ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Prospective study of effectiveness of ultrasoundguided radiofrequency ablation versus control group in patients affected by benign thyroid nodules Roberto Cesareo, MD*-, Valerio Pasqualini, MD**-, Carla Simeoni***, M. Sacchi, MD§ - , E. Saralli, MD§ - , G. Campagna, MD§§ - , Roberto Cianni, MD ** *Thyroid Diseases Center, “S.M.Goretti” Hospital, Latina, Italy; ** Department of Radiology, “S.M.Goretti” Hospital, Latina, Italy; ***Workers Compensation Autority (INAIL) – Research Area of Monteporzio Catone, Via di Fontana Candida, 1 - 00040 Monte Porzio Catone, Rome, Italy; § Departemnt of Internal Medecine, “S.M.Goretti” Hospital, Latina, Italy; §§ Department of Surgery, “S.M.Goretti” Hospital, Via G. Reni, 04100 - Latina, Italy.
Context: Ultrasound (US)-guided radiofrequency ablation (RFA) of solid thyroid nodules (TNs) is a minimally invasive procedure that may induce a volume reduction of symptomatic solid benign thyroid nodules (TNs). Objective: The aim of the study was to evaluate the effectiveness and safety of RFA in debulking benign TNs. Design and Patients: Eighty-four consecutive patients with symptomatic and cytologically benign solid nodules were randomly assigned to either a single RFA session (Group A; n ⫽ 42) or follow up (Group B; n ⫽ 42) at our centre. Entry criteria were: solid thyroid nodule or predominantly solid (with a fluid component ⱕ30% of the volume), normal thyroid function, no autoimmunity, no previous thyroid gland treatment. Three subgroups were formed according to baseline volume of nodules: small (ⱕ 12 mL), medium (from 12 to 30mL), or large (⬎30mL). Methods: Group A: RFA was performed in a single session with the moving-shot technique. Volume and local symptom changes were evaluated 1 and 6 months after RFA. Results: Group A: Volume decreased from 24.5.5 ⫾ 19.6 to 8.6 ⫾ 9.5 six months after RFA (p ⫽ 0.001). The greatest volume reduction was in small nodules. Pressure symptom score improved only in medium and large nodules (p⬍0.001), whereas cosmetic score improved in all treated patients (p⬍0.001). The rate of thyroid volumetric reduction (TVR) was not statistically different between solid and predominantly solid nodules. Only one patient experienced permanent right paramedian vocal cord palsy with inspiratory stridor without dysphonia. In Group B, nodule volume remained unchanged while symptom score was worse at six-month evaluation (p⫽0.01). Conclusions: RFA is effective in reducing thyroid nodule volume. The best reduction rate was observed in small TNs. TVR does not change according to sonographic features. The mean treatment duration was longer in larger TNs.
odular thyroid disease is a common clinical problem whose prevalence increases with age and with a more widespread use of thyroid ultrasonography (US) (1– 4). While most thyroid nodules are benign and need only
N
periodic monitoring, some may require treatment for associated pressure and/or cosmetic symptoms. Although thyroid surgery is the main therapeutic approach for compressive thyroid nodules, it may be associated with several
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received April 28, 2014. Accepted November 5, 2014.
Abbreviations:
doi: 10.1210/jc.2014-2186
J Clin Endocrinol Metab
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drawbacks (5). Long-term levothyroxine suppression treatment in elderly patients with large nodular goiters is unsatisfactory as it is ineffective. Further, it is associated with adverse effects on bones and the cardiovascular system (3– 4). In addition, radioiodine therapy may be ineffective in large nonhyperfunctioning nodules (6). Nonsurgical, minimally invasive treatment modalities such as percutaneous ethanol injection (PEI) (7–9), percutaneous laser ablation (LA) (10 –15), and radiofrequency ablation (RFA) (16 –22) have been used to treat thyroid nodules. PEI is known to be very successful in treating cystic nodules, but is less effective for solid nodules (23–25). LA, investigated primarily for the treatment of solid nodules (26), is successful in reducing the volume of treated thyroid nodules by 40% to 80% (24 –27)and clinical outcomes in patients followed for more than 5 years indicate that LA results in a satisfactory midto longterm clinical response in most patients (15). RFA of thyroid nodules, introduced in 2006 (16), has been reported to be both a safe and effective treatment for benign thyroid nodules (24 –25, 28). The aims of this prospective study comparing a group treated with a single RF session (Group A) with a nontreated group (Group B) were to evaluate: a) the effectiveness and safety of RFA technique on debulking benign TNs; b) the relationship between RF treatment and baseline nodule volume; c) the relationship between baseline sonographic characteristics of thyroid nodular disease and radiofrequency treatment.
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(ⱕ 12 mL), medium (12 to 30 mL), or large (over 30 mL). One single nodule per patient was treated with RFA. In patients with multiple thyroid nodules, the largest and/or most symptomatic one was treated. All patients were clinically, biochemically, and morphologically evaluated at 1 and 6 months after treatment in both groups A and B. Age, gender, thyroid nodule volume, function, and ultrasound characteristics did not differ significantly between groups at baseline. We classified thyroid nodules according to sonographic features as solid or predominantly solid (with a fluid component ⱕ 30% of its volume). The study was not registered on Clinicaltrials.gov. The protocol for this study was approved by the Hospital Ethics Committee and all patients provided written informed consent.
Clinical evaluation We classified symptom and cosmetic scores as described in a previous consensus statement (29). All patients were asked to rate pressure symptoms on a 10-cm visual analog scale (grade 0 –10 cm) at enrollment and during follow up. A cosmetic score was obtained according to the following scale: 1, no palpable mass; 2, no cosmetic problem but palpable mass; 3, a cosmetic problem on swallowing only; 4, easily visible mass.
Biochemical evaluation The laboratory studies included chemiluminescent enzyme immunoassay (EIA) (Architect i4000 SR, Abbott) for serum thyrotropin (normal range, 0.5– 4.9 mIU/L), serum free triiodothyronine (normal range, 1.7–3.7 pg/ml), serum-free thyroxine (normal range, 0.7–1.7 pg/ml), and serum antithyroid peroxidase antibodies (normal range, 0 –35 IU/ mL); immunoradiometric assay (IRMA) (Architect i4000 SR, Abbott) for serum calcitonin (normal range, 0 –10 pg/mL); blood coagulation tests (prothrombin time, activated partial thromboplastin time (PTT)).
Procedure
Patients and Methods From March 2011 to September 2013, a total of 84 patients were consecutively enrolled at “S.M.Goretti” hospital in Latina, Italy in a prospetctive randomized controlled (RCT) trial. Eighty-four patients (51 women, 33 men; mean age 54.4 ⫾ 13.3 years) were randomized as follows: 42 patients were treated with a single RFA session (Group A), and 42 patients did not receive any treatment and were only followed up (Group B). A computerbased number generator was used to randomly assign each patient to one of the two groups. Inclusion criteria were: age above 18 yrs, thyroid nodules with cosmetic or compressive symptoms or nodules over 5 ml, or with maximum diameter ⬎ 2 cm steadily grooving over time, benign thyroid solid nodule (solid portion over 70%) at repeat (at least two) ultrasound-guided fine needle aspiration findings cytologic examinations (Thy2), cold nodule at 99mTc-pertechnetate scintigraphy, serum thyroid hormone thyrotropin and calcitonin levels within normal limits, no history of radioiodine therapy or thermal ablation, no previous neck or trunk external beam radiotherapy, or refusal of or ineligibility for surgery. Exclusion criteria were pregnancy, malignant or suspicious thyroid nodules, or nodules that were confluent in a compressive lobar mass. We classified nodules according to baseline volume as small
US was performed using a 7.5–12 MHz linear probe equipped with CD and PD modules (Technos MPX; Esaote My Lab 50, Italy). Nodule volume and percentage of volume reduction (PVR) were calculated with the following equations: volume percentage (ellipsoid equation): V ⫽ length x width x depth x 0.525; volume reduction percentage: PVR ⫽ ([initial volume – final volume] ⫻ 100)/initial volume. A single TN volume was measured in case of uninodular goiter or in case of multinodular goiter when characterized by one predominant nodule associated with other nonclinically significant thyroid nodules. We took photos of all enrolled patients at baseline and at one and six months after RFA. A radiofrequency generator (Cool-tip, E-Series Covidien) and a 17 gauge, 15 cm electrode with a 1 cm active tip was used. All RF procedures were carried out by the same operator under US control with the same scanner used for the initial diagnostic evaluation. The intra- and interobserver coefficients of variation for sonographic volume assessment were previously defined as 4% and 6%, respectively. The patients were treated with 2% Mepivacain 2–5 mL (Carbosen) and 3 mL of Ropivacaine (Naropine, Fresenius Kabi, USA) for local anesthesia at the puncture site. Four mg of prednisone IV before RFA of large thyroid nodule were prescribed to reduce post-treatment edema. Anxiolytic drugs were never needed prior to the procedure and in fact, as suggested by other authors, we never wanted to induce deep sedation (29). On the basis of previous experience,
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doi: 10.1210/jc.2014-2186
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the procedure utilized included the transisthmic approach along the short axis of the nodule, and the nodules were managed with the “moving-shot technique” as described elsewhere by Beak et al (18, 20). We adopted a variant of the aforementioned technique, using 60 W of radiofrequency out-power and exposure time needed to obtain a transient multiple hyperechoic zones as a sign of the effectiveness of ablation maneuver. We also calculated mean treatment time of every single RFA session from initial insertion of RF needle into the thyroid nodule to final assessment of the treatment session.
Statistical analysis Statistical analysis was performed using IBM-SPSS Statistics version 21. Descriptive statistics (median, mean, standard deviation, range) were computed on thyroid volume and other clinical variables. To compare group mean values, appropriate parametric test of statistical significance (t test) was used, where a Shapiro–Wilk test indicated that the data conformed to a lognormal distribution. Otherwise, equivalent non parametric test was employed (Mann–Whitney U-test, Kruskal–Wallis test). Changes in within-subject control or RFA between baseline, 1 month, and 6 month samples were analyzed using the Wilcoxon signed rank test. To test statistical significance of mean percentage of volumetric reduction between classes of nodules was applied nonparametric test Kruskal-Wallis (1-way ANOVA). To compare the degree of variation from one data series to the other has been used the CV (also known as relative standard deviation - RSD) The significance level was defined as P ⱕ .05.
Results Nodule volume Characteristics and clinical data on groups A and B are summarized in Table 1. At enrollment, the clinical data Table 1.
showed no statistical difference between group A and group B. TNs volume decrease in group A (17.5 ⫾ 34.7 at 1 month, 8.6 ⫾ 9.5 at 6 months), whereas it remained unchanged in group B (27.6 ⫾ 22.1 at 1 month, 27.8 ⫾ 22.1 at 6 months). The difference between TNs volume in group A and group B after 1 month and after 6 months was statistically significant (P ⬍ .001). TNs volume in group A decreased from 24.5 ⫾ 19.6 to 12.7 ⫾ 11.8 at 1 month and to 8.6 ⫾ 9.5 at 6 months (Table 2). In group A, the mean percentage decrease of TN volume was 49.7 ⫾ 14.5% at 1 month and 68.5 ⫾ 13.5%. at 6 months. The mean percentage of volumetric reduction after 6 months in treated patients, differs significantly between the three classes of nodules (P ⫽ .027): for small nodules, the mean percentage decrease was 57.5 ⫾ 8.6% at 1 month and 78.2 ⫾ 10.7% at 6 months; for medium nodules it was 47 ⫾ 15% at 1 month and 67 ⫾ 12.2% at 6 months; for large nodules reduction was 47.7 ⫾ 16.3% at 1 month and 62.8 ⫾ 14.8% at 6 months. It should be noted that the variability of the percentage decrease for the large nodules was greater than in the other groups. In fact, coefficient of variation (CV) of the large group was greater than the CV of the other two groups, both at the first and the sixth month (at 6 months the CV was in small group of 14%, in medium of 18% while in large group of 23%). Treatment duration time increase with increasing initial volume of the nodules (Table 3). No significant difference was detected in volume reduction between solid and predominantly solid thyroid nodules (P ⫽ 0,46 at 1 month and P ⫽ 0,09 at 6 month).
Main characteristics of the study population and clinical data at baseline. Values are reported as mean ⫾
SD
Parameter N Sex (males/ females) Age in years Thyroid nodule volume (mL) TSH (mIU/ mL) FT3 (pg/ mL) FT4 (pg/ mL) Cosmetic score Symptom score
3
Group A
Group B
p
42 15/27
42 18/24
ns
56 ⫾ 14 (24 – 80)
53 ⫾ 12 (30 –76)
ns
24.5 ⫾ 19.6 (3.4 – 89)
27.5 ⫾ 22.1 (3.2–90)
ns
2.1 ⫾ 0.9 (0.6 – 4.1)
2.3 ⫾ 1.1 (0.6 – 4.4)
ns
2.7 ⫾ 0.6 (1.2–3.7)
2.6 ⫾ 0.6 (1.8 –3.6)
ns
1.2 ⫾ 0.3 (0 –1.7)
1.2 ⫾ 0.4 (0 –1.7)
ns
2.6 ⫾ 0.9 (1– 4)
2.6 ⫾ 1 (1– 4)
ns
2.8 ⫾ 3.3 (0 –10)
2.7 ⫾ 3 (0 – 8)
ns
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radiofrequency ablation for thyroid nodules
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Table 2. Thyroid nodule volume (ml) in Radiofrequency ablation Group. Values are reported as mean ⫾ SD Baseline Whole group (n ⫽ 42) TN vol. TN vol. variation (%) Small (n ⫽ 10) TN vol. TN vol. variation (%) Medium (n ⫽ 21) TN vol. TN vol. variation (%) Large (n ⫽ 11) TN vol. TN vol. variation (%)
1 month
6 months
24.5 ⫾ 19.6 17.5 ⫾ 34.7*** 8.6 ⫾ 9.5*** ⫺49.7 ⫾ 14.5 ⫺68.6 ⫾ 13.5
7.4 ⫾ 2.7
3 ⫾ 1.2** ⫺57.5 ⫾ 8.6
1.6 ⫾ 1** ⫺78.2 ⫾ 10.7
18.1 ⫾ 4.4
9.3 ⫾ 3*** ⫺47 ⫾ 15
5.9 ⫾ 2.5*** ⫺67 ⫾ 12.2
52.3 ⫾ 17.5 27.8 ⫾ 13.7* ⫺47.7 ⫾ 16.3
20.1 ⫾ 12.1** ⫺62.8 ⫾ 14.8
Differences in mean volumes are considered between value at 1 month and 6 month vs. baseline. *P ⱕ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001.
Table 3. Thyroid treatment time (minutes). Values are reported as mean ⫾ SD (min-max)
Symptom and cosmetic score evaluation Symptom score was not significantly different between group A (2.8 ⫾ 3.3 at baseline, 1.4 ⫾ 1.7 at 1 month, 0.4 ⫾ 0.8 at 6 months) and group B (2.7 ⫾ 3 at baseline, 2.7 ⫾ 3 at 1 month, 2.9 ⫾ 3.2 at 6 months) at baseline or at 1 month. At 6-month evaluation, however, symptom score had progressively improved in group A (P ⬍ .001), while in group B, it remained unchanged at one month and was worse at six-month evaluation (P ⫽ .01). From the whole group of the examined population 39 patients had pressure symptoms. In the treated group 19 patients suffered from pressure symptoms before RF session and 10 after RF session at 6-month follow up. Pressure symptom score significantly improved in the medium and large subgroups whereas no improvement was observed in the small subgroup. (Figure 1). The cosmetic score improved in all group A patients at one- and six-month follow-up evaluation (2.6 ⫾ 0.9 at baseline, 2 ⫾ 0.6 at 1 month, 1.7 ⫾ 0.7 at 6 months; (P ⬍ .001). We did not find any significant difference during the observation follow-up in group B (cosmetic score remained 2.6 ⫾ 1.0 at baseline, 1 month and 6 months). Cosmetic score significantly improved in all subgroups (Figure 2). Complications and Safety RFA was safe and well tolerated in all patients, who were placed under observation for about 4 hours after the procedure. No major complications were observed, and no patient needed hospitalization after treatment. During the RFA procedure, 8 (21.4%) of the 42 patients experienced local pain, occasionally radiating to the ear or jaw or chest, but it was limited and resolved quickly after the power was switched off. In one patient, however, the pro-
Time Whole group Small Medium Large
37 ⫾ 17.4 (17– 85) 20.7 ⫾ 2.8 (17–25) 31.9 ⫾ 6.7 (24 – 45) 61.6 ⫾ 12.5 (48 – 85)
Hormonal evaluation After treatment, hormonal parameters did not change at any time during follow up. All patients were euthyroid at baseline and had normal serum thyroid function tests after 1 and 6 months. No significant changes were observed either in TgAb and TPOAb titers or in calcitonin serum concentrations during the follow-up period except for one patient with a large nodule who developed autoimmune thyroid diseases with hyperthyroidism six months after RF ablation. In group B, no hormonal changes were observed compared with initial values.
Figure 1. Pressure symptoms score in all subgroups at 1 month and at 6 months vs baseline. . ns ⫽ not significant; * P ⱕ .05; **P ⬍ .01
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doi: 10.1210/jc.2014-2186
cedure was stopped due to severe chest pain. The most feared complication was voice change after RFA. Only 2 patients (4.7%) had voice change immediately after the RFA session but it resolved completely 2 or 3 hours after the procedure. One patient experienced permanent right paramedian vocal cord palsy with inspiratory stridor without dysphonia. None developed perinodular hematoma or local infection.
Discussion This study, which compares thermo-ablative radiofrequency treatment of thyroid nodules with an untreated control group, proves that this treatment results in significant volume reduction, with significant improvement in cosmetic and pressure symptoms. All patients underwent a single treatment session. The study shows that there is a direct correlation between the initial volume of nodules and volumetric reduction percentage six months after percutaneous treatment, ie, the smaller the initial volume of the nodule, the greater its volumetric reduction. Further, the study does not demonstrate any significant correlation between initial baseline sonographic characteristics of the thyroid nodule and the degree of volume reduction (P ⬎ .2). In other words, while the initial volume affects the extent of volumetric reduction, the initial ultrasonographic characteristics do not play any role. Hence, our classification, while arbitrary, helped us to better understand the role played by initial volume in determining the magnitude of shrinkage over time. In addition, a careful analysis of our data showed that the CV of the large subgroup was greater than that of the other two
Figure 2. Cosmetics score in all groups at 1 month and at 6 months vs baseline. *P ⱕ .05; **P ⬍ .01; ***P ⬍ .001.
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subgroups, both at one and at six months. In light of this marked variability in the degree of volume reduction, we thus believe that it is not possible to predict the magnitude of shrinkage over time of larger nodules with initial volume over 30 mL. In fact, we observed a significant reduction of volume in some nodules and a minimal or very poor response in others. We do not know exactly what might explain these conflicting data within this subgroup. We only know that treatment of these nodules takes longer than it does in the other two subgroups (Table 3). Because the baseline structural sonographic characteristics of nodules have no role in determining the magnitude of the shrinkage, we believe that in these cases longer treatment times or planning a second or third treatment would be necessary, as other authors using the same moving- shot technique do (18, 22, 30 –31). Thanks to the nodule classification system we adopted, this study highlights that pressure symptom score significantly improves only in the medium and large subgroups, whereas there is no improvement in the small subgroup (Figure 1). It stands to reason that the small nodules with a volume ⱕ 12 mL will usually cause only cosmetic signs, not significant pressure symptoms, if they are located in the isthmus or at least in the superficial site, where they cause a deformation of the margins of the thyroid gland. In our experience, this is the reason why we observe an improvement of pressure symptoms only in subgroups with larger nodule volumes (Figures 1). These particular data have not been reported by many of the authors who have treated nodules with volumes below or comparable to small nodules of our classification with either movingshot technique (16, 18, 20, 22, 31) or with fixed-needle technique by multitined electrode (17, 19, 21). Because of the differences in study designs and patient populations, any direct comparison of our results with those of other trials should be performed with caution. Nevertheless, if we exclude the data reported by the authors who have used the fixed-needle technique by multitined electrode and we analyze the data reported by the controlled study conducted by the researchers who have used moving shot technique (20), we see that the volumetric reduction obtained by the latter appears to be 80% and thus very high. A more careful study, however, reveals that these authors treated nodules with very small volumes of approximately 7 mL and thus their results are comparable to those we obtained in the nodules classified as small. Further, these nodules not only had a small volume but also had a cystic component of approximately 40% (20). More in general, it should be stressed that the nodules treated by most authors who use moving-shot technique in uncontrolled studies have volumetric values ranging from 6 to 13 mL and a fluid component varying from 40% to
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radiofrequency ablation for thyroid nodules
80% (16, 18, 20, 22, 31). Last but not least, it is important to note that these types of nodules, above all the larger ones, underwent repeated RF treatment sessions in these studies, even up to seven times in some cases (18, 22). In fact also in our study in large nodule subgroup a 60% volume reduction could be satisfactory but we cannot exclude that a second treatment may be necessary considering the large size of these nodules at baseline. Furthermore, in this subgroup of nodules the coefficient of variation is higher, which means that compared to a large volume reduction in one nodule, there is another which decreases much less. As for a possible comparison between the laser technique and RF, no head-to-head studies have yet been conducted; it is thus impossible to compare the results of laser with those of radiofrequency techniques. The series of patients treated with these procedures are not comparable, in terms of baseline volumes or in terms of fluid content of the lesions undergoing laser ablation. In particular, laser ablation has been performed on solid or nearly completely solid thyroid nodules (10 –15, 26 –27, 32–34), while the series of nodules undergoing radiofrequency have had a highly variable solid component, as previously stated (16 – 18, 20 –21, 35–36). To date there are no guidelines or any consensus statement providing a clear classification of thyroid nodules with respect to both their volume and their fluid component. A future discussion to establish inclusion criteria shared by all operators would be useful. Which nodules should be treated? When is a nodule small? When is it large? In addition, can repeated RF treatment sessions cause fibrosis, such as occurs with PEI, with technical problems arising during a possible subsequent thyroidectomy (8)? How can we avoid making multiple RFA maneuvers? If performed by a team of experts, this procedure does not present serious side effects, although it is not devoid of risks. In our study we observed transitory dysphonia in two patients (4.7%) and one case (2.3%) of right paramedian vocal cord palsy with inspiratory stridor but without dysphonia. The limit of our study was the relatively short-term follow-up period, despite the fact that clinical evidence shows that greater volume reduction is achieved at about six months (28). In conclusion, we believe that RF ablation is effective in patients suffering from thyroid nodules. Further studies and longer follow-up periods are of course needed to confirm the safety and effectiveness of RFA mainly for larger nodules.
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Acknowledgments Address all correspondence and requests for reprints to: Corr: Roberto cesareo M.D. [email protected] Thyroid Diseases Center, “S.M.Goretti” Hospital, Latina, Italy - INTERNAL MEDICINE G. RENI 1 Latina Lazio, ITALY 04 100, 0773601439. Disclosure Summary: The authors have nothing to disclose This work was supported by .
References 1. Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am. 2007;36: 707–735, vi 2. Hegedus L. Thyroid ultrasonography as a screening tool for thyroid disease. Thyroid. 2004;14:879 – 880. 3. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–1214. 4. Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedus L, Vitti P. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010;33:51–56. 5. Bergenfelz A, Jansson S, Kristoffersson A, Martensson H, Reihner E, Wallin G, Lausen I. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008;393:667– 673. 6. Fast S, Nielsen VE, Bonnema SJ, Hegedus L. Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy. Eur J Endocrinol. 2009;160:517–528. 7. Bennedbaek FN, Nielsen LK, Hegedus L. Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: a randomized trial. J Clin Endocrinol Metab. 1998;83:830 – 835. 8. Bennedbaek FN, Karstrup S, Hegedus L. Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol. 1997;136:240 –250. 9. Hegedus L. Therapy: a new nonsurgical therapy option for benign thyroid nodules? Nat Rev Endocrinol. 2009;5:476 – 478. 10. Pacella CM, Bizzarri G, Spiezia S, Bianchini A, Guglielmi R, Crescenzi A, Pacella S, Toscano V, Papini E. Thyroid tissue: USguided percutaneous laser thermal ablation. Radiology. 2004;232: 272–280. 11. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasoundguided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules - a randomised study. Eur J Endocrinol. 2005; 152:341–345. 12. Papini E, Guglielmi R, Bizzarri G, Graziano F, Bianchini A, Brufani C, Pacella S, Valle D, Pacella CM. Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid. 2007;17:229 – 235. 13. Gambelunghe G, Fatone C, Ranchelli A, Fanelli C, Lucidi P, Cavaliere A, Avenia N, d’Ajello M, Santeusanio F, De Feo P. A randomized controlled trial to evaluate the efficacy of ultrasound-guided laser photocoagulation for treatment of benign thyroid nodules. J Endocrinol Invest. 2006;29:RC23–26. 14. Valcavi R, Riganti F, Bertani A, Formisano D, Pacella CM. Percu-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 November 2014. at 14:49 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2186
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
taneous laser ablation of cold benign thyroid nodules: a 3-year follow-up study in 122 patients. Thyroid. 2010;20:1253–1261. Dossing H, Bennedbaek FN, Hegedus L. Long-term outcome following interstitial laser photocoagulation of benign cold thyroid nodules. Eur J Endocrinol. 2011;165:123–128. Kim YS, Rhim H, Tae K, Park DW, Kim ST. Radiofrequency ablation of benign cold thyroid nodules: initial clinical experience. Thyroid. 2006;16:361–367. Deandrea M, Limone P, Basso E, Mormile A, Ragazzoni F, Gamarra E, Spiezia S, Faggiano A, Colao A, Molinari F, Garberoglio R. USguided percutaneous radiofrequency thermal ablation for the treatment of solid benign hyperfunctioning or compressive thyroid nodules. Ultrasound Med Biol. 2008;34:784 –791. Jeong WK, Baek JH, Rhim H, Kim YS, Kwak MS, Jeong HJ, Lee D. Radiofrequency ablation of benign thyroid nodules: safety and imaging follow-up in 236 patients. Eur Radiol. 2008;18:1244 –1250. Spiezia S, Garberoglio R, Milone F, Ramundo V, Caiazzo C, Assanti AP, Deandrea M, Limone PP, Macchia PE, Lombardi G, Colao A, Faggiano A. Thyroid nodules and related symptoms are stably controlled two years after radiofrequency thermal ablation. Thyroid. 2009;19:219 –225. Baek JH, Kim YS, Lee D, Huh JY, Lee JH. Benign predominantly solid thyroid nodules: prospective study of efficacy of sonographically guided radiofrequency ablation versus control condition. AJR Am J Roentgenol. 2010;194:1137–1142. Faggiano A, Ramundo V, Assanti AP, Fonderico F, Macchia PE, Misso C, Marciello F, Marotta V, Del Prete M, Papini E, Lombardi G, Colao A, Spiezia S. Thyroid Nodules Treated with Percutaneous Radiofrequency Thermal Ablation: A Comparative Study. J Clin Endocrinol Metab. 2012. Lim HK, Lee JH, Ha EJ, Sung JY, Kim JK, Baek JH. Radiofrequency ablation of benign non-functioning thyroid nodules: 4-year follow-up results for 111 patients. Eur Radiol. 2013;23:1044 –1049. Paschke R, Hegedus L, Alexander E, Valcavi R, Papini E, Gharib H. Thyroid nodule guidelines: agreement, disagreement and need for future research. Nat Rev Endocrinol. 2011;7:354 –361. Gharib H, Hegedus L, Pacella CM, Baek JH, Papini E. Clinical review: Nonsurgical, image-guided, minimally invasive therapy for thyroid nodules. J Clin Endocrinol Metab. 2013;98:3949 –3957. Papini E, Pacella CM, Hegedus L. Thyroid Ultasound (US) and USassisted procedures: from the shodows into an array of applications. EJE. 2014;170:R1–R15. Dossing H, Bennedbaek FN, Karstrup S, Hegedus L. Benign solitary solid cold thyroid nodules: US-guided interstitial laser photocoagulation–initial experience. Radiology. 2002;225:53–57.
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27. Cakir B, Topaloglu O, Gul K, Agac T, Aydin C, Dirikoc A, Gumus M, Yazicioglu K, Ersoy RU, Ugras S. Effects of percutaneous laser ablation treatment in benign solitary thyroid nodules on nodule volume, thyroglobulin and anti-thyroglobulin levels, and cytopathology of nodule in 1 yr follow-up. J Endocrinol Invest. 2006;29: 876 – 884. 28. Papini E, Pacella CM, Misischi I, Guglielmi R, Bizzarri G, Dossing H, Hegedus L. The advent of ultrasound-guided ablation techniques in nodular disease:Towards a patient-tailored approach. Best Practice, Research Clinical Endocrinolgy, Metabolism. 2014:1–18. 29. Na DG, Lee JH, Jung SL, Kim JH, Sung JY, Shin JH, Kim EK, Kim DW, Park JS, Kim KS, Baek SM, Lee Y, Chong S, Sim JS, Huh JY, Bae JI, Kim KT, Han SY, Bae MY, Kim YS, Baek JH. Radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers: consensus statement and recommendations. Korean J Radiol. 2012;13:117–125. 30. Baek JH, Jeong HJ, Kim YS, Kwak MS, Lee D. Radiofrequency ablation for an autonomously functioning thyroid nodule. Thyroid. 2008;18:675– 676. 31. Huh JY, Baek JH, Choi H, Kim JK, Lee JH. Symptomatic benign thyroid nodules: efficacy of additional radiofrequency ablation treatment session–prospective randomized study. Radiology. 2012; 263:909 –916. 32. Spiezia S, Vitale G, Di Somma C, Pio Assanti A, Ciccarelli A, Lombardi G, Colao A. Ultrasound-guided laser thermal ablation in the treatment of autonomous hyperfunctioning thyroid nodules and compressive nontoxic nodular goiter. Thyroid. 2003;13:941–947. 33. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasoundguided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid. 2006; 16:763–768. 34. Amabile G, Rotondi M, Pirali B, Dionisio R, Agozzino L, Lanza M, Buonanno L, Di Filippo B, Fonte R, Chiovato L. Interstitial laser photocoagulation for benign thyroid nodules: time to treat large nodules. Lasers Surg Med. 2011;43:797– 803. 35. Spiezia S, Garberoglio R, Di Somma C, Deandrea M, Basso E, Limone PP, Milone F, Ramundo V, Macchia PE, Biondi B, Lombardi G, Colao A, Faggiano A. Efficacy and safety of radiofrequency thermal ablation in the treatment of thyroid nodules with pressure symptoms in elderly patients. J Am Geriatr Soc. 2007;55:1478 –1479. 36. Baek JH, Lee JH, Valcavi R, Pacella CM, Rhim H, Na DG. Thermal ablation for benign thyroid nodules: radiofrequency and laser. Korean J Radiol. 2011;12:525–540. 37. Dossing H, Bennedbaek FN, Hegedus L. Interstitial laser photocoagulation (ILP) of benign cystic thyroid nodules–a prospective randomized trial. J Clin Endocrinol Metab. 2013;98:E1213–1217.
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ARTICLE
E n d o c r i n e
C a r e
Prospective study of effectiveness of ultrasoundguided radiofrequency ablation versus control group in patients affected by benign thyroid nodules Roberto Cesareo, MD*-, Valerio Pasqualini, MD**-, Carla Simeoni***, M. Sacchi, MD§ - , E. Saralli, MD§ - , G. Campagna, MD§§ - , Roberto Cianni, MD ** *Thyroid Diseases Center, “S.M.Goretti” Hospital, Latina, Italy; ** Department of Radiology, “S.M.Goretti” Hospital, Latina, Italy; ***Workers Compensation Autority (INAIL) – Research Area of Monteporzio Catone, Via di Fontana Candida, 1 - 00040 Monte Porzio Catone, Rome, Italy; § Departemnt of Internal Medecine, “S.M.Goretti” Hospital, Latina, Italy; §§ Department of Surgery, “S.M.Goretti” Hospital, Via G. Reni, 04100 - Latina, Italy.
Context: Ultrasound (US)-guided radiofrequency ablation (RFA) of solid thyroid nodules (TNs) is a minimally invasive procedure that may induce a volume reduction of symptomatic solid benign thyroid nodules (TNs). Objective: The aim of the study was to evaluate the effectiveness and safety of RFA in debulking benign TNs. Design and Patients: Eighty-four consecutive patients with symptomatic and cytologically benign solid nodules were randomly assigned to either a single RFA session (Group A; n ⫽ 42) or follow up (Group B; n ⫽ 42) at our centre. Entry criteria were: solid thyroid nodule or predominantly solid (with a fluid component ⱕ30% of the volume), normal thyroid function, no autoimmunity, no previous thyroid gland treatment. Three subgroups were formed according to baseline volume of nodules: small (ⱕ 12 mL), medium (from 12 to 30mL), or large (⬎30mL). Methods: Group A: RFA was performed in a single session with the moving-shot technique. Volume and local symptom changes were evaluated 1 and 6 months after RFA. Results: Group A: Volume decreased from 24.5.5 ⫾ 19.6 to 8.6 ⫾ 9.5 six months after RFA (p ⫽ 0.001). The greatest volume reduction was in small nodules. Pressure symptom score improved only in medium and large nodules (p⬍0.001), whereas cosmetic score improved in all treated patients (p⬍0.001). The rate of thyroid volumetric reduction (TVR) was not statistically different between solid and predominantly solid nodules. Only one patient experienced permanent right paramedian vocal cord palsy with inspiratory stridor without dysphonia. In Group B, nodule volume remained unchanged while symptom score was worse at six-month evaluation (p⫽0.01). Conclusions: RFA is effective in reducing thyroid nodule volume. The best reduction rate was observed in small TNs. TVR does not change according to sonographic features. The mean treatment duration was longer in larger TNs.
odular thyroid disease is a common clinical problem whose prevalence increases with age and with a more widespread use of thyroid ultrasonography (US) (1– 4). While most thyroid nodules are benign and need only
N
periodic monitoring, some may require treatment for associated pressure and/or cosmetic symptoms. Although thyroid surgery is the main therapeutic approach for compressive thyroid nodules, it may be associated with several
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received April 28, 2014. Accepted November 5, 2014.
Abbreviations:
doi: 10.1210/jc.2014-2186
J Clin Endocrinol Metab
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drawbacks (5). Long-term levothyroxine suppression treatment in elderly patients with large nodular goiters is unsatisfactory as it is ineffective. Further, it is associated with adverse effects on bones and the cardiovascular system (3– 4). In addition, radioiodine therapy may be ineffective in large nonhyperfunctioning nodules (6). Nonsurgical, minimally invasive treatment modalities such as percutaneous ethanol injection (PEI) (7–9), percutaneous laser ablation (LA) (10 –15), and radiofrequency ablation (RFA) (16 –22) have been used to treat thyroid nodules. PEI is known to be very successful in treating cystic nodules, but is less effective for solid nodules (23–25). LA, investigated primarily for the treatment of solid nodules (26), is successful in reducing the volume of treated thyroid nodules by 40% to 80% (24 –27)and clinical outcomes in patients followed for more than 5 years indicate that LA results in a satisfactory midto longterm clinical response in most patients (15). RFA of thyroid nodules, introduced in 2006 (16), has been reported to be both a safe and effective treatment for benign thyroid nodules (24 –25, 28). The aims of this prospective study comparing a group treated with a single RF session (Group A) with a nontreated group (Group B) were to evaluate: a) the effectiveness and safety of RFA technique on debulking benign TNs; b) the relationship between RF treatment and baseline nodule volume; c) the relationship between baseline sonographic characteristics of thyroid nodular disease and radiofrequency treatment.
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(ⱕ 12 mL), medium (12 to 30 mL), or large (over 30 mL). One single nodule per patient was treated with RFA. In patients with multiple thyroid nodules, the largest and/or most symptomatic one was treated. All patients were clinically, biochemically, and morphologically evaluated at 1 and 6 months after treatment in both groups A and B. Age, gender, thyroid nodule volume, function, and ultrasound characteristics did not differ significantly between groups at baseline. We classified thyroid nodules according to sonographic features as solid or predominantly solid (with a fluid component ⱕ 30% of its volume). The study was not registered on Clinicaltrials.gov. The protocol for this study was approved by the Hospital Ethics Committee and all patients provided written informed consent.
Clinical evaluation We classified symptom and cosmetic scores as described in a previous consensus statement (29). All patients were asked to rate pressure symptoms on a 10-cm visual analog scale (grade 0 –10 cm) at enrollment and during follow up. A cosmetic score was obtained according to the following scale: 1, no palpable mass; 2, no cosmetic problem but palpable mass; 3, a cosmetic problem on swallowing only; 4, easily visible mass.
Biochemical evaluation The laboratory studies included chemiluminescent enzyme immunoassay (EIA) (Architect i4000 SR, Abbott) for serum thyrotropin (normal range, 0.5– 4.9 mIU/L), serum free triiodothyronine (normal range, 1.7–3.7 pg/ml), serum-free thyroxine (normal range, 0.7–1.7 pg/ml), and serum antithyroid peroxidase antibodies (normal range, 0 –35 IU/ mL); immunoradiometric assay (IRMA) (Architect i4000 SR, Abbott) for serum calcitonin (normal range, 0 –10 pg/mL); blood coagulation tests (prothrombin time, activated partial thromboplastin time (PTT)).
Procedure
Patients and Methods From March 2011 to September 2013, a total of 84 patients were consecutively enrolled at “S.M.Goretti” hospital in Latina, Italy in a prospetctive randomized controlled (RCT) trial. Eighty-four patients (51 women, 33 men; mean age 54.4 ⫾ 13.3 years) were randomized as follows: 42 patients were treated with a single RFA session (Group A), and 42 patients did not receive any treatment and were only followed up (Group B). A computerbased number generator was used to randomly assign each patient to one of the two groups. Inclusion criteria were: age above 18 yrs, thyroid nodules with cosmetic or compressive symptoms or nodules over 5 ml, or with maximum diameter ⬎ 2 cm steadily grooving over time, benign thyroid solid nodule (solid portion over 70%) at repeat (at least two) ultrasound-guided fine needle aspiration findings cytologic examinations (Thy2), cold nodule at 99mTc-pertechnetate scintigraphy, serum thyroid hormone thyrotropin and calcitonin levels within normal limits, no history of radioiodine therapy or thermal ablation, no previous neck or trunk external beam radiotherapy, or refusal of or ineligibility for surgery. Exclusion criteria were pregnancy, malignant or suspicious thyroid nodules, or nodules that were confluent in a compressive lobar mass. We classified nodules according to baseline volume as small
US was performed using a 7.5–12 MHz linear probe equipped with CD and PD modules (Technos MPX; Esaote My Lab 50, Italy). Nodule volume and percentage of volume reduction (PVR) were calculated with the following equations: volume percentage (ellipsoid equation): V ⫽ length x width x depth x 0.525; volume reduction percentage: PVR ⫽ ([initial volume – final volume] ⫻ 100)/initial volume. A single TN volume was measured in case of uninodular goiter or in case of multinodular goiter when characterized by one predominant nodule associated with other nonclinically significant thyroid nodules. We took photos of all enrolled patients at baseline and at one and six months after RFA. A radiofrequency generator (Cool-tip, E-Series Covidien) and a 17 gauge, 15 cm electrode with a 1 cm active tip was used. All RF procedures were carried out by the same operator under US control with the same scanner used for the initial diagnostic evaluation. The intra- and interobserver coefficients of variation for sonographic volume assessment were previously defined as 4% and 6%, respectively. The patients were treated with 2% Mepivacain 2–5 mL (Carbosen) and 3 mL of Ropivacaine (Naropine, Fresenius Kabi, USA) for local anesthesia at the puncture site. Four mg of prednisone IV before RFA of large thyroid nodule were prescribed to reduce post-treatment edema. Anxiolytic drugs were never needed prior to the procedure and in fact, as suggested by other authors, we never wanted to induce deep sedation (29). On the basis of previous experience,
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the procedure utilized included the transisthmic approach along the short axis of the nodule, and the nodules were managed with the “moving-shot technique” as described elsewhere by Beak et al (18, 20). We adopted a variant of the aforementioned technique, using 60 W of radiofrequency out-power and exposure time needed to obtain a transient multiple hyperechoic zones as a sign of the effectiveness of ablation maneuver. We also calculated mean treatment time of every single RFA session from initial insertion of RF needle into the thyroid nodule to final assessment of the treatment session.
Statistical analysis Statistical analysis was performed using IBM-SPSS Statistics version 21. Descriptive statistics (median, mean, standard deviation, range) were computed on thyroid volume and other clinical variables. To compare group mean values, appropriate parametric test of statistical significance (t test) was used, where a Shapiro–Wilk test indicated that the data conformed to a lognormal distribution. Otherwise, equivalent non parametric test was employed (Mann–Whitney U-test, Kruskal–Wallis test). Changes in within-subject control or RFA between baseline, 1 month, and 6 month samples were analyzed using the Wilcoxon signed rank test. To test statistical significance of mean percentage of volumetric reduction between classes of nodules was applied nonparametric test Kruskal-Wallis (1-way ANOVA). To compare the degree of variation from one data series to the other has been used the CV (also known as relative standard deviation - RSD) The significance level was defined as P ⱕ .05.
Results Nodule volume Characteristics and clinical data on groups A and B are summarized in Table 1. At enrollment, the clinical data Table 1.
showed no statistical difference between group A and group B. TNs volume decrease in group A (17.5 ⫾ 34.7 at 1 month, 8.6 ⫾ 9.5 at 6 months), whereas it remained unchanged in group B (27.6 ⫾ 22.1 at 1 month, 27.8 ⫾ 22.1 at 6 months). The difference between TNs volume in group A and group B after 1 month and after 6 months was statistically significant (P ⬍ .001). TNs volume in group A decreased from 24.5 ⫾ 19.6 to 12.7 ⫾ 11.8 at 1 month and to 8.6 ⫾ 9.5 at 6 months (Table 2). In group A, the mean percentage decrease of TN volume was 49.7 ⫾ 14.5% at 1 month and 68.5 ⫾ 13.5%. at 6 months. The mean percentage of volumetric reduction after 6 months in treated patients, differs significantly between the three classes of nodules (P ⫽ .027): for small nodules, the mean percentage decrease was 57.5 ⫾ 8.6% at 1 month and 78.2 ⫾ 10.7% at 6 months; for medium nodules it was 47 ⫾ 15% at 1 month and 67 ⫾ 12.2% at 6 months; for large nodules reduction was 47.7 ⫾ 16.3% at 1 month and 62.8 ⫾ 14.8% at 6 months. It should be noted that the variability of the percentage decrease for the large nodules was greater than in the other groups. In fact, coefficient of variation (CV) of the large group was greater than the CV of the other two groups, both at the first and the sixth month (at 6 months the CV was in small group of 14%, in medium of 18% while in large group of 23%). Treatment duration time increase with increasing initial volume of the nodules (Table 3). No significant difference was detected in volume reduction between solid and predominantly solid thyroid nodules (P ⫽ 0,46 at 1 month and P ⫽ 0,09 at 6 month).
Main characteristics of the study population and clinical data at baseline. Values are reported as mean ⫾
SD
Parameter N Sex (males/ females) Age in years Thyroid nodule volume (mL) TSH (mIU/ mL) FT3 (pg/ mL) FT4 (pg/ mL) Cosmetic score Symptom score
3
Group A
Group B
p
42 15/27
42 18/24
ns
56 ⫾ 14 (24 – 80)
53 ⫾ 12 (30 –76)
ns
24.5 ⫾ 19.6 (3.4 – 89)
27.5 ⫾ 22.1 (3.2–90)
ns
2.1 ⫾ 0.9 (0.6 – 4.1)
2.3 ⫾ 1.1 (0.6 – 4.4)
ns
2.7 ⫾ 0.6 (1.2–3.7)
2.6 ⫾ 0.6 (1.8 –3.6)
ns
1.2 ⫾ 0.3 (0 –1.7)
1.2 ⫾ 0.4 (0 –1.7)
ns
2.6 ⫾ 0.9 (1– 4)
2.6 ⫾ 1 (1– 4)
ns
2.8 ⫾ 3.3 (0 –10)
2.7 ⫾ 3 (0 – 8)
ns
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radiofrequency ablation for thyroid nodules
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Table 2. Thyroid nodule volume (ml) in Radiofrequency ablation Group. Values are reported as mean ⫾ SD Baseline Whole group (n ⫽ 42) TN vol. TN vol. variation (%) Small (n ⫽ 10) TN vol. TN vol. variation (%) Medium (n ⫽ 21) TN vol. TN vol. variation (%) Large (n ⫽ 11) TN vol. TN vol. variation (%)
1 month
6 months
24.5 ⫾ 19.6 17.5 ⫾ 34.7*** 8.6 ⫾ 9.5*** ⫺49.7 ⫾ 14.5 ⫺68.6 ⫾ 13.5
7.4 ⫾ 2.7
3 ⫾ 1.2** ⫺57.5 ⫾ 8.6
1.6 ⫾ 1** ⫺78.2 ⫾ 10.7
18.1 ⫾ 4.4
9.3 ⫾ 3*** ⫺47 ⫾ 15
5.9 ⫾ 2.5*** ⫺67 ⫾ 12.2
52.3 ⫾ 17.5 27.8 ⫾ 13.7* ⫺47.7 ⫾ 16.3
20.1 ⫾ 12.1** ⫺62.8 ⫾ 14.8
Differences in mean volumes are considered between value at 1 month and 6 month vs. baseline. *P ⱕ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001.
Table 3. Thyroid treatment time (minutes). Values are reported as mean ⫾ SD (min-max)
Symptom and cosmetic score evaluation Symptom score was not significantly different between group A (2.8 ⫾ 3.3 at baseline, 1.4 ⫾ 1.7 at 1 month, 0.4 ⫾ 0.8 at 6 months) and group B (2.7 ⫾ 3 at baseline, 2.7 ⫾ 3 at 1 month, 2.9 ⫾ 3.2 at 6 months) at baseline or at 1 month. At 6-month evaluation, however, symptom score had progressively improved in group A (P ⬍ .001), while in group B, it remained unchanged at one month and was worse at six-month evaluation (P ⫽ .01). From the whole group of the examined population 39 patients had pressure symptoms. In the treated group 19 patients suffered from pressure symptoms before RF session and 10 after RF session at 6-month follow up. Pressure symptom score significantly improved in the medium and large subgroups whereas no improvement was observed in the small subgroup. (Figure 1). The cosmetic score improved in all group A patients at one- and six-month follow-up evaluation (2.6 ⫾ 0.9 at baseline, 2 ⫾ 0.6 at 1 month, 1.7 ⫾ 0.7 at 6 months; (P ⬍ .001). We did not find any significant difference during the observation follow-up in group B (cosmetic score remained 2.6 ⫾ 1.0 at baseline, 1 month and 6 months). Cosmetic score significantly improved in all subgroups (Figure 2). Complications and Safety RFA was safe and well tolerated in all patients, who were placed under observation for about 4 hours after the procedure. No major complications were observed, and no patient needed hospitalization after treatment. During the RFA procedure, 8 (21.4%) of the 42 patients experienced local pain, occasionally radiating to the ear or jaw or chest, but it was limited and resolved quickly after the power was switched off. In one patient, however, the pro-
Time Whole group Small Medium Large
37 ⫾ 17.4 (17– 85) 20.7 ⫾ 2.8 (17–25) 31.9 ⫾ 6.7 (24 – 45) 61.6 ⫾ 12.5 (48 – 85)
Hormonal evaluation After treatment, hormonal parameters did not change at any time during follow up. All patients were euthyroid at baseline and had normal serum thyroid function tests after 1 and 6 months. No significant changes were observed either in TgAb and TPOAb titers or in calcitonin serum concentrations during the follow-up period except for one patient with a large nodule who developed autoimmune thyroid diseases with hyperthyroidism six months after RF ablation. In group B, no hormonal changes were observed compared with initial values.
Figure 1. Pressure symptoms score in all subgroups at 1 month and at 6 months vs baseline. . ns ⫽ not significant; * P ⱕ .05; **P ⬍ .01
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doi: 10.1210/jc.2014-2186
cedure was stopped due to severe chest pain. The most feared complication was voice change after RFA. Only 2 patients (4.7%) had voice change immediately after the RFA session but it resolved completely 2 or 3 hours after the procedure. One patient experienced permanent right paramedian vocal cord palsy with inspiratory stridor without dysphonia. None developed perinodular hematoma or local infection.
Discussion This study, which compares thermo-ablative radiofrequency treatment of thyroid nodules with an untreated control group, proves that this treatment results in significant volume reduction, with significant improvement in cosmetic and pressure symptoms. All patients underwent a single treatment session. The study shows that there is a direct correlation between the initial volume of nodules and volumetric reduction percentage six months after percutaneous treatment, ie, the smaller the initial volume of the nodule, the greater its volumetric reduction. Further, the study does not demonstrate any significant correlation between initial baseline sonographic characteristics of the thyroid nodule and the degree of volume reduction (P ⬎ .2). In other words, while the initial volume affects the extent of volumetric reduction, the initial ultrasonographic characteristics do not play any role. Hence, our classification, while arbitrary, helped us to better understand the role played by initial volume in determining the magnitude of shrinkage over time. In addition, a careful analysis of our data showed that the CV of the large subgroup was greater than that of the other two
Figure 2. Cosmetics score in all groups at 1 month and at 6 months vs baseline. *P ⱕ .05; **P ⬍ .01; ***P ⬍ .001.
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subgroups, both at one and at six months. In light of this marked variability in the degree of volume reduction, we thus believe that it is not possible to predict the magnitude of shrinkage over time of larger nodules with initial volume over 30 mL. In fact, we observed a significant reduction of volume in some nodules and a minimal or very poor response in others. We do not know exactly what might explain these conflicting data within this subgroup. We only know that treatment of these nodules takes longer than it does in the other two subgroups (Table 3). Because the baseline structural sonographic characteristics of nodules have no role in determining the magnitude of the shrinkage, we believe that in these cases longer treatment times or planning a second or third treatment would be necessary, as other authors using the same moving- shot technique do (18, 22, 30 –31). Thanks to the nodule classification system we adopted, this study highlights that pressure symptom score significantly improves only in the medium and large subgroups, whereas there is no improvement in the small subgroup (Figure 1). It stands to reason that the small nodules with a volume ⱕ 12 mL will usually cause only cosmetic signs, not significant pressure symptoms, if they are located in the isthmus or at least in the superficial site, where they cause a deformation of the margins of the thyroid gland. In our experience, this is the reason why we observe an improvement of pressure symptoms only in subgroups with larger nodule volumes (Figures 1). These particular data have not been reported by many of the authors who have treated nodules with volumes below or comparable to small nodules of our classification with either movingshot technique (16, 18, 20, 22, 31) or with fixed-needle technique by multitined electrode (17, 19, 21). Because of the differences in study designs and patient populations, any direct comparison of our results with those of other trials should be performed with caution. Nevertheless, if we exclude the data reported by the authors who have used the fixed-needle technique by multitined electrode and we analyze the data reported by the controlled study conducted by the researchers who have used moving shot technique (20), we see that the volumetric reduction obtained by the latter appears to be 80% and thus very high. A more careful study, however, reveals that these authors treated nodules with very small volumes of approximately 7 mL and thus their results are comparable to those we obtained in the nodules classified as small. Further, these nodules not only had a small volume but also had a cystic component of approximately 40% (20). More in general, it should be stressed that the nodules treated by most authors who use moving-shot technique in uncontrolled studies have volumetric values ranging from 6 to 13 mL and a fluid component varying from 40% to
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80% (16, 18, 20, 22, 31). Last but not least, it is important to note that these types of nodules, above all the larger ones, underwent repeated RF treatment sessions in these studies, even up to seven times in some cases (18, 22). In fact also in our study in large nodule subgroup a 60% volume reduction could be satisfactory but we cannot exclude that a second treatment may be necessary considering the large size of these nodules at baseline. Furthermore, in this subgroup of nodules the coefficient of variation is higher, which means that compared to a large volume reduction in one nodule, there is another which decreases much less. As for a possible comparison between the laser technique and RF, no head-to-head studies have yet been conducted; it is thus impossible to compare the results of laser with those of radiofrequency techniques. The series of patients treated with these procedures are not comparable, in terms of baseline volumes or in terms of fluid content of the lesions undergoing laser ablation. In particular, laser ablation has been performed on solid or nearly completely solid thyroid nodules (10 –15, 26 –27, 32–34), while the series of nodules undergoing radiofrequency have had a highly variable solid component, as previously stated (16 – 18, 20 –21, 35–36). To date there are no guidelines or any consensus statement providing a clear classification of thyroid nodules with respect to both their volume and their fluid component. A future discussion to establish inclusion criteria shared by all operators would be useful. Which nodules should be treated? When is a nodule small? When is it large? In addition, can repeated RF treatment sessions cause fibrosis, such as occurs with PEI, with technical problems arising during a possible subsequent thyroidectomy (8)? How can we avoid making multiple RFA maneuvers? If performed by a team of experts, this procedure does not present serious side effects, although it is not devoid of risks. In our study we observed transitory dysphonia in two patients (4.7%) and one case (2.3%) of right paramedian vocal cord palsy with inspiratory stridor but without dysphonia. The limit of our study was the relatively short-term follow-up period, despite the fact that clinical evidence shows that greater volume reduction is achieved at about six months (28). In conclusion, we believe that RF ablation is effective in patients suffering from thyroid nodules. Further studies and longer follow-up periods are of course needed to confirm the safety and effectiveness of RFA mainly for larger nodules.
J Clin Endocrinol Metab
Acknowledgments Address all correspondence and requests for reprints to: Corr: Roberto cesareo M.D. [email protected] Thyroid Diseases Center, “S.M.Goretti” Hospital, Latina, Italy - INTERNAL MEDICINE G. RENI 1 Latina Lazio, ITALY 04 100, 0773601439. Disclosure Summary: The authors have nothing to disclose This work was supported by .
References 1. Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am. 2007;36: 707–735, vi 2. Hegedus L. Thyroid ultrasonography as a screening tool for thyroid disease. Thyroid. 2004;14:879 – 880. 3. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–1214. 4. Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedus L, Vitti P. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010;33:51–56. 5. Bergenfelz A, Jansson S, Kristoffersson A, Martensson H, Reihner E, Wallin G, Lausen I. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008;393:667– 673. 6. Fast S, Nielsen VE, Bonnema SJ, Hegedus L. Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy. Eur J Endocrinol. 2009;160:517–528. 7. Bennedbaek FN, Nielsen LK, Hegedus L. Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: a randomized trial. J Clin Endocrinol Metab. 1998;83:830 – 835. 8. Bennedbaek FN, Karstrup S, Hegedus L. Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol. 1997;136:240 –250. 9. Hegedus L. Therapy: a new nonsurgical therapy option for benign thyroid nodules? Nat Rev Endocrinol. 2009;5:476 – 478. 10. Pacella CM, Bizzarri G, Spiezia S, Bianchini A, Guglielmi R, Crescenzi A, Pacella S, Toscano V, Papini E. Thyroid tissue: USguided percutaneous laser thermal ablation. Radiology. 2004;232: 272–280. 11. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasoundguided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules - a randomised study. Eur J Endocrinol. 2005; 152:341–345. 12. Papini E, Guglielmi R, Bizzarri G, Graziano F, Bianchini A, Brufani C, Pacella S, Valle D, Pacella CM. Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid. 2007;17:229 – 235. 13. Gambelunghe G, Fatone C, Ranchelli A, Fanelli C, Lucidi P, Cavaliere A, Avenia N, d’Ajello M, Santeusanio F, De Feo P. A randomized controlled trial to evaluate the efficacy of ultrasound-guided laser photocoagulation for treatment of benign thyroid nodules. J Endocrinol Invest. 2006;29:RC23–26. 14. Valcavi R, Riganti F, Bertani A, Formisano D, Pacella CM. Percu-
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doi: 10.1210/jc.2014-2186
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
taneous laser ablation of cold benign thyroid nodules: a 3-year follow-up study in 122 patients. Thyroid. 2010;20:1253–1261. Dossing H, Bennedbaek FN, Hegedus L. Long-term outcome following interstitial laser photocoagulation of benign cold thyroid nodules. Eur J Endocrinol. 2011;165:123–128. Kim YS, Rhim H, Tae K, Park DW, Kim ST. Radiofrequency ablation of benign cold thyroid nodules: initial clinical experience. Thyroid. 2006;16:361–367. Deandrea M, Limone P, Basso E, Mormile A, Ragazzoni F, Gamarra E, Spiezia S, Faggiano A, Colao A, Molinari F, Garberoglio R. USguided percutaneous radiofrequency thermal ablation for the treatment of solid benign hyperfunctioning or compressive thyroid nodules. Ultrasound Med Biol. 2008;34:784 –791. Jeong WK, Baek JH, Rhim H, Kim YS, Kwak MS, Jeong HJ, Lee D. Radiofrequency ablation of benign thyroid nodules: safety and imaging follow-up in 236 patients. Eur Radiol. 2008;18:1244 –1250. Spiezia S, Garberoglio R, Milone F, Ramundo V, Caiazzo C, Assanti AP, Deandrea M, Limone PP, Macchia PE, Lombardi G, Colao A, Faggiano A. Thyroid nodules and related symptoms are stably controlled two years after radiofrequency thermal ablation. Thyroid. 2009;19:219 –225. Baek JH, Kim YS, Lee D, Huh JY, Lee JH. Benign predominantly solid thyroid nodules: prospective study of efficacy of sonographically guided radiofrequency ablation versus control condition. AJR Am J Roentgenol. 2010;194:1137–1142. Faggiano A, Ramundo V, Assanti AP, Fonderico F, Macchia PE, Misso C, Marciello F, Marotta V, Del Prete M, Papini E, Lombardi G, Colao A, Spiezia S. Thyroid Nodules Treated with Percutaneous Radiofrequency Thermal Ablation: A Comparative Study. J Clin Endocrinol Metab. 2012. Lim HK, Lee JH, Ha EJ, Sung JY, Kim JK, Baek JH. Radiofrequency ablation of benign non-functioning thyroid nodules: 4-year follow-up results for 111 patients. Eur Radiol. 2013;23:1044 –1049. Paschke R, Hegedus L, Alexander E, Valcavi R, Papini E, Gharib H. Thyroid nodule guidelines: agreement, disagreement and need for future research. Nat Rev Endocrinol. 2011;7:354 –361. Gharib H, Hegedus L, Pacella CM, Baek JH, Papini E. Clinical review: Nonsurgical, image-guided, minimally invasive therapy for thyroid nodules. J Clin Endocrinol Metab. 2013;98:3949 –3957. Papini E, Pacella CM, Hegedus L. Thyroid Ultasound (US) and USassisted procedures: from the shodows into an array of applications. EJE. 2014;170:R1–R15. Dossing H, Bennedbaek FN, Karstrup S, Hegedus L. Benign solitary solid cold thyroid nodules: US-guided interstitial laser photocoagulation–initial experience. Radiology. 2002;225:53–57.
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27. Cakir B, Topaloglu O, Gul K, Agac T, Aydin C, Dirikoc A, Gumus M, Yazicioglu K, Ersoy RU, Ugras S. Effects of percutaneous laser ablation treatment in benign solitary thyroid nodules on nodule volume, thyroglobulin and anti-thyroglobulin levels, and cytopathology of nodule in 1 yr follow-up. J Endocrinol Invest. 2006;29: 876 – 884. 28. Papini E, Pacella CM, Misischi I, Guglielmi R, Bizzarri G, Dossing H, Hegedus L. The advent of ultrasound-guided ablation techniques in nodular disease:Towards a patient-tailored approach. Best Practice, Research Clinical Endocrinolgy, Metabolism. 2014:1–18. 29. Na DG, Lee JH, Jung SL, Kim JH, Sung JY, Shin JH, Kim EK, Kim DW, Park JS, Kim KS, Baek SM, Lee Y, Chong S, Sim JS, Huh JY, Bae JI, Kim KT, Han SY, Bae MY, Kim YS, Baek JH. Radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers: consensus statement and recommendations. Korean J Radiol. 2012;13:117–125. 30. Baek JH, Jeong HJ, Kim YS, Kwak MS, Lee D. Radiofrequency ablation for an autonomously functioning thyroid nodule. Thyroid. 2008;18:675– 676. 31. Huh JY, Baek JH, Choi H, Kim JK, Lee JH. Symptomatic benign thyroid nodules: efficacy of additional radiofrequency ablation treatment session–prospective randomized study. Radiology. 2012; 263:909 –916. 32. Spiezia S, Vitale G, Di Somma C, Pio Assanti A, Ciccarelli A, Lombardi G, Colao A. Ultrasound-guided laser thermal ablation in the treatment of autonomous hyperfunctioning thyroid nodules and compressive nontoxic nodular goiter. Thyroid. 2003;13:941–947. 33. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasoundguided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid. 2006; 16:763–768. 34. Amabile G, Rotondi M, Pirali B, Dionisio R, Agozzino L, Lanza M, Buonanno L, Di Filippo B, Fonte R, Chiovato L. Interstitial laser photocoagulation for benign thyroid nodules: time to treat large nodules. Lasers Surg Med. 2011;43:797– 803. 35. Spiezia S, Garberoglio R, Di Somma C, Deandrea M, Basso E, Limone PP, Milone F, Ramundo V, Macchia PE, Biondi B, Lombardi G, Colao A, Faggiano A. Efficacy and safety of radiofrequency thermal ablation in the treatment of thyroid nodules with pressure symptoms in elderly patients. J Am Geriatr Soc. 2007;55:1478 –1479. 36. Baek JH, Lee JH, Valcavi R, Pacella CM, Rhim H, Na DG. Thermal ablation for benign thyroid nodules: radiofrequency and laser. Korean J Radiol. 2011;12:525–540. 37. Dossing H, Bennedbaek FN, Hegedus L. Interstitial laser photocoagulation (ILP) of benign cystic thyroid nodules–a prospective randomized trial. J Clin Endocrinol Metab. 2013;98:E1213–1217.
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