcomes of RFA for T1bN0M0 PTC and compare these outcomes with T1aN0M0.

Patients
The following criteria were set for inclusion: (1) solitary PTC lesion was confirmed through fine-needle aspiration (FNA) or core-needle biopsy (CNB); (2) Chest and neck computed tomography (CT), as well as ultrasound all showed no signs of extrathyroidal extension (ETE), lymph node metastases, or distant metastases; (3) patients who were unsuitable for surgery or rejected surgery; (4) the duration of the follow-up was over 12 months.The following were the criteria for exclusion: (1) no significant indications of PTC on biopsy; (2) multiple PTC lesions; (3) distant metastases as seen on imaging, together with either ETE or LNM; (4) Disorders of consciousness and neck flexion; (5) organ failure or abnormal coagulation; (6) less than a year of follow-up.
In total, 703 patients with low-risk PTC received RFA at our hospital between January 2016 and December 2021; of these, we enrolled 310 participants in the study since they satisfied all of the inclusion criteria.Subsequently, 272 patients with microcarcinoma (largest diameter � 10 mm) were assigned to the T1a group whereas 38 patients with small carcinoma (largest diameter > 10 mm and � 20 mm) belonged to the T1b group (Figure 1).

Pretreatment ultrasound assessment
All of the patients received comprehensive examinations, which encompassed tests of complete blood count, coagulation and thyroid function, and imaging assessments, which constituted ultrasound and CT scans.The formula below was used to determine the volume of the tumor: V ¼ pabc/6.

RFA procedure
An ultrasound radiologist with 20 years of expertise in interventional ultrasonography conducted RFA procedures.An RFA instrument (LDRF-120S, Mianyang Lide Electronics Co., Ltd.) and an 18-gauge RFA electrode (working end 1 cm, needle bar length 8 cm) were used in this study.Doppler ultrasonography was employed to examine the intricate vascular structure along the approach path to avoid bleeding.The subcutaneous puncture site, as well as the thyroid anterior capsule, were both injected with a local anesthetic.To conduct RFA, we used a trans-isthmic strategy and employed a moving-shot method.Hydro dissection method was used when there was a < 5 mm gap between the tumor and vital cervical structures.
To reduce the risk of marginal residue and recurrence, we extended the ablation region such that it was larger than the tumor edge (by a minimum of 3 to 5 mm).Power output from the RFA ranged between 40 and 70 W.Following RFA, the ablated region was analyzed by means of contrastenhanced ultrasonography (CEUS).An enhancement, if present, required a complementary ablation to remove it.

Follow-up
During the clinical follow-up visits, ultrasound, CEUS, chest CT (once per year), and clinical assessments were conducted at 1, 3, 6, 9 and 12 months, and then every 6-12 months after that.The volume reduction rate (VRR) was determined as indicated: VRR ¼ ([initial volume À final volume] � 100)/initial volume.Biopsies were performed to investigate the development of any LNMs that seemed suspicious or the appearance of any new lesions.

Outcome measures
The primary outcomes were the rates of local tumor progression (LTP) and recurrence-free survival (RFS).There were three situations included in the definition of LTP: (1) a secondary recurrent lesion distinct from the ablated tumor, biopsied and identified as PTC; (2) biopsy results confirming cervical LNM; and (3) a biopsied lesion that has persisted at the location of prior treatment and been identified as PTC.In cases where symptoms suggested distant metastasis, imaging techniques like CT, positron emission tomography (PET), and bone scans were used to confirm the diagnosis.RFS was derived from the beginning of RFA to the time of tumor recurrence or the last date of follow-up.
Both the effectiveness of the treatment and the occurrence of complications were considered secondary outcomes.The reporting guidelines established by the Society of Interventional Radiology were used to analyze the complications that arose throughout the follow-up interval.The effectiveness of the ablation was assessed by the VRR and the rate of complete disappearance.If any of the following conditions about RFA were satisfied, we deemed it a success: (1) On ultrasonography, the ablated PTC region completely disappeared; (2) Scarring persisted in the ablated region on ultrasonography, and there was no enhancement in CEUS; (3) The ablation site remained visible, but CNB verified a negative result, which was done 3 to 6 months following RFA on the central zone, the periphery, and the surrounding thyroid parenchyma.

Statistical analysis
The SPSS statistical package (V.26.0) was utilized for the analyses of all statistical data.We employed propensity score matching (PSM) in the two groups in terms of sex, age, chronic lymphocytic thyroiditis (CLT), and follow-up duration to account for the possible biases inherent in any retrospective analyses.Statistics for categorical variables are shown graphically as percentages, and Chi-square or Fisher's exact tests are used to make comparisons between groups.The Mann-Whitney U test was used to detect statistical significance for continuous data, which was then presented as mean ± standard deviation.Mann-Whitney U tests were utilized to compare the volume before RFA and at each follow-up period.Kaplan-Meier analysis was conducted to produce RFS curves, and the log-rank test was utilized for comparison.A Cox proportional hazard model was used for univariate and multivariate analyses to determine which factors were significantly linked to recurrence.p < 0.05 indicated a significant difference.

Results
In total, 310 individuals who had RFA were involved in this study, consisting of 272 patients with T1aN0M0 and 38 with T1bN0M0.The follow-up duration was 29.16 ± 13.55 months on average with a median of 26.00 months before PSM.There were no significant variations between the T1a and T1b groups preand post-PSM in terms of age, sex, thyroid function, or duration of follow-up.Following a 1:2 PSM, the T1b group consumed more time and energy on RFA than the T1a group (p < 0.001) (Table 1).The follow-up duration was 28.61 ± 13.07 months on average with a median of 25.00 months after PSM.

Primary outcomes
LTP had an overall incidence rate of 2.58% (8/310).Specifically, LNM, recurrent PTMC, and persistent lesions had incidences of 0.97% (3/310), 1.61% (5/310), and 0% (0/310), respectively.Among the eight patients with LTP, one patient with recurrent PTC and one patient with LNM in the T1a group opted to receive conventional surgery.The remaining six patients underwent additional RFA, after which all of the lesions entirely disappeared.No indication of distant metastases was found, and none of the patients had their operations postponed due to LTP or anxiety.
At 1 and 3 years, the RFS rates for the T1a group were 98.90% and 97.43%, respectively, whereas those in the T1b group were 97.37% and 97.37%, respectively.In the T1a group, the RFS rates at 1 and 3 years post-PSM were 98.68% and 98.68%.When comparing RFS rates pre-and post-PSM, no significant difference was observed (p ¼ 0.959; p ¼ 0.610, respectively) (Figure 2).In addition, the Cox regression analysis did not find any strong association between T1b and recurrence (Table 3).

Secondary outcomes
The overall VRR was found to be 99.99 ± 0.11%.In the first six months post-RFA, T1b patients had more volume and higher VRR than T1a patients pre-PSM (all p < 0.05, except VRR at 1 month).After six months, however, there were no remarkable variations (all p > 0.05).Notably, tumors in 281 patients completely disappeared (90.65%); among these patients, there were 249 patients in the T1a group (91.54%) and 32 in the T1b group (84.21%) (p ¼ 0.146).After PSM, Only the volume in the first six months was considerably lower in the T1a group than that in the T1b group (all p < 0.05).During the duration of the follow-up, the volume and VRR did not exhibit any significant variations between the groups (all p > 0.05, after 6 months) (Tables 4 and 5, Figure 3).Furthermore, the total disappearance of tumors was observed in 70 individuals in the T1a group and 32 in the T1b group.When comparing the two groups, there was still not a significant variation in the rate of disappearance (92.11% vs. 84.21%,p ¼ 0.210) (Figure 4).The RFA therapy was well tolerated by all patients.Ten patients (3.68%) in the T1a group and two patients (5.26%) in the T1b group experienced local pain and bleeding, which disappeared without intervention within one week.Two T1a patients developed hoarseness post-RFA and recovered within three months.

Discussion
Long-term clinical outcomes of RFA treatment for T1b PTC were assessed in comparison with those of PSM-treated T1a PTC in this retrospective analysis.Our results suggest that RFA for individuals with solitary T1N0M0 PTC who are either surgically ineligible or surgically unwilling could be a viable and safe alternative.As for PTC, RFA was just as effective in treating T1aN0M0 as it was in treating T1bN0M0.No remarkable variation was observed post-RFA in the LTP and RFS rates between the T1a and T1b groups.Notably, the overall LTP rate in our study was 2.58% (8/310), which is relatively reduced in contrast with those identified in previous studies [24,25], wherein the LTP rates were 4.5% and 3.8%.
Surgery is a traditional treatment for PTC patients but may be excessive since it might result in consequences like hoarseness, hypoparathyroidism, and the need for lifelong medication.When there is no evidence of distant metastases, local invasion, or cytologically aggressive features, cancer is considered "low-risk" [30].Recently, AS of this PTC type has attracted attention as evidenced in the findings of a Japanese observational study [31,32].However, not everyone may readily tolerate AS.Thus, patients with low-risk PTCs could consider thermal ablation, a moderate approach between surgery and AS.
Even though early research on RFA for primary PTC therapy has shown promise, much of it has concentrated on low-risk PTMC [5][6][7][8][9][10][11][12][13][14][15][16].Neither the effectiveness nor the safety of RFA for T1b PTC has been intensively researched.The most recent studies show that in patients with low-risk PTC, the rates of tumor disappearance following thermal ablation vary from 57.6% to 68% for tumors < 2 cm [22][23][24].Our 91.5% tumor disappearance rate in the T1a group and 84.2% in the T1b group is consistent with previous research.This might be explained by the fact that the amount of coagulative necrosis was greater in the T1b group as compared to  the T1a group.Meanwhile, in a previous study, the VRR of T1bN0M0 PTC ranged from 92.62-100% at the termination of the follow-up [24].Our research found that the VRRs for the T1a and T1b groups were, respectively, 100% and 99.96%, which is close to the values that were previously published.Additionally, as a result of the T1b group having a larger initial tumor size, the T1b group required more time and energy for RFA than the T1a group.The reported rate of overall complications post-RFA was 3.5%, with the incidence of major complications being 1.6% [33], lower relative to those of thyroid surgery-specific complications (12.3%) [34].The RFA technique was well tolerated by all of the patients in our research.Twelve patients experienced minor bleeding and pain at the affected site, both of which subsided on their own within a week.It is considered that heat damage is the leading cause of recurrent laryngeal nerve (RLN) injury, which is the most prevalent serious consequence post-RFA.The injury rate to the RLN post-RFA was shown to be 0.7% in a recent research report [33].Two patients (0.6%) in our research developed hoarseness post-RFA, however, they recovered fully within three months.Accurate tumor targeting under ultrasound guidance, moving shots, and hydro-dissection techniques can minimize the incidence of complications [35].
Our study has some limitations.Firstly, this was retrospective research conducted in a single center.Secondly, the number of people who participated in the T1b PTC study was not very large.Thirdly, although the prognosis for T1N0M0 PTC is favorable, a longer follow-up time is required to validate the study's findings.Nevertheless, little research has compared the efficacy and safety of T1a and T1b PTC treated with RFA.Our results may shed light on the rationale for using RFA to treat individuals with primary T1N0M0 PTC.
In summary, there was little influence of tumor size on the prognosis post-RFA for low-risk PTC.Furthermore, RFA might be a promising treatment approach for patients with T1a or T1b PTC.

Figure 2 .
Figure 2. Treatment of T1a and T1b PTC patients with RFA as depicted by recurrence-free survival curves.A. Pre-propensity score matching; B. Post-propensity score matching.

Figure 4 .
Figure 4. US and CEUS scans of a 50-year-Old female with T1b PTC before and after RFA. A. Before RFA, the maximum diameter of the left thyroid lobe PTC tumor was 13 mm, and its original volume was 219.91 mm 3 .B. The volume of the ablation region was 186.39 mm 3 after three month of RFA. C. By six months following RFA, the volume of the ablation region was decreased by 95.45%, to 49.24 mm 3 .D. The ablation site healed completely nine months following RFA.

Figure 3 .
Figure 3. Changes in volume and VRR in the T1a and T1b groups at each follow-up time point post-RFA.A, B Pre-propensity score matching; C, D post-propensity score matching.

Table 1 .
Baseline clinical of patients before and after propensity score matching.

Table 2 .
The comparison of local tumor progression between the two groups after RFA Data are expressed as mean ± SD or number of nodules (percentages)

Table 3 .
Univariate and multivariate analyses evaluating the risk factors affecting recurrence-free survival.

Table 4 .
The changes of volume at each follow-up point after RFA

Table 5 .
The changes of VRR at each follow-up point after RFA