HIFU vs RAI in the Relapsed Graves' Disease
Condition: Graves Disease
MeSH terms: Graves Disease
Study type: Interventional

Summary: 
      Graves' disease (GD) is an autoimmune thyroid disorder caused by stimulating auto-antibodies
      to the thyrotrophin (TSH) receptor on thyroid follicular cells. It is the most common cause
      of hyperthyroidism and approximately 3% of women and 0.5% of men develop GD in their
      lifetime.

      RAI has been shown to be a cost-effective and safe therapy in patients with GD but with some
      disadvantages. In addition, despite its proven efficacy and safety, many patients do not wish
      to undergo RAI because of radiation fear and prefer to either continue ATDs or have surgery.

      High-intensity focused ultrasound (HIFU) is a non-invasive procedure that involves the
      application of a high-energy focused beam for thermal tissue ablation within a targeted zone.
      Similar to the principle of RAI (i.e. using ionizing radiation to ablate thyroid parenchyma
      and cause GD remission), we postulated that the heat energy generated from HIFU could also be
      used to ablate the thyroid parenchyma and cause GD remission. The idea of using heat energy
      to ablate thyroid parenchyma minimally invasively was recently reported using radiofrequency
      ablation but to our knowledge, we are one of the first (if not the first) group to propose
      using HIFU energy to ablate thyroid parenchyma as a definitive treatment for relapsed GD.

      Having obtained ethical approval, a pilot study was conducted to examine the efficacy and
      safety of HIFU as a treatment for relapsed GD. In the pilot study, all patients underwent a
      safe and successful HIFU ablation for relapsed GD. Based on the results of the pilot study,
      we hypothesize that a single HIFU treatment to the thyroid gland may be as effective as our
      standard outpatient fixed-dose of RAI (370MBq) in causing remission of GD at 6-month. If our
      hypothesis turns out to be true, HIFU could become a treatment option for patients who are
      indicated for RAI but do not wish to have it because of one reason or another. HIFU appears
      to induce a faster disease remission and lessen the need of deferring pregnancy and radiation
      precautions because of the absence of radioactivity.
    

Detailed description: 
      Graves' disease (GD) is an autoimmune thyroid disorder caused by stimulating auto-antibodies
      to the thyrotrophin (thyroid stimulating hormone [TSH]) receptor on thyroid follicular cells.
      It is the most common cause of hyperthyroidism and approximately 3% of women and 0.5% of men
      develop GD in their lifetime1. In our locality, like Europe and Japan, antithyroid drugs
      (ATDs) such as carbimazole or propylthiouracil have been preferred over radioactive iodine
      (RAI) and surgery as the initial treatment of GD2-4. This is because ATDs are relatively easy
      to administer, could induce disease remission (30-70%) and avoid life-long thyroid hormone
      replacement, operative risks and radioactivity2-4. However, because of possible side-effects,
      they are only recommended for a period of 12 to 18 months. Taking ATDs for a longer period
      does not seem to increase the chance of remission5. Therefore, currently, once the disease
      has relapsed after a 18-month of ATD treatment, more definitive treatment modalities like RAI
      or surgery are indicated. Regarding to which is more preferable, surgery is usually advised
      in patients with large compressive goiter (>80g), suspected or documented thyroid malignancy,
      planning to become pregnant within 6 months and moderate to severe Graves' ophthalmopathy
      (GO)2-4. As a result, most patients without these conditions are considered for RAI2-4.

      RAI has been shown to be a cost-effective and safe therapy in patients with GD4,6,7. In North
      America, clinical endocrinologists favor RAI as the initial treatment for GD2-4. However,
      since RAI is usually prescribed on an outpatient basis, it is necessary to consider nearby
      individuals' exposure doses and formulate radiation precautions carefully8. Other
      disadvantages include its slow induction of euthyroidism, potential worsening of GO and
      deferral of pregnancy2-4. Although various dosing techniques have been described to ensure an
      adequate radiation delivery to the thyroid gland, the simplest and most effective method has
      been to administer a fixed dose of RAI2. However, due to local regulations and our
      densely-populated areas, administering higher RAI doses (>400MBq) is not permitted on an
      outpatient basis9. As a result, the usual RAI dose usually ranges between 185 to 370MBq (i.e.
      up to 10mci)10. In addition, despite its proven efficacy and safety, many patients do not
      wish to undergo RAI because of radiation fear and prefer to either continue ATDs or have
      surgery11.

      High-intensity focused ultrasound (HIFU) is a non-invasive procedure that involves the
      application of a high-energy focused beam for thermal tissue ablation within a targeted zone.
      It has been applied in a variety of medical conditions including uterine fibroids and
      prostate, breast, pancreatic, and liver tumors12. Unlike other ablation devices (like
      radiofrequency or laser ablation), HIFU does not require needle puncture and is considered
      safer and less operator-dependent13. Single HIFU treatment has been shown to reduce size of
      benign thyroid nodules13,14. Histologic examination confirmed that HIFU induced complete
      tissue necrosis within a targeted area13. Similar to the principle of RAI (i.e. using
      ionizing radiation to ablate thyroid parenchyma and cause GD remission), we postulated that
      the heat energy generated from HIFU could also be used to ablate the thyroid parenchyma and
      cause GD remission. The idea of using heat energy to ablate thyroid parenchyma minimally
      invasively was recently reported using radiofrequency ablation15 but to our knowledge, we are
      one of the first (if not the first) group to propose using HIFU energy to ablate thyroid
      parenchyma as a definitive treatment for relapsed GD.

      Having obtained ethical approval, a pilot study was conducted to examine the efficacy and
      safety of HIFU as a treatment for relapsed GD. Over a 2-month period, 20 patients underwent a
      single HIFU treatment for relapsed GD. The treatment involved ablating the entire right, left
      and central (isthmic) lobes with HIFU pulses. To avoid inadvertent injury to heat-sensitive
      structures like the recurrent laryngeal nerve, parathyroid glands, trachea and esophagus, we
      deliberately left 2-3ml of thyroid parenchyma non-ablated close to the trachea-esophageal
      groove on each side. The reason for not leaving a larger amount of non-ablated parenchyma is
      because from the experience in subtotal thyroidectomy, leaving > 6ml of normal parenchyma may
      diminish the long-term remission rate16.

      In the pilot study, all patients underwent a safe and successful HIFU ablation for relapsed
      GD. By ultrasound (USG) volumetry, the mean pre-ablation total thyroid volume was 18.5 ±
      6.4ml. The average treatment time was 72.7 ± 31.0 mins and the total energy delivered to each
      patient was 21.4 ± 5.9 KJ. No patients suffered any major complications afterwards except for
      2 patients (10.0%) who had minor neck redness in the first week. By 4-week, all patients were
      either biochemically euthyroid (n=15) (without ATDs) or biochemically hypothyroid (requiring
      thyroxine replacement) (n=5). At 6-month, 15 (75.0%) patients remained biochemically
      euthyroid or hypothyroid without ATDs (i.e. remission) while 5 patients (25.0%) had
      biochemical hyperthyroidism. However, of these, only 3 required ATDs and 2 were kept
      observed.

      Based on the results of the pilot study, we hypothesize that a single HIFU treatment to the
      thyroid gland may be as effective as our standard outpatient fixed-dose of RAI (370MBq) in
      causing remission of GD at 6-month. If our hypothesis turns out to be true, HIFU could become
      a treatment option for patients who are indicated for RAI but do not wish to have it because
      of one reason or another. Apart from the benefit of being an outpatient treatment, HIFU
      appears to induce a faster disease remission and lessen the need of deferring pregnancy and
      radiation precautions because of the absence of radioactivity.
    

Intervention name(s): Echopulse
Intervention type(s): Device
Intervention description(s): Replacing HIFU for the Graves' disease patients who traditionally have RAI to remission
Other intervention name(s): High Intensity Focused Ultrasound (HIFU)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Relapsed Graves' disease; High Intensity Focused Ultrasound; RAI