This cohort study examines long-term outcomes of radiofrequency ablation for T1N0M0 papillary thyroid cancer and the risk factors associated with local tumor progression.
Key Points
Question
What is the long-term outcome of radiofrequency ablation (RFA) in the treatment of T1N0M0 papillary thyroid carcinoma (PTC)?
Findings
In this cohort study of 1613 adults with T1N0M0 PTC who underwent RFA, the local tumor progression rate was 4.3% with few complications (2.0%) during approximately 5 years of follow-up. Subcapsular tumor location 2 mm or less from the capsule or trachea and multifocal tumors were risk factors for local tumor progression.
Meaning
Findings of this study suggest that RFA for T1N0M0 PTC has excellent long-term outcomes, and patients with subcapsular tumors more than 2 mm from the capsule or trachea and unifocal tumors may be the best candidates for RFA.
Abstract
Importance
Radiofrequency ablation (RFA) has gained increasing interest as a minimally invasive procedure to treat low-risk papillary thyroid carcinoma (PTC). Considering the indolent nature of this disease, studies in large populations with long follow-up would be invaluable to further substantiate the effectiveness of RFA.
Objective
To evaluate the long-term (58.5 months) outcomes of patients with T1N0M0 PTC who underwent RFA and investigate risk factors for local tumor progression (LTP).
Design, Setting, and Participants
This cohort study included 1613 patients aged 18 years or older with T1N0M0 PTC who underwent ultrasonography-guided RFA between January 2014 and December 2020 at the Chinese People’s Liberation Army General Hospital in Beijing, China. Included in the analysis were patients with PTC (confirmed by biopsy) with a maximum diameter of 20 mm or less; no evidence of extrathyroidal extension (capsular disruption or involvement of perithyroidal tissue), lymph node metastasis, or distant metastasis on ultrasonography or computed tomography; and no evidence of an aggressive subtype of PTC on biopsy. Patients with PTC larger than 2 cm, less than 12 months of follow-up, or inadequate follow-up information were excluded. Data were analyzed in April 2023.
Main Outcomes and Measures
Long-term progression rate, disease-free survival, and complete tumor disappearance and their associations with patient and tumor characteristics. Disease-free survival was calculated using Kaplan-Meier analysis. Cox proportional hazards regression analyses were performed to assess risk factors for LTP and complete tumor disappearance.
Results
The study comprised 1613 patients (mean [SD] age, 43.3 [10.2] years; 1256 women [77.9%]) with 1834 T1N0M0 PTC tumors. During a mean follow-up of 58.5 months (range, 27 to 111 months), LTP was observed in 69 patients (4.3%), including 42 (2.6%) with tumor recurrence and 27 (1.7%) with tumor persistence. Cumulative disease-free survival rates at 1, 3, 5, and 8 years were 98.0%, 96.7%, 96.0%, and 95.7%, respectively. The overall complication rate was 2.0% (32 patients), with 6 (0.4%) major complications. Independent risk factors for LTP included subcapsular tumor location 2 mm or less from the capsule or trachea (hazard ratio [HR], 3.36; 95% CI, 2.02-5.59; P < .001) and multifocal tumors (HR, 2.27; 95% CI, 1.30-3.96; P = .004). Furthermore, 1376 patients (85.3%) showed complete tumor disappearance at follow-up ultrasonographic examination. Factors associated with complete tumor disappearance included age 40 years or less (HR, 0.78; 95% CI, 0.70-0.87; P < .001), stage T1a tumors (HR, 0.37; 95% CI, 0.31-0.45; P < .001), and unifocal tumors (HR, 0.50; 95% CI, 0.42-0.60; P < .001).
Conclusions and Relevance
In this cohort study, ultrasonography-guided RFA for T1N0M0 PTC had excellent long-term outcomes. Patients with unifocal T1N0M0 PTC and subcapsular tumor location more than 2 mm from the capsule or trachea may be the best candidates for RFA.
Introduction
Thyroid cancer incidence has substantially increased worldwide with the increased detection and diagnosis of indolent localized and small papillary thyroid carcinomas (PTCs), and mortality rates have remained stable.1,2 In response, the American Thyroid Association guidelines adopted a “less is more” approach for the management of low-risk PTC.3,4 Lobectomy was recognized as a sufficient treatment for low-risk PTC (stage T1 or T2 without extrathyroidal extension and without clinical evidence of any lymph node metastasis [LNM]).3 Active surveillance (AS) was endorsed as an alternative for low-risk papillary thyroid microcarcinoma (stage T1a, particularly in older patients), and the size threshold for AS has been broadened to 2 cm (stage T1b) in ongoing clinical trials.5,6
Radiofrequency ablation (RFA) is gaining attention as a minimally invasive procedure for low-risk PTC, and it has been proposed as an alternative therapeutic option to surgery or AS.7,8 Recent studies have reported favorable clinical outcomes in treating stage T1aN0M0 PTC with RFA, with similar short-term effectiveness as surgery.9,10 Several studies have also broadened the potential RFA candidates to include those with stage T1b or multifocal PTC.11,12 However, previous studies were limited by small patient cohorts and lack of long-term data. In addition, for the optimal selection of patients with PTC who are candidates for RFA, there is an urgent need to identify risk factors associated with local tumor progression (LTP), but such studies are lacking. Considering the indolent nature of PTC, a study of a large population with long-term follow-up would be invaluable to further substantiate the effectiveness of RFA. Therefore, this retrospective study aimed to evaluate the long-term outcomes of patients with T1N0M0 PTC who underwent RFA and to investigate risk factors for LTP.
Methods
This cohort study was approved by the ethics committee of the Chinese People’s Liberation Army General Hospital, and the requirement for obtaining informed consent from patients was waived because of its retrospective nature. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Patient Selection
The electronic medical records of all consecutive patients aged 18 years or older with PTC who underwent ultrasonography-guided RFA from January 2014 to December 2020 at the Chinese People’s Liberation Army General Hospital were reviewed. In our clinical practice, patients were fully informed about treatment options, including surgery, AS, and RFA. Radiofrequency ablation was recommended only for patients who were ineligible for or refused surgery or AS. The inclusion criteria were as follows: (1) PTC confirmed by biopsy with a maximum diameter of 20 mm or less; (2) no evidence of extrathyroidal extension (capsular disruption or involvement of perithyroidal tissue), LNM, or distant metastasis on ultrasonography or computed tomography (CT); and (3) no evidence of an aggressive subtype of PTC on biopsy. The exclusion criteria included (1) PTC larger than 2 cm, (2) less than 12 months of follow-up, and (3) inadequate follow-up information.
Preablation Evaluation
All patients underwent a thorough examination before treatment, including ultrasonography, contrast-enhanced ultrasonography (CEUS), thyroid function tests, laboratory tests, and chest CT. Ultrasonography was performed to identify tumor characteristics (eg, location, size) and to exclude clinical evidence of extrathyroidal extension or cervical LNMs. Contrast-enhanced ultrasonography (SonoVue; Bracco) was used to assess tumor enhancement patterns. Tumor volume was calculated by the following formula: V = πabc/6, where V is the volume and a, b, and c are 3 diameters in transverse, longitudinal, and anteroposterior planes, respectively. Core needle biopsy (CNB) or fine-needle aspiration (FNA) biopsy was performed on all tumors for pathological evaluation and BRAF V600E variant testing. All ultrasonography, CEUS, CNB, and FNA biopsy procedures were performed by physicians with more than 10 years of ultrasonography experience.
RFA Procedure
All RFA procedures were performed by a physician with 20 years of experience in thyroid ultrasonography and tumor ablation (Y. Luo). A Siemens Acuson Sequoia 512 scanner (Siemens Healthineers) with a 6.0-MHz linear array transducer was used for guidance. A bipolar RFA generator (CELON Power System; Olympus Surgical Technologies Europe) and an 18-gauge bipolar radiofrequency applicator with 0.9-cm active tip (CELON ProSurge micro100-T09; Olympus Surgical Technologies Europe) were used for ablation. The patients were placed in the supine position with the neck hyperextended. Local anesthesia with 1% lidocaine was injected into the subcutaneous tissue and capsule. The RFA procedures used the 4-step approach13: (1) thorough examination by ultrasonography, (2) proper use of the hydrodissection technique, (3) rigorous moving-shot ablation strategy,14 and (4) evaluation of the ablation area by CEUS (eFigure 1 in Supplement 1). The ablation area was confirmed to completely cover the original tumor margin to prevent marginal residual tumor and tumor recurrence. Complementary ablation was performed if residual enhancement was observed on CEUS.
Follow-up
Ultrasonography was performed at 1, 3, 6, and 12 months after RFA and every 6 to 12 months thereafter. Chest CT was recommended annually to rule out distant metastases. Contrast-enhanced ultrasonography was also performed at 1, 3, 6, and 12 months after RFA to evaluate the recovery of the ablation area before it disappeared. If the ablation area incompletely disappeared after RFA or showed blood perfusion (the ablation area had blood flow visible on color Doppler flow imaging or contrast medium perfusion visible on CEUS) or shrunk slowly (an ablation area difference <2 mm at intervals of >3 months), a CNB or FNA biopsy was performed in the central, peripheral, and surrounding thyroid parenchyma of the ablation area to verify the persistence of PTC cells. Ultrasonography was used to examine the thyroid gland and surrounding cervical lymph nodes by physicians with 3 years of experience (X.L., L.Y., J.X., and Y. Li.). A contrast-enhanced neck CT was performed if LNM was suspected on ultrasonography. Fine-needle aspiration biopsy was then performed for suspected PTCs and LNMs. All patients were advised to maintain thyrotropin levels within the range of 0.5 to 2 mIU/L.3 For patients with thyrotropin levels greater than 2 mIU/L, we recommended a starting dose of thyroxine of 25 μg/d (eTable 1 in Supplement 1).
Clinical End Points and Definitions
Tumor stage was defined as either 10 mm or less (stage T1a) or greater than 10 mm (stage T1b). The primary end points were LTP and disease-free survival (DFS). Local tumor progression was classified into recurrence and persistence. Tumor recurrence was defined as newly found PTC or cervical LNM confirmed by pathologic examination. Tumor persistence was defined as the persistence of PTC cells at the ablated location as confirmed by pathologic examination. Disease-free survival was calculated from the time of RFA to LTP or last follow-up date. Subcapsular tumor location was defined as the shortest distance between the tumor border and the adjacent capsule or trachea on transverse and longitudinal imaging views.
The secondary end points were complete tumor disappearance and complications. Complete tumor disappearance was defined as the complete disappearance of the ablated area on ultrasonography or the visible presence of a scar. Complications were recorded using the reporting standards of image-guided thyroid ablation.15
Statistical Analysis
Baseline characteristics of patients with or without LTP were summarized using frequency and percentage for categorical covariates and mean (with SD) for continuous covariates. Categorical and continuous covariables were compared using χ2 tests and independent t tests or Mann-Whitney U tests, respectively. Local tumor progression and DFS were calculated using the Kaplan-Meier estimation with log-rank test. Univariable and multivariable Cox proportional hazard regression analyses were used to assess independent factors associated with LTP, tumor recurrence, tumor persistence, and complete tumor disappearance. All statistical analyses were performed using SPSS Statistics, version 26.0 (IBM) and R, version 4.1.0 (R Foundation for Statistical Computing). All P values were 2-sided, and statistical significance was set at P < .05. Data were analyzed in April 2023.
Results
Patient Characteristics
A total of 1613 patients (mean [SD] age, 43.3 [10.2] years; 1256 women [77.9%] and 357 men [22.1%]) with 1834 T1N0M0 PTCs were included in this study (Figure 1). Demographic and tumor characteristics are summarized in Table 1. The maximum (SD) diameter and volume of the tumors (stage T1a, n = 1420; stage T1b, n = 193) were 7.0 (3.0) mm (range, 3.0-20.0 mm) and 180.2 (270.1) mm3 (range, 3.1-2367.6 mm3), respectively. Treatment parameters for RFA are summarized in eTable 2 in Supplement 1; there were no significant differences in ablation time or power or thyrotropin levels during follow-up between the groups who did and did not experience LTP.
Figure 1. Flowchart of Patient Selection.
PTC indicates papillary thyroid carcinoma.
Table 1. Patient and Tumor Characteristics at Baseline.
| Characteristic | No. (%) | LTP rate, % | P valuea | ||
|---|---|---|---|---|---|
| Total (N = 1613) | Patients without LTP (n = 1544) | Patients with LTP (n = 69) | |||
| Patient characteristics | |||||
| Sex | |||||
| Female | 1256 (77.9) | 1196 (77.5) | 60 (87.0) | 4.8 | .06 |
| Male | 357 (22.1) | 348 (22.5) | 9 (13.0) | 2.5 | |
| Age, y | |||||
| ≤40 | 636 (39.4) | 604 (39.1) | 32 (46.4) | 5.0 | .25 |
| 41-60 | 899 (55.7) | 863 (55.9) | 36 (52.2) | 4.0 | |
| >60 | 78 (4.9) | 77(5.0) | 1 (1.4) | 1.3 | |
| Preablation thyrotropin level, mean (SD) [range], mIU/L | 2.05 (1.73) [0.01-30.4] | 2.05 (1.75) [0.01-30.04] | 2.02 (1.08) [0.34-5.36] | NA | .93 |
| Follow-up, mean (SD) [range], mo | 58.5 (19.2) [27-111] | 58.1 (19.1) [27-111] | 66.9 (18.1) [32-109] | NA | <.001 |
| Tumor characteristics | |||||
| Stage | |||||
| T1a (size ≤10 mm) | 1420 (88.0) | 1368 (88.6) | 52 (75.4) | 3.7 | .001 |
| T1b (size >10 mm) | 193 (12.0) | 176(11.4) | 17 (24.6) | 8.8 | |
| Volume, mean (SD) [range], mm3 | 180.2 (270.1) [3.1-2367.6] | 174.5 (258.0) [6.2-2263.0] | 309.1 (448.1) [3.1-2367.6] | NA | .005 |
| Location | |||||
| Left lobe | 674 (41.8) | 648(42.0) | 26 (37.7) | 3.9 | .59 |
| Right lobe | 858 (53.2) | 820 (53.1) | 38 (55.1) | 4.4 | |
| Isthmus | 81 (5.0) | 76 (4.9) | 5 (7.2) | 6.2 | |
| No. of tumors | |||||
| Unifocal | 1418 (87.9) | 1366 (88.5) | 52 (75.4) | 3.7 | .001 |
| Multifocal | 195 (12.1) | 178 (11.5) | 17 (24.6) | 8.7 | |
| Subcapsular tumor location from capsule or trachea | |||||
| >2 mm | 1043 (64.7) | 1020 (66.1) | 23 (33.3) | 2.2 | <.001 |
| ≤2 mm | 570 (35.3) | 524 (33.9) | 46 (66.7) | 8.1 | |
| BRAF V600E mutation | |||||
| Yes | 1266 (86.4) | 1211 (86.1) | 55 (93.2) | 4.4 | .12 |
| No | 200 (13.6) | 196 (13.9) | 4 (6.8) | 2.0 | |
| Preablation CEUS | |||||
| Hyperenhancement | 58 (3.7) | 54 (3.6) | 4 (6.0) | 6.8 | .57 |
| Isoenhancement | 221 (13.9) | 211 (13.8) | 10 (14.9) | 4.5 | |
| Hypoenhancement | 1313 (82.4) | 1260 (82.6) | 53 (79.1) | 4.0 | |
Abbreviations: CEUS, contrast-enhanced ultrasonography; LTP, local tumor progression; NA, not applicable.
P < .05 was considered statistically significant.
Clinical Outcome and Complications After RFA
During a mean follow-up of 58.5 months (range, 27-111 months), LTP was observed in 69 of 1613 patients (4.3%), including tumor recurrence in 42 patients (2.6%) and tumor persistence in 27 patients (1.7%) (eTable 3 in Supplement 1). No distant metastasis was detected. The mean (SD) time after RFA to the development of LTP was 21.5 (19.7) months (range, 3-96 months). Rates of LTP differed significantly based on tumor size (3.7% in stage T1a tumors vs 8.8% in stage T1b tumors; P = .001), the number of tumors (3.7% in unifocal tumors vs 8.7% in multifocal tumors; P = .001), and subcapsular tumor location (2.2% when tumor was >2 mm from the adjacent capsule or trachea vs 8.1% when the distance was ≤2 mm; P = .001). Long-term outcomes also differed significantly by tumor stage. Compared with patients with stage T1a tumors, those with stage T1b tumors more often had LTP (8.8% vs 3.7%; P = .001) and tumor persistence (5.2% vs 1.2%; P < .001); however, the rate of tumor recurrence (3.6% vs 2.5%; P = .34), newly found PTC (3.1% vs 2.1%; P = .38), and LNM (0.5% vs 0.4%; P = .71) did not differ significantly (eTable 4 in Supplement 1).
At the final follow-up, 1376 of 1613 patients (85.3%) had complete tumor disappearance at ultrasonographic examination (eFigure 2 in Supplement 1). Complete tumor disappearance was first observed in 754 (46.7%), 444 (27.5%), 124 (7.7%), 37 (2.3%), 12 (0.7%), 2 (0.1%) and 3 (0.2%) patients at 1, 2, 3, 4, 5, 6, and 7 years after RFA, respectively. Multivariable Cox regression analysis showed age 40 years or younger (hazard ratio [HR], 0.78; 95% CI, 0.70-0.87; P < .001), stage T1a tumor (HR, 0.37; 95% CI, 0.31-0.45; P < .001) and unifocal tumors (HR, 0.50; 95% CI, 0.42-0.60; P < .001) were associated with complete tumor disappearance (eTable 5 in Supplement 1).
The overall complication rate was 2.0% (32 of 1613 patients), including 0.4% (6 of 1613 patients) major complications and 1.6% (26 of 1613 patients) minor complications (Table 2). All complications resolved within 6 months.
Table 2. Complications and Adverse Effects After Radiofrequency Ablation in Patients With T1N0M0 Papillary Thyroid Carcinoma.
| Eventa | No. of patients (%) | Event gradeb | Management | Time to recoveryc |
|---|---|---|---|---|
| Major complication | ||||
| Voice change lasting >1 mo | 6 (0.4) | C | Mecobalamin or dexamethasone | 2-6 mo |
| Minor complications | ||||
| Voice change lasting <1 mo | 11 (0.7) | B | Surveillance | Within 1 mo |
| Hematoma | 15 (0.9) | B | Manual compression | 1-2 wk |
| Adverse effects | ||||
| Pain | 45 (2.8) | A0 | Observation or analgesic drugs | Within 24 h |
| Fever (temperature, 37.5 °C-38.5 °C) | 4 (0.2) | A0 | Supportive care | 1-3 d |
| Coughing | 3 (0.2) | A0 | Observation | Within 2 h |
| Vasovagal syncope | 1 (0.1) | A0 | Supportive care | Within 30 min |
Complications were defined according to the reporting standards of image-guided thyroid ablation.15 A major complication is an unexpected event that leads to substantial morbidity and disability that increases the level of care. All other unexpected events are considered minor complications. Adverse effects are expected adverse events that occur during or after a procedure and do not result in long-term clinical sequelae.
Grade A0: undesired events that are somewhat expected during or after a procedure; grade A: no therapy, no consequence; grade B, nominal therapy, no consequence; grade C: require therapy, minor hospitalization (<48 hours).
All complications resolved within 6 months.
Risk Factors for LTP of PTC and DFS
Univariable Cox regression analysis revealed that tumor size (HR, 2.50; 95% CI, 1.44-4.33; P = .001), number of tumors (HR, 2.55; 95% CI, 1.47-4.42; P = .001), and a subcapsular tumor location 2 mm or more from the capsule or trachea (HR, 3.68; 95% CI, 2.23-6.07; P < .001) were risk factors for LTP of stage T1N0M0 PTC after RFA (Table 3). Multivariable Cox regression analysis found that multifocal tumors (adjusted HR (AHR), 2.27; 95% CI, 1.30-3.96; P = .004) and a subcapsular tumor location 2 mm or less from the capsule or trachea (AHR, 3.36; 95% CI, 2.02-5.59; P < .001) were associated with LTP after RFA (Table 3). Tumor recurrence was associated with a subcapsular tumor location 2 mm or less from the capsule or trachea (AHR, 3.61; 95% CI, 1.89-6.91; P < .001). Risk factors for tumor persistence were stage T1b tumor (AHR, 2.76; 95% CI, 1.21-6.27; P = .015), multifocal tumors (AHR, 3.45; 95% CI, 1.55-7.67; P = .002), and a subcapsular tumor location 2 mm or less from the capsule or trachea (AHR, 2.90; 95% CI, 1.27-6.63; P = .011) (eTable 6 in Supplement 1). Cumulative DFS rates of LTP after RFA at 1, 3, 5, and 8 years were 98.0%, 96.7%, 96.0%, and 95.7%, respectively. The DFS rate differed significantly based on tumor size (AHR, 2.49; 95% CI, 1.19-5.20; P < .001, Figure 2A), number of tumors (AHR, 2.54; 95% CI, 1.21-5.34; P < .001, Figure 2B), and subcapsular tumor location 2 mm or less from the capsule or trachea (AHR, 3.67; 95% CI, 2.24-4.50; P < .001, Figure 2C).
Table 3. Univariable and Multivariable Analyses Evaluating the Prognostic Factors for Local Tumor Progression After Radiofrequency Tumor Ablation in Patients With T1N0M0 Papillary Thyroid Carcinoma.
| Characteristic | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P value | AHR (95% CI) | P value | |
| Sex | ||||
| Female | 1 [Reference] | .07 | NA | NA |
| Male | 0.52 (0.26-1.05) | |||
| Age, y | ||||
| ≤40 | 1 [Reference] | .22 | NA | NA |
| >40 | 0.74 (0.46-1.19) | |||
| Preablation thyrotropin level, mIU/L | 0.99 (0.82-1.20) | .92 | NA | NA |
| Tumor stage | ||||
| T1a (size ≤10 mm) | 1 [Reference] | .001 | 1 [Reference] | .07 |
| T1b (size >10 mm) | 2.50 (1.44-4.33) | 1.68 (0.95-2.97) | ||
| Tumor location | ||||
| Left lobe | 1 [Reference] | .49 | NA | NA |
| Right lobe or isthmus | 1.19 (0.73-1.93) | NA | NA | |
| No. of tumors | ||||
| Unifocal | 1 [Reference] | .001 | 1 [Reference] | .004 |
| Multifocal | 2.55 (1.47-4.42) | 2.27 (1.30-3.96) | ||
| Subcapsular tumor location from capsule or trachea | ||||
| >2 mm | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≤2 mm | 3.68 (2.23-6.07) | 3.36 (2.02-5.59) | ||
| BRAF V600E mutation | ||||
| No | 1 [Reference] | .11 | NA | NA |
| Yes | 2.27 (0.82-6.25) | NA | NA | |
| Preablation CEUS | ||||
| Hypoenhancement | 1 [Reference] | .46 | NA | NA |
| Hyperenhancement or isoenhancement | 1.25 (0.69-2.25) | NA | NA | |
Abbreviations: AOR, adjusted odds ratio; CEUS, contrast-enhanced ultrasonography; NA, not applicable; OR, odds ratio.
Figure 2. Disease-Free Survival of Patients With T1N0M0 Papillary Thyroid Carcinoma Undergoing Radiofrequency Ablation.
Subcapsular tumor location is the shortest distance between the tumor border and the adjacent capsule or trachea on transverse and longitudinal imaging views.
Management of LTP
All management decisions for patients with LTP were made by the physician and the patient in consultation based on the patient’s circumstances and preferences. Of 69 patients with LTP, 59 patients (39 with tumor recurrence and 20 with tumor persistence) were treated with repeat RFA, 1 patient (with LNM) underwent surgery, and 9 patients (2 with tumor recurrence and 7 with tumor persistence) chose AS. None of the 59 patients who underwent reablation experienced tumor recurrence or persistence, and 36 patients (61.0%) had complete tumor disappearance after a mean follow-up of 42.5 (range, 0-76) months (eFigure 3 in Supplement 1). The patient who underwent surgery had no evidence of disease after 76 months of follow-up. The 9 patients who underwent AS had stable lesions after a median follow-up of 53.3 (range, 29-82) months.
Discussion
In this large cohort study of 1613 patients with T1N0M0 PTC who underwent RFA with a mean follow-up of 58.5 months, the incidence rate of LTP was 4.3%, including a tumor recurrence rate of 2.6% and a tumor persistence rate of 1.7%. The overall complication rate was 2.0%, with 6 (0.4%) major complications. Subcapsular tumor location 2 mm or less from the capsule or trachea and multifocal tumors were identified as risk factors for LTP. The complete tumor disappearance rate at ultrasonographic examination at 58.5 months was 85.3%, and prognostic factors included age 40 years or younger, stage T1a tumor, and unifocal tumors.
For stage T1aN0M0 PTC, our findings add to the growing body of evidence of good outcomes associated with RFA. The LTP rate of 3.7%, including a recurrence rate of 2.5% and a persistence rate of 1.2% after almost 5 years of follow-up, found in the present study is comparable to rates reported in other studies.16,17,18,19 In a recent meta-analysis of 3 studies that involved 207 patients with 219 stage T1aN0M0 PTCs and reported 5-year follow-up results after thermal ablation, new tumors were observed in 4 patients (2.7%), and none of these 207 patients experienced LNMs.20 The slightly higher LTP rate in the present study could be attributed to the larger sample, which highlights the heterogeneity of the patient population. Furthermore, we assessed tumor response to RFA in patients with PTC by biopsy of the ablation area. Only 27 patients (1.7%) with persistent disease were identified; these patients received individualized treatment and had a good prognosis at follow-up.
To our knowledge, this study is the first to report on the long-term outcomes of RFA for stage T1bN0M0 PTC. Despite comparable recurrence rates (3.6% vs 2.5%, P = .34), the T1b group showed a higher rate of tumor persistence than the T1a group (5.2% vs 1.2%, P < .001). Stage T1b PTC was also an independent risk factor associated with tumor persistence. Larger tumors pose a greater challenge for RFA due to the limited size of the ablation zone obtained. Therefore, more meticulous and rigorous RFA procedures may be required to ensure both safety and effectiveness in the treatment of stage T1b PTC. As expected, stage T1b tumors showed a later disappearance, and the complete disappearance rate was lower than that of stage T1a tumors.21 Therefore, these results also emphasize that larger tumors require vigorous assessment of tumor response to validate the effectiveness of RFA.
Analysis of risk factors for LTP may help in selecting patients who would benefit more from RFA. Several risk factors, including subcapsular tumor location 2 mm or less from the capsule or trachea and multifocal tumors, were associated with LTP after RFA in this study. Subcapsular tumor location 2 mm or less from the capsule or trachea was also associated with tumor recurrence and persistence. The association of tumors located close to the capsule with the risk of tumor recurrence and LNMs remains controversial and inconsistent.22,23 However, tumors located close to the capsule near the injected fluid of hydrodissection may not be easy to ablate completely because the liquid absorbs some energy. Moreover, adequate safety margins are difficult to obtain in the subcapsular tumor location. For complete ablation, we suggest expanding ablation beyond the capsule with adequate hydrodissection to ensure technical safety with complete tumor coverage. The ablation of subcapsular tumors warrants future research. Given the propensity of PTC to be multifocal,3 patients with multifocal T1N0M0 PTC who underwent RFA were included in this study with the first reported 5-year clinical outcomes. Multifocal tumors tended to develop LTP more often than unifocal tumors (8.7% vs 3.7%), which may be related to the biology of the tumor. Moreover, multifocal tumors were risk factors for both tumor persistence and complete tumor disappearance, so assessment of tumor response should be emphasized. Furthermore, patient age was not a risk factor for LTP. We found that RFA had similar effectiveness in both young patients (≤40 years) and older patients (>40 years). However, several studies have found that younger age was associated with poorer clinical outcomes under AS.24,25 Radiofrequency ablation (vs AS) may eliminate differences in outcomes based on patient age, but more research is needed. In addition, younger patients in our study were more likely to experience complete tumor disappearance, suggesting a better immune function and ability to repair damaged tissue than older patients.
For AS of patients with stage T1aN0M0 PTC, a recent meta-analysis reported a size enlargement rate of 5.3% and a LNM rate of 1.6% rate of at 5 years.26 However, 8.7% to 32.0% of patients in that study had delayed surgery due to anxiety or disease progression.26 Our study found a higher rate of target stage T1a tumors successfully eradicated (98.8%, 1403 of 1420 patients) and a lower rate of LNMs (0.4%, 5 of 1420 patients) at 5 years, suggesting that RFA may control local tumor growth and reinforce AS, reducing patients’ anxiety due to indwelling cancer, which in turn reduces unnecessary surgery. In addition, the overall complication rate of RFA was low in the entire cohort (2.0%), with 6 (0.4%) major complications. These results are in line with reported complication rates ranging from 2.7% to 3.6% for all complications and 0.2% to 3% for major complications.10,11,20 Rigorous RFA procedures and standardized practices, especially the judicious use of hydrodissection, can help avoid hyperthermic injury to surrounding critical structures. Previous studies comparing RFA and surgery for PTC showed similar short-term oncologic outcomes, while suggesting that RFA was associated with fewer complications, faster recovery time, higher quality of life, lower financial costs,9,27,28 and less reliance on thyroid hormone replacement.29 Optimal treatment decisions for AS, RFA, and lobectomy require a balanced discussion between the patient and the multidisciplinary team, including which candidates are suitable for each option and benefits and drawbacks of each option, while taking into account the patient’s motivation and treatment adherence, life expectancy, and financial situation.
Limitations
This study has several limitations. First, as it was a retrospective, single-center study, selection bias might have occurred. Multicenter and prospective studies are warranted to confirm the results. Second, since microwave ablation can provide a larger ablation zone than RFA in a given time, further studies are necessary to compare the effectiveness and safety of RFA and microwave ablation for larger tumors. Third, patient age was classified according to the grouping of patients with PTC under AS by Ito et al.24 We investigated the clinical prognosis of RFA in a proportion of young patients considered high risk under AS. However, a comparison of patients who underwent RFA only and those who underwent AS only is still lacking. Future studies are needed to provide guidance for selection of optimal treatment modalities for each patient.
Conclusions
This retrospective cohort study found that favorable outcomes were associated with use of ultrasonography-guided RFA for T1N0M0 PTC, with low complication rates. Subcapsular tumor location 2 mm or less from the capsule or trachea and multifocal tumors were associated with LTP. Therefore, patients with unifocal T1N0M0 PTC and subcapsular tumor location more than 2 mm from the capsule or trachea may be the best candidates for RFA. More research with data on more patients from different populations and longer follow-up is warranted to confirm these findings.
eFigure 1. The 4-Step Approach Used in the Radiofrequency Ablation Procedure
eFigure 2. Pre- and Post-RFA Follow-Up US Images in a 30-Year-Old Woman with T1a PTC With Complete Tumor Disappearance
eFigure 3. Pre- and Post-RFA Follow-Up US Images in a 39-Year-Old Woman with T1a PTC and Tumor Persistence
eTable 1. TSH Levels and Thyroid Hormone Treatment
eTable 2. RFA Treatment Parameters
eTable 3. Local Tumor Progression After RFA at Final Follow-Up
eTable 4. Patient Characteristics in T1a and T1b Groups
eTable 5. Univariable and Multivariable Analyses Evaluating the Prognostic Factors for Complete Tumor Disappearance
eTable 6. Multivariable Analyses for the Prognostic Factors of Recurrence and Persistence
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure 1. The 4-Step Approach Used in the Radiofrequency Ablation Procedure
eFigure 2. Pre- and Post-RFA Follow-Up US Images in a 30-Year-Old Woman with T1a PTC With Complete Tumor Disappearance
eFigure 3. Pre- and Post-RFA Follow-Up US Images in a 39-Year-Old Woman with T1a PTC and Tumor Persistence
eTable 1. TSH Levels and Thyroid Hormone Treatment
eTable 2. RFA Treatment Parameters
eTable 3. Local Tumor Progression After RFA at Final Follow-Up
eTable 4. Patient Characteristics in T1a and T1b Groups
eTable 5. Univariable and Multivariable Analyses Evaluating the Prognostic Factors for Complete Tumor Disappearance
eTable 6. Multivariable Analyses for the Prognostic Factors of Recurrence and Persistence
Data Sharing Statement