Efficacy and safety of high-intensity focused ultrasound (HIFU) for treating benign thyroid nodules: a systematic review and meta-analysis

Abstract

Background

High-intensity focused ultrasound (HIFU) is an emerging thermal ablation technique that has been successfully applied to various benign thyroid nodules.

Purpose

To evaluate the efficacy and safety of HIFU for the treatment of benign thyroid nodules.

Material and Methods

The Ovid-MEDLINE and EMBASE databases were searched up to 9 July 2018 for studies describing the use of HIFU to treat benign thyroid nodules. We included studies that have outcomes with sufficient detail to evaluate the volume reduction rate (VRR). The pooled proportions of VRR ≥50% and pooled VRR at one, three, and six months after HIFU were assessed using random-effects modeling. Heterogeneity among studies was determined using Chi-square statistics for pooled estimates and the inconsistency index I².

Results

Seven studies were included in the systematic review and four in the meta-analysis. The pooled VRR at one, three, and six months after HIFU were 17.59 (95% confidence interval [CI] 12.56–22.62), 48.93 (95% CI 42.20–55.66), and 60.43 (95% CI 51.88–68.98). The pooled proportions of VRR ≥50% at six months after HIFU were 75% (95% CI 53–89; I²=73.6%). There were no major complications of HIFU.

Conclusion

HIFU may be a safe and effective treatment modality for benign thyroid nodules, especially for small nodules.

Keywords

High-intensity focused ultrasound ablation thyroid nodule meta-analysis treatment outcome

Introduction

Thyroid nodules are a common finding in clinical practice and have been detected by ultrasound (US) examination in approximately 19%–68% of the general population (1). Although most thyroid nodules are small benign and asymptomatic, others grow to a large size, cause pressure symptoms or cosmetic problems, and require treatment (2). Traditional treatment modalities include surgery, radioiodine treatment, and drugs that suppress thyroid-stimulating hormone (TSH); however, all of these treatments have drawbacks (3). Percutaneous ablation methods—including ethanol ablation (EA), radiofrequency ablation (RFA), laser ablation (LA), and microwave ablation (MWA)—have thus become alternative treatments for benign thyroid modules (2,4,5).

Although EA is regarded as a first-line treatment modality for cystic and predominantly cystic thyroid nodules (6 –8), the high rate of recurrence of thyroid nodules with a vascular solid component limit its use (9). Thermal ablation techniques—such as LA, RFA, and MWA—show excellent results in the treatment of solid thyroid nodules, inducing necrosis and subsequent nodule shrinkage (5,9–17).

High-intensity focused ultrasound (HIFU) is an emerging thermal ablation technique that has been successfully applied to various benign and malignant tumors of the pancreas, prostate, bone, liver, and breast (18). Its major advantage over other thermal techniques is its ability to induce focused thermal tissue destruction at temperatures up to 85°C without needing needle puncture and skin penetration (19). In the United States, the use of US-guided HIFU for benign thyroid nodules is currently under review by the Food and Drug Administration (FDA). Moreover, clinical application of HIFU to benign thyroid nodules has been increasing with various therapeutic efficacies (48.7%–77.6%) (16,20–23). However, several complications from minor complications, such as pain and redness of overlying skin, to more serious complications, including injury of the recurrent laryngeal nerve, have been reported after HIFU (24,25). To our knowledge, however, only one systematic review to date has assessed the efficacy and safety of HIFU for treatment of benign thyroid nodules (26). This systematic review and meta-analysis therefore evaluated the efficacy and safety of HIFU for treatment of benign thyroid nodules and compared the results of HIFU with those of other treatment options for thyroid nodules.

Material and Methods

Literature search strategy

The MEDLINE, EMBASE, and Cochrane Library databases were searched by computer to identify studies assessing the efficacy of HIFU for the treatment of benign thyroid nodules. The search terms used were: (“High intensity focused ultrasound” OR “high-intensity focused ultrasound” OR “HIFU”) AND (“thyroid nodule” OR “thyroid tumor” OR “thyroid nodules” OR “thyroid tissue”). The search was limited to studies published in English up to 9 July 2018. In addition, the bibliographies of the selected articles were screened to identify other suitable articles.

Inclusion criteria

Studies (or subsets of studies) investigating HIFU for the treatment of benign thyroid nodules were eligible for inclusion. Studies (or subsets of studies) satisfying all of the following criteria were included: (i) the study included patients who underwent image-guidance HIFU for the treatment of benign thyroid nodules; (ii) benign thyroid nodules were confirmed by US-guided fine-needle aspiration or core needle biopsy before HIFU; (iii) the study design was observational, either retrospective or prospective; and (iv) outcomes were reported in sufficient detail to evaluate the volume reduction rate (VRR). If studies met all the inclusion criteria but had insufficient outcome data, attempts were made to contact the study authors to obtain these data.

Exclusion criteria

The following exclusion criteria were applied: (i) case reports and series involving < 8 patients, and studies with a potential selection bias (e.g. non-consecutive series); (ii) review articles, editorials, letters, comments, and conference proceedings; (iii) studies with overlapping patients and data; and (iv) studies with insufficient data on volume reduction of treated nodules. Two reviewers (SRC and CHS) independently selected the studies using a standardized form. If the two reviewers could not reach consensus, the study was reviewed by a third reviewer (JHB) with 25 years of clinical experience in performing thyroid US.

Data extraction

Data were extracted from all included studies onto standardized data forms. These data included: (i) study characteristics, such as authors, year of publication, institution at which the patients were treated, duration of patient recruitment, sample size, and study design; (ii) the demographic and clinical characteristics of included patients, such as mean age, sex, thyroid function status, clinical experience of the operator, nodule characteristics (size, composition, and pathology), and HIFU techniques (e.g. mean ablation time and number, mean power and duration, type of HIFU device, and type of anesthesia); (iii) VRR of the nodules; and (iv) major and minor complications. VRR was calculated as [(initial volume – final volume) × 100)/initial volume], and VRR ≥50% as a lesion with VRR ≥50% at the final follow-up US examination. One reviewer (SRC) extracted the data from the selected studies, and two reviewers (CHS and JHB) verified the accuracy of the extracted data.

Quality assessment

The methodological quality of the included studies was independently assessed by two study reviewers (SRC and CHS) using tailored questionnaires and criteria provided by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) (27).

Data synthesis

The efficacy of HIFU is assessed by VRR of the treated nodule. The pooled proportions of treated nodules with VRR ≥50% were the main indices for this meta-analysis. Meta-analytic pooling was performed using the inverse variance method for calculating weights, and the pooled proportion and 95% confidence interval (CI) were determined using Der Simonian-Laird random-effects modeling (28,29). Heterogeneity among studies was determined using the χ² statistic for the pooled estimates, with P < 0.05 indicating significant heterogeneity, and the inconsistency index I², with 0%–40% indicating slight heterogeneity, 30%–60% indicating moderate heterogeneity, 50%–90%, indicating substantial heterogeneity, and 75%–100% indicating considerable heterogeneity (30). We also calculated pooled VRR at one month, three months, and six months using a random-effects model. All statistical analyses were performed using R v3.0.2 (The R Foundation for Statistical Computing, Vienna, Austria) software with the metafor package.

Results

Literature search

The study selection process is illustrated in Fig. 1. A search of the Ovid-MEDLINE, EMBASE, and Cochrane Library databases identified 74 articles, 12 of which were eliminated after removal of duplicates. Of the remaining 62 articles, 43 were excluded after reviewing the titles and abstracts; these included 13 articles that were not in the field of interest; 13 review articles; 15 letters, editorials, or conference abstracts; one case report; and one book. The full texts of the remaining 19 articles were retrieved. An additional search of their bibliographies failed to identify any additional eligible studies. Of the 19 articles selected, 12 were excluded after a review of their full texts; these included 11 articles suspected of having overlapping patient cohorts (23,25,31 –36) and one with insufficient data about VRR (37). Finally, seven studies, involving 180 patients and 184 thyroid nodules, were deemed eligible and included in our systematic review and meta-analysis (22,24,38 –42).

Fig. 1.

Study flow diagram.

Characteristics of the included studies

The characteristics of the seven included studies are detailed in Table 1. Of these seven studies, four were prospective (22,24,38,42) and three were retrospective (39 –41) in design. All included studies had clear descriptions of the HIFU technique and equipment. Two studies were from Asian countries (22,39) and five were from Europe (24,38,40 –42). The mean ages of patients in these studies was in the range of 44.5–62 years. All nodules were confirmed as benign and included 18 functioning nodules. The mean volume of the target nodules was 9.1 mL (range = 1.77–39.2 mL). In all but one study (39), the mean volume of the target nodules was < 5 mL. Six studies (22,24,38,39,41,42) described the compositions of the treated nodules, with all being solid or predominantly solid nodule with cystic portion < 30%. Most patients underwent one session of HIFU, with only three patients undergoing two sessions. All of the included studies used the same device for HIFU, while four used the latest software named Beamotion (22,39,41,42). The total energy of HIFU was in the range of 1.6–31.7 KJ and the duration of HIFU was in the range of 3–153.3 min. The mean follow-up period of these studies was 7.7 months (range = 3–21 months). QUADAS-2 quality of the included studies was moderate overall, and all the studies satisfied at least five of the seven items (27) (Fig. 2).

Table 1.

Characteristics of the included studies.

First author (year of publication) (ref.)	Affiliation (study period)	Patients/nodules (n/n)	Mean age (years)	Mean nodule volume (mL)	HIFU sessions (n)	Type of deviceand probe	Total amount of DIAE per nodule (KJ)	Treatment duration (min)	F/U period (months)	Volume reduction ratio at finalF/U (%)
Korkusuz (2015) (38)	University Hospital Frankfurt, Germany (2013–2014)	9/9	52 (36–80)	3.5 (0.8–7.7)	1	Theraclion, extracorporeal probe (3 MHz)	9.9 (5.7–12.5)	62 (42–96)	3	48.8
Kovatcheva (2015) (24)	Medical University Sofia, Bulgaria (2012–2013)	20/20	44.5 (24–65)	4.96 (1.56–9.35)	1 (17), 2 (3)	Theraclion, extracorporeal probe (3 MHz)	16.4 (5.5–31.7)	86.8 (37–152)	6	48.7
Lang (2017, subgroup analysis)* (39)	The University of Hong Kong, China (2015–2016)	I: 31II: 27III: 15	I: 52 (34–76)II: 49.5 (19–59)III: 48 (45–57)	I: 5.3 (0.6–9.8)II: 14.7 (10.4–26.8)III: 39.2 (30.1–47.9)	I (73)	Theraclion, extracorporeal probe (3 MHz)	I: 10.4 (3–17.9)II: 17.3 (10.1–22.6)III: 24.5 (21.7–25.9)	I: 50 (22–87)II: 73 (56–100.5)III: 82 (74–121)	6	I: 77.6II: 67.9III: 48.1
Lang (2017) (22)	The University of Hong Kong, China(2015)	22	53.1 ± 11.4	6.98 ± 4.04	1 (22)	Theraclion, extracorporeal probe (3 MHz)	15.2 (5.9–28.4)	75.7 (48.8–153.3)	12	68.7
Sennert (2018) (40)	University Hospital Frankfurt, Germany(2014–2016)	15/19	58.7 (36–80)	2.6 (0.1–7.7)	1 (29)	Theraclion, extracorporeal probe (3 MHz)	N/A	N/A	3	58
Trimboli (2018) (41)	Oncology Institute of Southern Switzerland, Switzerland(2016–)	26/26	62 ± 19	2.8 ± 2.0	1 (26)	Theraclion, extracorporeal probe (3 MHz)	2.1 ± 1.1	9 (3–18)	12	48
Giovanella (2018) (42)	Oncology Institute of Southern Switzerland, Switzerland (2016)	15/15	62 (33–79)	1.8 (0.5–6.5)	1 (15)	Theraclion, extracorporeal probe (3 MHz)	N/A	N/A	12	58.8

Values are given as median (range) or mean ± SD unless otherwise specified.

*Group I, patients with a pre-ablation nodule volume <10 mL; group II, patients with a pre-ablation nodule volume of 10–30 mL; group III, patients with a pre-ablation nodule volume >30 mL.

F/U, follow-up; N/A, not available.

Fig. 2.

Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria of the included studies.

Efficacy of HIFU

Follow-up schedules of these studies were not standardized. The pooled VRR at one, three, and six months after HIFU were 17.59 (95% CI = 12.56–22.62), 48.93 (95% CI = 42.20–55.66), and 60.43 (95% CI = 51.88–68.98). No nodules had completely disappeared at final follow-up US. The pooled proportions of VRR > 50% at six months after HIFU were assessed using two studies (22,39). Because one study divided nodules into three groups by their baseline volumes, each group was analyzed separately. The pooled proportion of VRR ≥50% was 75% (95% CI = 53–89; I² = 73.6%) (Fig. 3) with substantial heterogeneity among studies. Publication bias was not evaluated due to the small number of included studies.

Fig. 3.

Forest plots showing the pooled proportions of VRR ≥50% at six months after HIFU.

Safety

Four of the seven studies mentioned pain during HIFU (22,24,38,39). Patients were asked to report pain during and immediately after the completion of HIFU using a visual analog scale (22,24,39) or a numeric rating scale (38). Pain score was in the range of 2.8–5.5 (range = 0–10), with most patients experiencing relief of pain after completion of the procedure. The most common complication other than pain was skin redness and edema, as described in four studies (22,24,38,41). Most patients in two studies experienced skin edema (22,38), and 1/10 in another study experienced skin changes (24). By contrast, one study reported that no patient experienced this complication, with this study differing from other studies in the use of less energy for HIFU (41). In most patients, skin redness and edema spontaneously regressed without any intervention. No patient experienced any major complications, such as full-thickness skin burn, voice change, tracheal injury, or esophageal rupture.

Discussion

The present systematic review and meta-analysis showed that the pooled VRR at one, three, and six months after HIFU were 17.59 (95% CI = 12.56–22.62), 48.93 (95% CI = 42.20–55.66), and 60.43 (95% CI = 51.88–68.98), respectively, and that the pooled proportion of patients with VRR ≥50% at six months after HIFU for benign thyroid nodule was 75% (95% CI = 53–89; I² = 73.6%). However, no patient experienced complete nodule disappearance after HIFU. The most common complication was pain, followed by skin redness and edema, which is spontaneously regressed in most patients. No patient experienced any major complications. Taken together, these findings indicate that HIFU may be a safe and effective alternative treatment modality for benign thyroid nodules.

The VRRs of other minimally invasive techniques—RFA, LA, and MWA—are reported to be 76.1%, 49.9%, and 73.5, respectively, after six months (4,43). Although direct comparisons are limited by differences in the baseline characteristics of nodules, these findings indicate that RFA and MWA is somewhat more effective than HIFU, while LA is as effective as HIFU, for volume reduction after six months.

One of the major concerns in comparing the results of our meta-analysis to other ablation methods were the relatively short follow-up duration. Because RFA achieved slightly higher volume reduction after two years than after one year (44), HIFU may also achieve better results after longer follow-up. However, longer follow-up studies reported thyroid nodule recurrence in 5.6% and 9% of patients who underwent RFA and LA, respectively (21,44), indicating the need to assess the long-term efficacy of HIFU, as determined by VRR and rate of recurrence. The second major concern in comparing the results of HIFU with those of RFA and LA was the small volume of target nodules (<5 mL) in six of the seven studies. The study investigating the efficacy of HIFU for larger nodules found that the VRR (48.1% vs. 77.6%) and therapeutic success rates (40% vs. 83.9%) were significantly lower for nodules >30 mL than for smaller nodules (39). In addition, a recent study reported that treatment success was associated with small pre-ablation nodule volume (22). The negative association between target nodule volume and efficacy may be associated with the mechanical limits of the current USG-guided HIFU device, as it generally does not allow complete ablation of an area >3.5–4.0 cm. Similarly, deeply situated thyroid nodules or nodules in patients with large amounts of subcutaneous fat may be not suitable for HIFU (24,38). Thus, despite the current absence of a recommended nodule size threshold for HIFU ablation, our findings suggest that relatively small-sized thyroid nodules may be suitable for HIFU ablation. However, considering that VRRs of RFA also tend to be lower for large nodules, with these nodules requiring an additional treatment session to achieve sufficient volume reduction (45 –47) and a recent article revealed that sequential application of HIFU for large size nodule showed better treatment efficacy than single treatment group (48), sequential application of HIFU can be applied for the ablation of large size thyroid nodule.

The other factor that should be considered when performing HIFU ablation of thyroid nodules is nodule composition. All target nodules in the included studies were solid or predominantly solid with < 30% cystic portion. The effectiveness of HIFU in treating solid and cystic nodules may be associated with acoustical energy that cannot be absorbed, thereby reducing energy transfer and leaving the cyst-border wall untreated (40). Furthermore, the energy emitted by HIFU can be distributed within a large volume of cyst liquid, interfering with the temperature increase within the nodule (38). Therefore, solid and predominantly solid thyroid nodules with small amounts of cyst are suitable for HIFU ablation.

HIFU has several advantages compared with other thermal ablation techniques. The major advantage is that HIFU does not require puncturing the skin, making it truly non-invasive. Moreover, because the entire ablation can be programmed and carried out automatically with little input from the operator, the treatment success of HIFU is likely less dependent on the skill of the operator and the operator does not require complete knowledge of US. None of the studies included in this meta-analysis reported major complications after HIFU, such as voice change or esophageal or tracheal injury. However, Lang et. al (25) reported that 4/103 (3.9%) patients experienced transient voice change after single session of HIFU ablation for benign thyroid nodule. This study was excluded in our meta-analysis because of overlapped study period with other studies. By comparison, the major complication rate after RFA treatment of benign thyroid nodules was 2.11%, with voice changes being the most frequent (49). Furthermore, a large retrospective study of patients who underwent LA for benign thyroid nodules reported that about 0.8% experienced voice changes (16). The major complication rate of HIFU is similar or somewhat higher than other ablation techniques, but the data about major complications are limited and needed a large cohort study. The most frequent minor complications of HIFU were pain, skin change, and edema, with the latter associated with the non-invasiveness of HIFU in that its energy is absorbed through subcutaneous fat and skin overlying the nodules. Thus, the main technical challenge of HIFU is to avoid damage to pre-focal tissues while delivering sufficient heating to the target volume (38).

An important drawback of HIFU is the long treatment duration, which requires patient sedation and treatment of individual layers treatment. This may result in incomplete ablation (38). A recent study reported that very low energy HIFU ablation of small nodules can achieve the temperature cut-off for cellular necrosis, resulting in a VRR of 48% at 12 months (20,41). Future multicenter studies in large numbers of patients are required to assess the efficacy and safety of combinations of moderate energy HIFU for safe areas and lower energy around the danger triangle (41). These improvements may improve the efficacy and safety of HIFU over time and may enable the use of HIFU as a treatment modality for benign thyroid nodules.

Our study was limited by the small number of studies, as well as by their potential biases and heterogeneity. This precluded our ability to perform meta-analysis, analyze subgroups, and identify potentially important covariates. Many of the questions raised by this systematic review are based on qualitative analysis of the data from the included studies, suggesting the possibility of bias in the interpretation of these data.

Further meta-analysis considering the factors that cause heterogeneity may be needed when sufficient papers have been published in the future. Finally, we only included articles in English, which may have resulted in an overestimation or underestimation of the results.

In conclusion, the present systematic review and meta-analysis provides a thorough summary of the current literature on the efficacy and safety of HIFU for benign thyroid nodules. These results suggest that HIFU may be an effective and safe alternative treatment modality, especially for small nodules. Larger clinical trials with longer follow-up are needed to evaluate the effectiveness of this treatment.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Jung Hwan Baek

Young Jun Choi

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