Efficacy and Safety of Radiofrequency Ablation for Treatment of Locally Recurrent Thyroid Cancers Smaller than 2 cm.

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Original Research n Vascular

Ji-hoon Kim, MD, PhD Won Sang Yoo, MD Young Joo Park, MD, PhD Do Joon Park, MD, PhD Tae Jin Yun, MD Seung Hong Choi, MD, PhD Chul-Ho Sohn, MD, PhD Kyu Eun Lee, MD, PhD Myung-Whun Sung, MD, PhD Yeo-Kyu Youn, MD, PhD Kwang Hyun Kim, MD, PhD Bo Youn Cho, MD, PhD

Purpose:

To evaluate the efficacy and safety of radiofrequency ablation (RFA) for localized small recurrent thyroid cancers less than 2 cm by comparing them with those at repeat surgery.

Materials and Methods:

This retrospective study was institutional review board– approved, and informed consent was waived. From December 2008 to December 2011, this study evaluated 73 patients (17 men and 56 women; age, 50.3 years 6 13.6) with recurrent thyroid cancer who had been treated with RFA (n = 27) or repeat surgery (n = 46) who met the following criteria: (a) three or fewer recurrences or lesions with high probability of recurrence at ultrasonography; (b) no tumor other than the target tumors; and (c) at least 1 year of follow-up. RFA was recommended and performed in cases of surgical ineligibility, such as patient refusal and poor medical condition. Recurrencefree survival rates and posttreatment complication rates (eg, hoarseness and hypocalcemia) were compared between RFA and reoperation groups after adjustment with weighted analysis by using inverse probability of treatment weights.

Results:

After this adjustment, the 1- and 3-year recurrence-free survival rates were comparable (P = .681) for RFA (96.0% and 92.6%, respectively) and reoperation (92.2% and 92.2%, respectively) groups. The posttreatment hoarseness rate did not differ between the RFA (7.3% [1.8 of 24]) and reoperation (9.0% [3.6 of 39.5]) groups (P = .812), and posttreatment hypocalcemia occurred exclusively in the reoperation group (11.6% [4.6 of 39.5]) but not in the RFA group (0% [0 of 24]) (P = .083).

Conclusion:

RFA may be an effective and safe alternative to repeat surgery in patients with locally recurrent small thyroid cancers.

1

From the Departments of Radiology (J.H.K., T.J.Y., S.H.C., C.H.S.), Internal Medicine (W.S.Y., Y.J.P., D.J.P., B.Y.C.), Surgery (K.E.L., Y.K.Y.), and Otolaryngology—Head and Neck Surgery (M.W.S.), Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Dankook University Hospital, Republic of Korea (W.S.Y.); Department of Otolaryngology: Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea (K.H.K.); and Department of Internal Medicine, Chung-Ang University Hospital, College of Medicine, Chung-Ang University, 224-1 Heukseok-dong, Dongjak-gu, Seoul 156-755, Republic of Korea (B.Y.C.). Received January 13, 2014; revision requested February 24; revision received August 19; accepted September 10; final version accepted January 6, 2015. Address correspondence to B.Y.C. (e-mail: [email protected]).

and Interventional Radiology

Efficacy and Safety of Radiofrequency Ablation for Treatment of Locally Recurrent Thyroid Cancers Smaller than 2 cm1

RSNA, 2015

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RSNA, 2015

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Radiology: Volume 000: Number 0—   2015 n radiology.rsna.org

1

VASCULAR AND INTERVENTIONAL RADIOLOGY: Efficacy and Safety of Radiofrequency Ablation for Treatment of Thyroid Cancers

I

n recent decades, incidence of differentiated thyroid cancer rapidly increased. The low differentiated thyroid cancer mortality rate of about 0.5 deaths per 100 000 people prompted a debate over small cancer detection (1– 3). However, the long-term recurrence rate of differentiated thyroid cancer after initial treatment is reportedly as high as 30% (4–6). Surgical removal is the treatment of choice in most cases of recurrent thyroid cancer, and it reportedly improves long-term survival of the patient (7). However, repeated surgeries can leave the patient debilitated and can be a challenge for the surgeon because of postoperative fibrosis and normal tissue plane distortion, which can cause complications such as hoarseness and hypocalcemia (6–8). Especially in cases of small recurrences, which can be sensitively detected with ultrasonographic (US) imaging, surgery can be technically difficult and is of limited therapeutic efficacy (6,7,9). Regarding less invasive alternatives, recent publications demonstrated that percutaneous ethanol injection produced favorable results for control of recurrent thyroid cancers (10–15).

Advances in Knowledge nn After adjustment with inverse probability of treatment weights, the 1- and 3-year recurrence-free survival rates were comparable (P = .681) in the radiofrequency ablation (RFA) (96.0% and 92.6%, respectively) and reoperation (92.2% and 92.2%, respectively) groups for patients with localized small recurrent thyroid cancers. nn After adjustment with inverse probability of treatment weights, the posttreatment hoarseness rate did not differ between the RFA (7.3% [1.8 of 24]) and reoperation (9.0% [3.6 of 39.5]) groups (P = .812), and posttreatment hypocalcemia occurred exclusively in the reoperation group (11.6% [4.6 of 39.5]) but not in the RFA group (0% [0 of 24]) (P = .083). 2

Although percutaneous US-guided radiofrequency ablation (RFA) is reportedly an alternative to surgery in patients who have malignant tumors of the liver, kidney, or lung (16–18), the efficacy and safety of RFA in recurrent thyroid cancers were explored in only a few studies with limited numbers of patients, and there were no reports that compared RFA and repeat surgery (19– 21). There was also a lack of studies on RFA focused on small recurrent thyroid cancers, which are often more difficult to decide to operate on. In this regard, the purpose of our study was to evaluate the efficacy and safety of RFA for localized small recurrent thyroid cancers less than 2 cm by comparing them with those at repeat surgery.

Materials and Methods Patients Our retrospective study was approved by the institutional review board of Seoul National University Hospital, and informed consent was waived. The medical records of recurrent thyroid cancer patients who were treated by using RFA or repeat surgery at our hospital between December 2008 and December 2011 were reviewed. Their clinical outcomes were followed until April 2013. During this period, 103 consecutive patients underwent RFA or repeat surgery for recurrent thyroid cancer treatment. In our practice, repeat surgery was initially recommended and performed to treat recurrent thyroid cancer. However, in cases of surgical ineligibility, such as patient refusal and poor medical condition, RFA was recommended and performed if it was accepted by the patients. Included patients met the following criteria before RFA or repeat surgery: (a) three or fewer recurrences or lesions that showed high probability of recurrence Implication for Patient Care nn RFA may be an effective and safe alternative to repeat surgery in patients with locally recurrent small thyroid cancers.

Kim et al

at US imaging; (b) a maximum tumor dimension of less than 2 cm; (c) no other recurrent or metastatic cancers beyond the target neck tumors; and (d) 1 year or more of clinical and imaging follow-up after the treatments. The lesions with high probability of recurrence at US imaging showed diffuse hyperechogenicity, micro- or macrocalcification, cystic changes, and irregular vascular patterns (22). After the exclusion of 30 patients according to the above criteria, 73 patients (27 patients in the RFA group and 46 patients in the reoperation group) with papillary thyroid carcinoma were included in our study cohort.

RFA Procedure Written informed consent was obtained from each patient before they underwent RFA. In the RFA group, US-guided fine-needle aspiration was performed in all patients suspected of having cancerous lesions to confirm the recurrence and to guide RFA. One radiologist (J.H.K., 8 years of experience performing thyroid US imaging) performed all of the RFA procedures by using a 5- to 12-MHz linear transducer and a realtime US system (Iu22; Philips Healthcare, Andover, Mass). A radiofrequency Published online before print 10.1148/radiol.15140079 Content codes: Radiology 2015; 000:1–10 Abbreviations: IPTW = inverse probability of treatment weights RF = radiofrequency sTg = thyroid-stimulating hormone stimulated serum Tg Tg = thyroglobulin Tg-Ab = anti-Tg antibody Author contributions: Guarantors of integrity of entire study, J.H.K., Y.J.P., Y.K.Y., B.Y.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, J.H.K., Y.J.P., D.J.P., C.H.S., K.E.L., M.W.S., Y.K.Y., K.H.K., B.Y.C.; clinical studies, J.H.K., W.S.Y., Y.J.P., D.J.P., K.E.L., M.W.S., Y.K.Y., K.H.K., B.Y.C.; experimental studies, Y.K.Y.; statistical analysis, J.H.K., W.S.Y., Y.J.P., Y.K.Y., B.Y.C.; and manuscript editing, J.H.K., Y.J.P., T.J.Y., S.H.C., C.H.S., K.E.L., M.W.S., Y.K.Y., K.H.K., B.Y.C. Conflicts of interest are listed at the end of this article.

radiology.rsna.org n Radiology: Volume 000: Number 0—   2015


generator (Radionics Cool-tip; Integra, Burlington, Mass) and a 7-cm-long 18-gauge internally cooled electrode with a 0.5-cm active tip (Well-point Radiofrequency Electrode; Taewoong Medical, Goyang, Korea) were used. By using the moving-shot technique described by Jeong et al (23), 2% lidocaine was injected and used as local anesthesia, and the recurrent cancer was divided into a few conceptual units and completely ablated with a 2-mm safety margin from the deepest and most remote portion of the cancer in a unit-byunit manner by moving the electrode. Any sedative or analgesic agent was not used for the procedure. Ablation started with 10–15 W of power. If a transient hyperechoic zone, which indicated effective ablation, was not formed at the electrode tip within 5–10 seconds, the radiofrequency power was increased gradually, up to 40 W (17 W 6 7; range, 10–40 W). To prevent normal structure injury, the techniques suggested by Monchik et al (19) were applied with some modifications: The recurrent cancers were separated from the normal structures by infusing 5% dextrose solution or lidocaine into the space between the cancer and the normal structures and/or by tilting or pushing the electrodes after their insertion into the cancer. Real-time monitoring by using US imaging was performed to ascertain the correct position of the needle in the tumors that were treated at all times during the procedures. All of the patients were treated in the outpatient clinic and were discharged when their vital signs were stable after observation for 0.5–1 hour. Of 27 patients with 36 tumors, 24 patients (88.9%) with 31 tumors (one tumor in 17 patients and two tumors in seven patients) underwent one session of RFA. For the remaining three patients (11.1%) with five tumors (one tumor in two patients and three tumors in one patient), two sessions of RFA were performed because of the difficulty in accessing the tumors or tumor multiplicity. Although two of 27 patients (7.4%) complained of severe pain during the ablation, the pain could be controlled by a reduction of RFA power

or by stopping the ablation for several seconds. The ablation time per session was 5.5 minutes 6 1.5 (range, 3–8 minutes).

Reoperation Procedure In the reoperation group, at least one tumor was confirmed as recurrent by using fine-needle aspiration before the operation, and the other lesions with high probability of recurrence at preoperative US imaging were resected and evaluated with pathologic examination. All of the repeat surgeries were performed while the patient underwent general anesthesia (K.H.K., Y.K.Y., M.W.S., and K.E.L., with 33, 30, 23, and 8 years of experience in thyroid surgery, respectively). By using a 3.5to fivefold magnification loupe, comprehensive neck dissection was performed to include all of the compartments with the tumor recurrences and the adjacent compartments if the patient had not previously undergone comprehensive neck dissection. Intraoperative US tumor localization was used if needed. To minimize the risk of permanent hypoparathyroidism, healthy parathyroid tissue was confirmed with pathologic analysis and autotransplanted whenever necessary. The admission time per repeat surgery was 6.5 days 6 2 (range, 3–16 days). Pretreatment Work-up and Follow-up Protocol Before RFA or repeat surgery, most patients underwent regular monitoring involving clinical examinations, serum thyroglobulin (Tg), serum anti-Tg antibody (Tg-Ab), serum thyroid-stimulating hormone, and US imaging of the neck every 6–12 months. US imaging and contrast agent–enhanced computed tomographic (CT) examinations of the neck were performed immediately before RFA or repeat surgery in all patients. After RFA or repeat surgery, regular Tg and Tg-Ab measurements were performed in all patients. In the RFA group, US imaging was performed 2, 6, and 12 months after RFA and every 6–12 months thereafter. CT examinations were performed 1 year after RFA and every 1–2 years thereafter. If an ablation


Kim et al

zone was persistently visible for at least 1 year after RFA, fine-needle aspiration was performed on the ablation zone. In the reoperation group, US or CT imaging was performed at 6- to 12-month intervals. In both groups, fine-needle aspiration was also performed when new lesions that were possibly recurrence developed during the follow-up. Additional diagnostic examinations, such as fluorine 18 (18F) fluorodeoxyglucose– positron emission tomographic or chest CT imaging, were performed in patients who exhibited persistently elevated serum Tg or thyroid-stimulating hormone stimulated serum Tg (sTg) to exclude the presence of distant metastases. All US examinations were performed by one of four radiologists (C.H.S., J.H.K., S.H.C., and T.J.Y., with 19, 8, 6, and 5 years of experience, respectively, in thyroid US imaging). Blinded to the clinical characteristics of the patients, two radiologists (C.H.S. and T.J.Y.) reviewed US and CT images in consensus to determine the size change of the recurrent tumor after each treatment. Data on clinical and laboratory findings were reviewed by one endocrinologist (W.S.Y., with 7 years of experience in thyroid endocrinology).

Study End Points and Definition The primary end points were recurrence-free survival rates and after-treatment complication rates that included hoarseness and hypocalcemia. The secondary endpoints were responses of serum Tg, Tg-Ab, and sTg after each treatment. Recurrence was defined as an identification of new tumors or persistent ablation zones with pathologic confirmation of malignancy in the neck at follow-up after RFA or repeat surgery. Recurrence at distant sites was not considered in this report because no distant metastatic tumors developed during follow-up in either group. We considered RFA to be successful if the following criteria were met: complete disappearance on US and/or CT images (n = 31) (Fig 1) or an ablation zone too small to be aspirated (n = 1); or no detectable malignant cells and Tg on fine-needle aspiration at the ablation zone in cases in which US and/or CT 3


Kim et al

Figure 1

Figure 1: Images of RFA in a 58-year-old woman with solitary recurrent papillary thyroid cancer at right cervical level Vl, according to the level system defined by the American Head and Neck Society. (a) Axial US image shows a recurrent tumor (black arrows) at the medial aspect of the right common carotid artery (white arrows). (b) Contrast-enhanced CT image shows a recurrent tumor (black arrow) located at the center among the right common carotid artery (white arrow), right extraforaminal vertebral artery (dashed arrow), and superior cornu of the right thyroid cartilage (arrowhead). (c) One year after RFA, contrast-enhanced CT image shows complete disappearance of the recurrent tumor (arrow) in the same area.

imaging helped to show a remaining ablation zone (n = 2). The biochemical remission status was defined as sTg levels of less than 1 ng/mL.

Statistical Analysis Continuous outcomes were analyzed by using Wilcoxon rank-sum tests or paired t tests, and categorical variables were analyzed by using a x2 test or Fisher exact test, as appropriate. Recurrence-free survival curves were generated according to the Kaplan-Meier method and were compared by using the log-rank test and Cox proportional hazards model. Continuous data were presented as the mean 6 standard deviation, and categorical data were summarized as percentages. To minimize the effect of potential confounders on selection bias, we conducted weighted analysis by using inverse probability of treatment weights (IPTW) and crude analysis. The IPTWs were estimated with the propensity scores for undergoing reoperation by using a logit model. The model included the following: sex; age at the time of RFA or repeat surgery; radioactive iodine treatment before RFA or repeat surgery; number of previous operations; interval from first operation; number, size, and location of the recurrent tumor; and serum Tg. We 4

trimmed the sample by removing nine patients (RFA, three patients; repeat surgery, six patients) whose serum Tg could not be assessed because of the presence of Tg-Ab from the 73 patients. Thus, adjusted comparisons by IPTW were based on data from 64 patients (RFA, 24 patients; repeat surgery, 40 patients). After adjustment, recurrence-free survival rates and complication rates were recalculated and compared for the two groups. A post hoc power analysis was performed for the results of IPTW-adjusted recurrencefree survival and complication rates. Statistical analyses were performed by using statistical software (SAS software, version 9.3; SAS Institute, Cary, NC). Statistical tests were two sided, and P values less than .05 were considered to indicate statistical significance.

Results Clinical Characteristics of Participants The baseline clinical characteristics before IPTW are summarized in Table 1. There were no significant differences between the two groups, except in interval from first operation at the time of RFA (89.00 months 6 63.61) or repeat surgery (62.83 months 6 63.42; P = .014). As for central compartment location

of the tumors that were treated, there was no significant difference between RFA (14 of 36 [38.9%]) and reoperation groups (30 of 84 [35.7%]; P = .741). In the reoperation group, the number of patients who received adjuvant highdose radioactive iodine treatment after RFA (one of 26 [3.7%]) was greater than that after repeat surgery (13 of 46 [28.3%]; P = .012) and the number of surgically proven tumors (1.83 tumors 6 0.80) was greater than the number of lesions with high probability of preoperative tumors at US imaging (1.57 tumors 6 0.69; P = .027).

Treatment Response after RFA All of the 36 ablation zones exhibited a volume reduction greater than 70% (mean, 98.4% 6 6.2; median, 100%; range, 77%–100%) after RFA (from 191.8 mm3 6 273.3 to 8.6 mm3 6 45.5; P , .001) at the last follow-up. At follow-up US imaging, 17 ablation zones (47.2%) disappeared at 6 months, 11 ablation zones (total, 77.8% [28 of 36]) disappeared at 1 year, and an additional three ablation zones (total, 86.1% [31 of 36]) disappeared at the last follow-up. Their disappearance was also confirmed at CT examinations performed 1–3 years after RFA (Fig 1). Among the other five ablation zones that did not disappear completely, two were confirmed to contain



Table 1 Baseline Patient Characteristics before IPTW Parameter

RFA (n = 27)

No. of men 7 (25.9) No. of women 20 Mean age at the time of the first operation (y) 42.37 6 10.26 No. of patients with thyroid lobectomy 2 (7.4) No. of patients with thyroidectomy 1 (3.7) Total no. of patients with thyroidectomy 24 (88.9) No. of patients with no neck dissection 3 (14.3) No. of patients with central neck dissection 4 (19.0) No. of patients with radical neck dissection* 14 (66.7) Mean tumor size (cm)† 2.12 6 1.01 Tumor multiplicity (no. of patients with positive tumor 9/23 (39.1) multiplicity/no. of patients with pathologic report) Single 9 (30.1) Multiple 14 (60.9) Extrathyroid extension‡ None 2 (9.5) Minimal 15 (71.4) Gross 4 (19.0) Presence of lymph node metastases‡ None 3 (13.6) Central 5 (22.7) Lateral§ 14 (63.6) RAI treatment before RFA or repeat surgery‡ 23 (85.2) Mean no. of previous operations 1.48 6 0.58 Mean age at repeat surgery (y) 51.56 6 12.49 Mean interval from first operation (m) 89.00 6 63.61 Mean no. of recurrent tumors|| 1.33 6 0.55 Mean size of recurrent tumors (cm)# 0.98 6 0.36 No. of patients with central recurrent tumors 11 (40.7) No. of patients with lateral recurrent tumors 14 (51.9) No. of patients with central and lateral recurrent tumors 2 (7.4) Patients who showed .100 U/mL 3 (11.1) serum Tg-Ab** Mean level of serum Tg (ng/mL)** 1.68 6 3.13 Patients who showed 1 ng/mL serum Tg** 7 (29.2) Mean level of sTg (ng/mL)†† 8.89 6 10.61 Patients who showed 1 ng/mL sTg†† 11 (84.6)

Repeat Surgery (n = 46) P Value 10 (21.7) 36 44.17 6 13.79 1 (2.2) 1 (2.2) 44 (95.6) 6 (13.6) 6 (13.6) 32 (72.7) 1.84 6 1.10 16/41 (39.0)

.683 … .793 .611 … .085 … … .239 .993

16 (39.0) 25 (61.0) 8 (21.6) 23 (62.2) 6 (16.2)

.618 … …

8 (18.2) 9 (20.5) 27 (61.4) 42 (91.3) 1.28 6 0.54 49.61 6 14.23 62.83 6 63.42 1.57 6 0.69 0.93 6 0.38 17 (37.0) 24 (52.2) 5 (10.9) 6 (13.0)

..999 … … .457 .094 .499 .014 .156 .579 .941 … … ..999

4.89 6 15.29 15 (37.5) 44.93 6 114.42 17 (94.4)

..999 .497 .523 .558

Note.—Unless otherwise indicated, data are means 6 standard deviation. Data in parentheses are percentages. Patients with Tg-Ab levels higher than 100 U/mL were excluded from the analysis. RAI = radioactive iodine. * Irrespective of performance of central neck dissection, for these data, patients were regarded as radical neck dissection if radical neck dissection was performed. †

Data were obtained from 22 patients in RFA group and 42 patients in reoperation group.

‡

Data are number of patients.

§ Patient-based analysis. Whether or not there was lymph node metastasis in the central compartment in a patient, it was regarded as lateral if there was lymph node metastasis in the lateral compartment. ||

Defined as tumors proven at fine-needle aspiration or highly suspected at US.

#

Only largest tumor per patient was included in these data.

** These were obtained from all patients at mean 3.7 months before RFA and mean 1.9 months before repeat surgery. †† These data were obtained at mean 12.3 months before RFA in 17 patients and mean 8.8 months before repeat surgery in 28 patients. There were a total of 13 RFA patients and 18 reoperation patients.

no malignant cells and had undetectable Tg at fine-needle aspiration, and one was

too small to be aspirated (99% volume reduction; 0.2-cm calcified residue 3


Kim et al

years after RFA). Therefore, these three ablation zones were regarded as successfully treated. One ablation zone could not be aspirated because of patient refusal (77% volume reduction; 1.1-cm residue 18 months after RFA), and its status was therefore not determined. However, fine-needle aspiration revealed malignant cells in one ablation zone (87% volume reduction; 0.4 cm at 1 year after RFA) in one patient, and an additional RFA was performed on the ablation zone. However, four new tumors were detected 6 months after the second RFA, and therefore surgery was planned for the patient. As a result, RFA was initially successful in 25 (96.2% [95% confidence interval: 81.1%, 99.3%]) of 26 patients (34 of 35 tumors [97.1%] [95% confidence interval: 85.5%, 99.5%]). During the follow-up, recurrent tumors, which were clearly distinguishable from the ablation zones, were detected in two patients 1 year or 3 years after RFA. The two patients underwent one additional RFA session each, and this resulted in successful responses for the 2 months or 3 years of follow-up. In total, a recurrence developed in three (11.5%) of the 26 treated patients at 37.7 months 6 10.8 of follow-up.

Treatment Response after Repeat Surgery Among the 46 patients who underwent repeat surgery, four patients (8.7%) exhibited a new recurrence at 29.3 months 6 10.2 of follow-up. One patient exhibited multiple tumors in a new location after 7 months and remained diseasefree for the 7 months of follow-up after repeated surgery. In the other three patients, one or two recurred tumors developed at 2, 3, or 11 months after surgery around the previously recurred area. Two patients underwent one or two sessions of RFA, which resulted in successful responses for the 6 months or 2 years of follow-up, and the other patient was followed up for 2 years without any surgical or ablation treatment. Biochemical Response Comparison of the RFA and Reoperation Groups The negative conversion rates of TgAb after treatment in patients who 5


the interval from the first operation at the time of RFA (mean, 83.8 months) or repeat surgery (mean, 76.3 months; P = .655), there were no significant differences (Table 3). The 1- and 3-year recurrence-free survival rates were also comparable (P = .681) in the RFA group (96.0% and 92.6%, respectively) and reoperation group (92.2% and 92.2%, respectively) for patients with localized small recurrent thyroid cancers (Fig 2, B). The IPTW-adjusted hazard ratio of recurrence in RFA over reoperation group was 0.69 (95% confidence interval: 0.113, 4.152). A post hoc power analysis resulted in a power of 0.107 to detect a hazard ratio of 0.5.

Table 2 Serum Tg Level Changes after RFA or Repeat Surgery for Recurrent Cancers Parameter Patients with posttreatment serum Tg-Ab level .100 U/mL (%)* Posttreatment serum Tg level*† Mean posttreatment serum Tg level (ng/mL) Mean no. of patients with 1 ng/mL Patients with serum Tg level 1 ng/mLn (%) Mean decreases in serum Tg level (ng/mL)‡ Biochemical remission rate in patients with pretreatment serum Tg level 1 ng/mL (%)‡ Posttreatment sTg level†§ Mean posttreatment sTg level (ng/mL) Mean posttreatment sTg level in patients whose pretreatment sTg level was 1 ng/mL Patients with sTg level 1 ng/mL (%) Mean decreases in sTg level (ng/mL )‡ Biochemical remission rate in patients with pretreatment sTg level 1 ng/mL (%)‡

RFA Group 7.4 (2)

Reoperation Group 8.7 (4)

P Value ..999

0.90 6 1.44 2.24 6 1.80 24 (6/25) 2.67 6 4.09 28.6 (2/7)

1.24 6 4.42 3.22 6 7.00 7.3 (3/41) 10.14 6 19.15 78.6 (11/14)

.040 .032 .072 .205 .056

7.29 6 9.94 7.70 6 10.62

46.11 6 109.20 48.79 6 111.95

.630 .654

69.2 (9/13) 5.49 6 8.70 27.3 (3/11)

55.6 (10/18) 15.45 6 119.01 41.2 (7/17)

.484 .655 .689

Note.—Data are means 6 standard deviation. Data in parentheses are numerators and denominators. * These were obtained from all patients at mean 35.4 months after RFA and 30.8 months after repeat surgery. †

Patients with Tg-Ab level higher than 100 U/mL were excluded from the analysis.

‡

Patients whose pretreatment serum Tg or sTg level was 1 ng/mL or greater were included for analysis.

§

These posttreatment sTg levels were obtained at mean 7 months after RFA in 17 patients and at mean 7.8 months after repeat surgery in 26 patients; among these cases, 13 in the RFA group and 18 in the reoperation group had records of both pre- and posttreatment sTg levels.

exhibited positive pretreatment Tg-Ab levels were same in RFA group (one of three patients [33.3%]) and reoperation group (two of six patients [33.3%]; P . .999) (Tables 1, 2). The mean serum Tg or sTg values decreased after treatment in both groups (Tables 1, 2); however, statistical significance was not obtained (for Tg in the RFA group and in the reoperation group, .143 and .062, respectively; P values for sTg in the RFA group and in the reoperation group, .141 and .599, respectively). Posttreatment serum Tg levels in all patients and in patients whose pretreatment Tg levels were 1 ng/mL or greater were higher in the reoperation group than in the RFA group (Table 2). However, the negative conversion rate of serum Tg or sTg was higher in the reoperation group (for serum Tg, 78.6% vs 28.6%, respectively; for sTg, 41.2% vs 27.3%, respectively), although the difference was not statistically significant (P = .056 and 0.689, respectively). 6

Kim et al

Comparison of Recurrence in the RFA and Reoperation Groups before and after Inverse Probability of Treatment Weights Over the 32.4 months 6 11.1 of posttreatment follow-up, further recurrence occurred in three of 26 patients in the RFA group and four of 46 patients in the reoperation group. Although statistical significance was not obtained (P = .057), the time lag for recurrence was longer in the RFA group (12, 12, and 36 months for the three patients in the RFA group; mean, 20 months 6 13.9) than in the reoperation group (2, 3, 7, and 11 months for the four patients in the reoperation group; mean, 5.8 months 6 4.1). The overall recurrencefree survival rate did not differ between the groups (P = .934); the 1- and 3-year recurrence-free survival rates were 92.6% and 87.9%, respectively, for the RFA group and 91.4% and 91.4%, respectively, for the reoperation group (Fig 2, A). After IPTW, in all of the baseline characteristics, which included

Comparison of Complication in the RFA and Reoperation Groups before and after Inverse Probability of Treatment Weights Regarding complications, only one patient (3.7%) developed transient hoarseness in the RFA group. In contrast, there were three patients who developed transient hoarseness (6.5%), two patients who developed transient hypocalcemia (4.4%), and four patients who developed persistent hypocalcemia (8.7%; total complications, 19.6% of patients) in the reoperation group. However, rates were not significantly different between the RFA and reoperation groups for the total complication rate (3.7% vs 19.6%; P = .080) and hoarseness and hypocalcemia (Table 4). After IPTW, there was also no significant difference in posttreatment hoarseness (7.3% [1.8 of 24.0] vs 9.0% [3.6 of 39.5]; P = .812), hypocalcemia (0.0% [0 of 24.0] vs 11.6% [4.6 of 39.5]; P = .083), and the total complication rate (7.3% [1.8 of 24.0] vs 20.6% [8.1 of 39.5]; P = .156) between the RFA and reoperation groups (Table 4). A post hoc power analysis resulted in a power of 0.21 for the difference of complication between RFA and repeat surgery. Discussion In our study, we demonstrated that RFA might be an effective and safe treatment for locally recurrent thyroid cancers that were less than 2 cm. These results suggest that RFA may



Kim et al

Figure 2

Figure 2: Graphs show recurrence-free survival curves for patients treated with RFA and repeat surgery, A, before and, B, after adjustment with IPTW.

be considered an alternative treatment for local recurrent thyroid cancer, especially when the tumors are small. Our study demonstrated a high complete disappearance rate of 86.1% (31 of 36 ablation zones) and a low recurrence rate of 11.5% (three of 26 treated patients) after approximately 3 years of follow-up. Compared with a previous study that reported a complete disappearance rate of 50% (six of 12 ablation zones) (20), our study demonstrated better outcomes, possibly because of the limited number and size of the tumors in our study. This difference suggests that a higher success rate might be expected if RFA is used in smaller tumors. The American Thyroid Association guidelines recommended evaluation of lesions that are possibly recurrent only when they are larger than 0.8 cm because of the technical difficulty of fine-needle aspiration or surgery and caution about the recurrence of coexistent occult tumors after repeat surgery (7,11,24). Along with a general understanding of the indolent nature of thyroid cancer, these factors permit the so-called watch-andwait policy for small recurrent tumors, especially in patients who have already undergone repeated surgeries, because surgical difficulty increases with the number of operations (11). In addition, the risk of general anesthesia,

which is commonly performed in repeat surgery for recurrent thyroid cancer, increases with age (25); therefore, some physicians and patients may delay reoperation (12,21). However, there remains concern that untreated tumors could suddenly become aggressive tumors (26). RFA may be a good alternative to surgery because it can be performed in outpatient clinics without general anesthesia. In the event that recurrence develops repeatedly, RFA may be applied relatively easily and effectively in most cases; we applied RFA successfully in four cases of recurrence after RFA or repeat surgery. However, concern remains about concomitant recurrent tumors that are not found with imaging modalities and are only detected in pathologic specimens after surgical dissection. In our study, although clinical significance was unknown, the number of tumors in the surgical specimens was significantly greater than that expected preoperatively, which might be related to the more complete removal of the tumors or the wider extent of dissection, including the adjacent compartment for some patients in repeat surgery, compared with RFA. In addition, although not significantly so, the biochemical remission rates of serum Tg and sTg in the reoperation group were higher than those in


the RFA group (Table 2). Therefore, if performed successfully, repeat surgery was undoubtedly a more definitively curative treatment than RFA. Although there was no significant difference in recurrence between the two groups, there might be a trend toward a difference in the severity of the diseases between the groups in our study; the percentage of posttreatment radioactive iodine and the pretreatment Tg or sTg levels were higher in the reoperation group. Therefore, we cannot easily conclude that the biochemical status of the RFA group was comparable to that of the reoperation group in our study and that RFA could completely replace repeat surgery based on the results of our study. However, in the cases of surgical ineligibility, such as patient refusal for surgery because of concern of high reoperation morbidity or poor medical condition for surgery, RFA may have an important role to replace selective surgical excision. Another important factor in treatment choice is the development of potential complications. In general, the more aggressive surgery is more likely to cause complications (6,27,28). The reported rate of permanent recurrent laryngeal nerve paralysis after repeat surgery ranges from 0% to 12%, and that of permanent hypocalcemia ranges from 0% to 7% (9,29), which 7


Table 3 Baseline Patient Characteristics after IPTW Parameter Men (%) Women (%) Mean age at time of initial operation (y)* Type of initial operation (%) Thyroid lobectomy Subtotal thyroidectomy Total thyroidectomy None Central neck dissection Radical neck dissection† Mean tumor size (cm)* Tumor multiplicity (%) Tumor invasion (%) None Microscopic Gross Lymph node metastasis (%) None Central Lateral‡ Patients treated with RAI before procedure (%) Mean no. of previous operations per patient* Mean patient age (y)* Mean interval from first operation (m)* Recurrent tumors§ Mean no. of tumors* Mean size of tumors (cm)*|| Central location (%) Lateral location (%) Central and lateral locations (%) Patients who received .100 U/mL serum Tg-Ab (%) Mean level of serum Tg (ng/mL)*# Patients who received 1 ng/mL serum Tg (%)# Mean level of sTg (ng/mL)*# Patients who received 1 ng/mL sTg (%)#

RFA Group

Reoperation Group

P Value

24.7 75.3 43.3 6 2.7

25.1 75.0 44.2 6 2.1

.977 … .800

4.2 2.4 93.4 11.9 11.6 76.4 1.96 6 0.23 33.9

3.1 1.9 95.0 13.0 14.4 72.6 1.86 6 0.17 34.5

.964 … … .948 … … .737 .960

7.8 66.7 25.5

20.3 66.8 12.9

.333 … …

11.6 14.2 74.3 86.9 1.37 6 0.11 52.3 6 2.87 83.8 6 13.2

18.9 23.6 57.6 86.4 1.35 6 0.09 50.7 6 2.23 76.3 6 10.3

.455 … … .952 .877 .674 .655

1.49 6 0.13 0.95 6 0.08 38.8 50.0 11.2 0 3.1 6 2.1 45.5 9.4 6 20.5 82.6

1.48 6 0.10 0.91 6 0.06 39.0 51.2 9.7 0 3.7 6 1.7 35.2 38.3 6 15.8 93.0

.952 .704 .982 … … ..999 .314 .415 .272 .562

Note.—RAI = radioactive iodine. * Data are means 6 standard error unless otherwise indicated. Means were calculated by using least squares analysis. †

Irrespective of performance of central neck dissection; regarded as radical neck dissection if radical neck dissection was performed.

‡

Patient-based analysis. Whether or not there was lymph node metastasis in the central compartment in a patient, it was regarded as lateral if there was lymph node metastasis in the lateral compartment.

§

Defined tumor proven at fine-needle aspiration or US imaging shows possible tumor.

||

This information is related to largest tumor per patient.

#

Patients with Tg-Ab levels higher than 100 U/mL were excluded from the analysis.

is comparable with our results. RFA seems to present fewer complications. In our study, there was only one reported complication after RFA, transient vocal cord paralysis, and this result was concordant with the results reported by 8

Monchik et al (one of 16 cases [6.3%]) (19) and Baek et al (one of 10 cases [10.0%]) (20). Hypocalcemia did not develop in our RFA group, and, to our knowledge, it was not reported in other RFA studies (19–21). This lower

Kim et al

incidence of complications with RFA might have been related to the ability of high-resolution US imaging to target the tumor exactly and to manipulate techniques during the procedure to avoid the unnecessary ablation of normal structures. Therefore, for the management of recurrent thyroid cancers, RFA may be a safe alternative to repeat surgery. Regarding less invasive treatment, percutaneous ethanol injection may have advantages, which include reduced cost and pain. However, given the results of the hepatocellular carcinoma comparison reports (30,31), RFA may have advantages in volume reduction and requires fewer treatment sessions than percutaneous ethanol injection to control recurrent thyroid cancers (20,32,33). More studies are needed to compare the efficacy of these two modalities for recurrent thyroid cancer. Despite the efficacy of RFA for recurrent thyroid cancers, some limitations for this application exist. RFA cannot eradicate occult recurrent tumors that are not visible on US images, and it is difficult to ablate tumors located in areas that are inaccessible to US imaging, such as retropharyngeal and superior mediastinal areas. Additionally, many RFA sessions may be required for large or numerous tumors. Therefore, the decision to perform RFA instead of repeat surgery to control recurrent tumors should be made carefully. Our study had some limitations. It lacked adequate power to show clinically meaningful differences because of the small number of patients enrolled. It was nonrandomized and retrospective, and only one doctor performed RFA. These issues may have caused selection bias, which could have affected the results of the study. It is also possible that the patients who underwent repeat surgery had more aggressive tumors than those in the RFA group, which might have resulted in more favorable outcomes. Regardless, RFA seemed to be quite effective and safe. Therefore, to generalize the outcomes of RFA, a prospective, randomized study with a larger patient number and longer follow-up is warranted.



Table 4 Posttreatment Complications after RFA and Repeat Surgery for Recurrent Tumors Before IPTW Parameter Total complications Hoarseness* Hypocalcemia Transient Persistent

RFA Group (n = 27)

Reoperation Group (n = 46)

1 (3.7) 1 (3.7)

9 (19.6) 3 (6.5)

0 (0) 0 (0)

2 (4.4) 4 (8.7)

After IPTW P Value .080 ..999 .079† … …

RFA Group (n = 24)

Reoperation Group (n = 40)

1.8 (7.3) 1.8 (7.3)

8.1 (20.6) 3.6 (9.0)

0 (0.0) 0 (0)

0.6 (1.6) 3.9 (10.0)

P Value .156 .812 .083† … …

Note.—Data in parentheses are percentages. * In all patients, hoarseness was only transient. No persistent hoarseness occurred. †

P value was obtained from Fisher exact test on posttreatment transient or persistent hypocalcemia development rates between the two groups.

In conclusion, based on the comparable recurrence-free survival and complication rates between RFA and reoperation groups, RFA may be performed as an effective and safe alternative to repeat surgery in patients with localized small recurrent thyroid cancers. Disclosures of Conflicts of Interest: J.H.K. disclosed no relevant relationships. W.S.Y. disclosed no relevant relationships. Y.J.P. disclosed no relevant relationships. D.J.P. disclosed no relevant relationships. T.J.Y. disclosed no relevant relationships. S.H.C. disclosed no relevant relationships. C.H.S. disclosed no relevant relationships. K.E.L. disclosed no relevant relationships. M.W.S. disclosed no relevant relationships. Y.K.Y. disclosed no relevant relationships. K.H.K. disclosed no relevant relationships. B.Y.C. disclosed no relevant relationships.

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