HIFU Ablation vs Fixed-dose RAI-131 Therapy in Moderate-sized Non-toxic MNG

After obtaining informed consent, eligible subjects will be assigned randomly into either High intensity focused ultrasound group (HIFU) or Radioactive iodine (131I) therapy group (RAIT). After treatment, they will be followed up for 4 visits (1-month, 3-month, 6- month, 12-month of post treatment). At each visit, they will have physical examination, regular blood test and questionnaire to evaluate their quality of life. The collected data will be used to compare the effectiveness between HIFU and RAIT for non-toxic multi-nodular goiter (NMNG). The primary purepose is to find out the best non-invasive way in treating NMNG.

For HIFU, you may experience:

1. Mild bruising and redness at the site of treatment
2. Edema of the skin tissue
3. Pain/discomfort during the procedure
4. Skin burns but rare (\<1%)
5. Vocal cord paresis on the side of the treated lobe but rare (\<1%)
6. Unintentional damage to the surrounding tissue (outside the planned treatment area).

For RAIT, you may experience neck tenderness or sore throat in the following few days as developing moderate inflammation in the thyroid and producing discomfort in the neck or throat area. Your symptoms may turn worse for first few week, but will improve over weeks.

Non-toxic multinodular goiter (NMNG) is a condition referred to as a nodular enlargement of the thyroid gland due to the presence of two or more nodules without clinical hyper- or hypothyroidism. It is undoubtedly one of the most common thyroid disorders worldwide and it is estimated that more than 5% of the female population have a clinically-palpable NMNG (1,2).

Although the majority of NMNGs do not cause symptoms and therefore, do not require any intervention other than simple surveillance, some can cause local pressure symptoms and cosmetic concerns over time (1-3).

For NMNGs that cause symptoms, the most widely-accepted treatment has been surgical resection either in the form of a hemithyroidectomy or total thyroidectomy. Despite being safe when done in experienced hands, surgery is associated with complications such as recurrent laryngeal nerve injury and hypoparathyroidism, both of which can be permanent. In addition, a general anesthesia is almost inevitably required when surgery is performed. As a result, non-surgical thermal ablation techniques have been increasingly recognized as an alternative treatment in symptomatic NMNG (4). These ablation techniques utilize thermal energy to cause shrinkage of adenomatous nodules and thereby, relieve symptoms. Types of ablation include radiofrequency, laser and microwave ablations and more recently, high intensity focused ultrasound (HIFU). Regardless of which ablation technique, they have all been shown to not only induce significant nodule shrinkage but also alleviate symptoms (4-6). Radioactive iodine (131I) therapy (RAIT) is another promising non-surgical alterative which is recommended in patients who refuse or have contraindications for surgery. Despite being a less recognized treatment in both Asia and North America, this treatment has increasingly been adopted. In some European countries such as Denmark and Netherlands, it has replaced surgery as the treatment of choice in moderately-sized NMNG as recommended in recently-published clinical practice guidelines (1,7,8). However, RAIT has limitations. For example, it is less applicable in very large-sized NMNG (\>100 mL) because large goiters tend to have a lower radioiodine uptake leading to suboptimal shrinkage. Also considerable inconsistency in goiter shrinkage has been reported (7). With our population getting older and the general public placing a greater emphasis on preserving organ function and lessinvasive treatments, non-surgical treatment alternatives will have an increasing role in the future treatment of NMNG. To our knowledge, it remains unknown whether one particular treatment modality is superior over the other modality because there has not been any direct comparison between the two modalities. Only one previous study compared treatment efficacy between laser ablation and RAIT. However, it mainly focused on the treatment of toxic thyroid nodules (9). To enhance treatment efficacy, a recent study reported promising results of combining the effect of thermal ablation and RAIT (10).

Eligibility Criteria:
Inclusion Criteria:

* Have a moderate-sized NMNG. The dimension of the largest nodule cannot exceed 50mm in diameter. Also on USG volumetry, the total combined volume of the three largest nodules (i.e. the largest nodule volume + second largest nodule volume + third largest nodule volume) or in short, TNV cannot exceed 80 mL or cm\^3.
* The NMNG has to benign. Each nodule within the goiter will be carefully evaluated on USG by an experienced clinician to look for suspicious features for malignancy. Suspicious-looking nodules will be biopsied by USG-guided FNAC. Only nodules with Bethesda II on FNAC will be considered benign.
* Aged between 18 and 70 years old at the time of informed consent.
* Have genuine cosmetic and/or pressure symptoms.
* Have to have normal serum free T4 (FT4) and thyroid-stimulating hormone (TSH) levels.

Exclusion Criteria:

* Have a non-toxic diffuse goiter or a NMNG with the largest nodule \< 20mm in diameter.
* Prefer or have a clear indication for thyroidectomy (such as rapidly growing, compressive goiter or suspected or documented thyroid malignancy).
* Have a pre-existing vocal cord palsy.
* Unable to tolerate even slight neck extension during HIFU ablation.
* Pregnant, lactating women or women wishing to become pregnant within 6 months.
* Previous thyroid surgery or neck irradiation.
* Family history of non-medullary thyroid carcinoma.
* Have any medical conditions that would make them too ill to undergo treatment.