A Trial Comparing USG-HIFU vs AS in Management of Low-risk PTMC

Study Overview
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Brief Summary
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Papillary thyroid microcarcinoma (PTMC) is a common tumor in Hong Kong. Early immediate surgery has traditionally been recommended. However, given its excellent prognosis, some have recommended Active Surveillance (AS) as an alternative. AS involves monitoring the patients who have PTMC until the tumor progresses. On the other hand, a new technology of ablation has been developing to be an alternative treatment for thyroid nodules comparing with traditional surgery, named High intensity focused ultrasound (HIFU). In our previous study, HIFU is proved in shrinking the size of target site by 6 months gradually and effectively. The investigator hypothesize that HIFU is an effective treatment for PTMC. Compared to AS, HIFU may be a better option as it not only halts disease progression but also has a longer progression-free survival, longer time to tumor progression and is less likely to harbor active disease.

Detailed Description
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Differentiated thyroid cancer has been rising in incidence and is expected to be a leading cancer by the year 2030 . However, the rise has been mostly attributed to an increased detection of incidentally-discovered papillary thyroid microcarcinoma (PTMC). PTMC is a papillary thyroid carcinoma (PTC) measuring ≤ 10mm in its greatest dimension. Previous screening and autopsy studies have confirmed these lesions are common and could be found in up to 15% of normal healthy individuals. However, since the incidence of clinically-significant PTC has historically been <0.5% (i.e. 100 times less than the occult rate), most occult PTMCs probably do not cause harm in one's life-time and could be safely observed without immediate surgery. As a result, several groups of investigators worldwide began evaluating the feasibility and safety of observing PTMC without surgery. Rather than offering immediate surgery, well selected patients with low-risk PTMC (i.e. no extrathyroidal extension, nodal and distant metastases) were followed with regular ultrasound (USG) alone and only proceeded to definitive to surgery when the PTMC showed progression. As expected, >90% PTMCs did not progress and of those who progressed and had surgery, all were cured. This meant even when the initial surgery was deferred, there was no compromise in the chance of cure. With a recent shift towards a more conservative approach in the management of PTC, it has become increasingly accepted that perhaps active surveillance (AS) might be a safe alternative in well selected low-risk PTMCs. However, despite the fact that AS is a viable alternative, there are issues and challenges. First, although the majority of occult tumors do not progress initially, the accumulative risk of tumor progression increases with time. From an analysis of the 1479 PTMCs observed over 5 years, 212 (14.3%) eventually met the progression criteria (such as tumor enlargement, local invasion, new lymph node metastasis or becoming clinical disease) and had surgery. Therefore, with longer observation, a greater proportion of patients would end up having surgery. Second some patients tend to find it difficult to accept AS as a treatment. Even if they do initially, the wait and see approach may distress patients leading to non-compliance. To date, little is known how this may affect patients' well-being and health-related quality of life (HRQOL) over time. Third, since there are no clinical or molecular parameters to predict which tumors are more likely to progress, patients often need life-long follow-up. However, this may be challenging because patients may move to different places. Lastly, there are now less invasive, non-surgical options available to potentially eradicate PTMCs. Image-guided thermal ablation (IGTA) using laser ablation or radiofrequency ablation appears promising. With technological advances, they may eventually replace surgery in the future. However, reports have so far been non-randomized, uncontrolled and short follow-up. Furthermore, despite being less-invasive, they still require a small skin incision. High intensity focused ultrasound (HIFU) is a form of IGTA that needs no skin incision or needle insertion and so, is a truly noninvasive treatment. Under USG guidance, it is able to cause irreversible tissue destruction deep to the skin and subcutaneous layer. Apart from being non-invasive, it is less dependent on the operator's skill as the treatment could be controlled by an automated program. In fact, HIFU is highly successful in a number of solid cancers. In the thyroid, it induces tissue damage via the cavitation and thermal effects. To date, several groups (including us) have confirmed that HIFU ablation is highly effective in inducing shrinkage of benign thyroid nodules.

Official Title
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A Prospective Randomized Trial Comparing Ultrasound-guided High Intensity Focused Ultrasound (HIFU) Ablation With Active Surveillance (AS) in the Management of Low-risk Papillary Thyroid Microcarcinoma (PTMC)

Conditions
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Papillary Thyroid Microcarcinoma

Intervention / Treatment
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* Device: Echopulse


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a thyroid nodule ≤10mm in the largest dimension that is confirmed on FNAC to be PTC (Bethesda class VI cytology) or suspicious of PTC (Bethesda V cytology). For the latter, the nodule needs to have an additional suspicious sonographic feature (i.e. marked hypoechogenicity, irregular margins, height-to-wide ratio >1 and intravascular microcalcifications); Have not expressed a strong desire for immediate surgery after PTMC has been confirmed. Exclusion Criteria: Age ≤ 18 or ≥ 75 years old; Have another thyroid nodule that is either indeterminate or malignant on FNAC; Have concomitant hypo- or hyperthyroidism (i.e. thyroid stimulating hormone (TSH) and/or free thyroxine levels outside the normal ranges) Have sonographic evidence of chronic lymphocytic thyroiditis (because this generally makes it difficult to assess and reassess tumor size accurately on USG alone) Have a tumor considered not suitable for AS. This includes a PTMC with extrathyroidal extension, concomitant nodal or distant metastasis or a PTMC located within 3mm from trachea-esophageal groove or recurrent laryngeal nerve. Have a condition considered not suitable for HIFU treatment (pregnancy, history of neck irradiation, known contralateral vocal cord palsy, a tumor with coarse, macroscopic intranodular calcifications or located outside the treatable depth of 5-30 mm from the skin, family history of non-medullary thyroid carcinoma and medical conditions precluding intravenous sedation).

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be arranged into either HIFU group or AS group randomly
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Intensity Focused Ultrasound<br>Apply the machine 'Echopulse' with High Intensity Focused Ultrasound to treat the papillary thyroid microcarcinoma. | Device: Echopulse<br>* This is a machine to apply high intensity focused ultrasound to ablation the target zone. In this study, we would apply it to the papillary thyroid microcarcinoma.<br>* Other names: High Intensity Focused Ultrasound (HIFU);|
| No Intervention: Active surveillance<br>The participants will be monitored by the doctors actively, like more frequent in follow-up to observe their current situation. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of tumors exhibiting disease progression | To compare the proportion of patients with PTMC exhibiting signs of progression between HIFU and AS group at 24 months | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median duration of progression-free survival | To examine the median duration of progression-free survival within 2 years | 24 months | 
| Change in tumor volume | Tumor volume change from baseline (%) at 2 years | 24 months | 
| Proportion of patients with active disease | The proportion of patients with active disease confirmed by re-biopsy and CEUSG (%) at 2 years | 24 months | 
| Proportion of patients undergoing planned and unplanned thyroidectomy | To calculate the proportion of patients who undergoing thyroidectomy in planned or unplanned. | 24 months | 
| Health related quality of life (HRQOL) | To examine participants HRQOL during the study with a questionnaire combined with different measurement tools: SF-12 (12-Item Short Form Health Survey), SF-6D (Short Form 6 Dimensions), EQ-5D-5L (EuroQoL 5 Dimensions 5 Levels) and FACT-G (Functional Assessment of Cancer Therapy - general scale). The total score would be the health score of participants, as high score as high quality of life. | 24 months | 
| Incidence of potential side-effects from intensity focused ultrasound treatment | To examine any treatment-related side-effects after the treatment | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Papillary Thyroid Microcarcinoma, High intensity focused ultrasound, Active surveillance