Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

I Love What I do, i.e. Nuclear Medicine … RADIOACTIVE THERAPY FOR No other relevant disclosures HYERTHYROIDISM Mark Tulchinsky, MD, FACNM, CCD or conflicts of interest Professor of Radiology and Medicine Division of Nuclear Medicine Penn State University Hospital

Radioactive Iodine (RAI) Learning Objectives Administration for Graves’ • Treatment Options Disease: Birthplace of • Medications Radiotheranostics • Surgery Saul Hertz, M.D. • 131I Treatment (RAIT) (April 20, 1905 – July 28, 1950) • The first to study RAI in an • Graves’ Disease w/o Orbitopathy animal model of hyperthyroidism • Graves’ Disease with Orbitopathy • March 31st, 1941, at the age of 35 y, administered • Toxic Adenoma the first RAI treatment • Multinodular Toxic Goiter (RAIT) to a patient with Grave’s disease • Intermittent (recurrent) Thyroiditis • The first to use RAI uptake to inform RAIT, i.e. • Amiodarone Thyrotoxicosis radiotheranostic principle

Therapeutic Options for Productive Conditions Amenable to RAIT Hyperthyroidism

Condition Etiology • Antithyroid Drug therapy (ATDT) Graves’ disease (~80%) TSH-R-Ab stimulation of thyrocyte  Symptomatic control with beta blockers Toxic Multinodular Goiter mutation → TSH-R-Ab activation → Toxic Adenoma autonomous function  , aka Thionamides, Anti- Hashimoto’s Thyroiditis in autoimmune disease - a variety of Thyroid Drugs (ATD’s) productive phase (“Hashi- cell- and antibody-mediated toxicosis”, overlaps Graves’) immune processes  Corticosteroids Intermittent/recurrent Thyroiditis* Unknown  Stable Iodine (SSKI, etc.) Amiodarone thyroiditis Multifactorial  Rituximab *RAIT in recovery phase, prevents recurrences • Radioactive Iodine Treatment (RAIT) Abbreviations: TSH-R-Ab = thyroid stimulating hormone  Alone or with adjuncts (steroids ± other DT) receptor autoantibobdy, RAIT = RAI treatment • Surgery

Mark Tulchinsky, MD, FACNM, CCD 1 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

Hyperthyroidism Drug Therapy Hyperthyroidism Drug Therapy Thioureas: (PTU) & Methimazole (MZ) Propylthiouracil (PTU) & Methimazole (MZ)

•PTUATD’s & MZ divert oxidizedPTU iodide & MZ away from , effectively ceasing thyroid Major Minor hormone biosynthesis Rare (0.2%–0.5%) Common (1%–5%) ATD’s do NOT Agranulocytosis Urticaria or other rash block I- trapping  Inhibition of hormone synthesis depletes Very rare (<0.1%) Arthralgia existing stores of iodinated thyroglobulin as Thrombocytopenia Fever the protein is hydrolyzed and hormone Aplastic anemia Transient granulocytopenia released, depleting thyroid hormone stores Vasculitis, lupus-like syndrome Uncommon (<1%) Hypoglycemia (anti-insulin Ab) (MZ) Gastrointestinal upset • ATD’s bind intrathyroidal iodide and Cholestatic hepatitis (MZ) Abnormalities of taste and smell facilitate its clearance from the thyroid, Fulminant hepatitis (PTU) Arthritis depleting thyroid iodine content Hypoprothrombinemia (PTU) • PTU inhibits peripheral T4 to T3 conversion X = the site of biochemical block by thioureas

Disadvantages of RAIT When Compared to Long-term ATDT: Realizations of 1990’s and 2000’s • RAI may induce or worsen Graves’ Orbitopathy (GO) in 15-33% • RAIT practice not standardized with erratic clinical & biochemical outcomes  Euthyroid goal (Eu-RAIT) The Thyrotoxicosis Therapy Follow-up Study,  multiple, fixed or calculated SMALL activities assembled in 1961, comprises 35,000 subjects  Hypothyroid goal (Ablation) treated for hyperthyroidism at over 20 medical  Fixed activity (15 mCi), over & under treat a lot centers in the US and 1 in the UK between 1946  Radiation dose to thyroid, prolonged dosimetry and 1964. This is the largest group of  Activity per g of thyroid, simple & fewest failures hyperthyroid patients that has been followed up for subsequent cancer and other health outcomes.

Thyrotoxicosis Therapy Follow-up Study 1946-1964 Typical Approach to GD in the USA: First Decade of 21st Century

• ATD ± beta blocker for 1-2 years • Stop therapy to check for remission • If no remission or patient recurs after short remission → RAIT or Surgery • Eu-RAIT used in early days, ablation became dominant after 2005 study that showed mortality advantage* • No standardization of hypo-RAIT technique, approaches vary widely

* Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA. 2005;294:71-80.

Mark Tulchinsky, MD, FACNM, CCD 2 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

RAIT n=102 pts MMI n=114 pts

Abbreviation: MMI = Methimazole

Between 1995 and 2013, Brazil (Campinas & São Paulo): What NM Docs Should Know? Reviewed • Be proactive in confronting GO concerns  Post RAIT Hypothyroidism→ minimize

 Practice RAIT that has predictable outcome

15 mCi  Guide referring about timing for TH replacement  Selective steroid prophylaxis • Be proactive in improving symptoms before, during, and after RAIT Worsened Unchanged  Pre-treat with ATDT, beta blockers RAITImproved group MZ group • Good practice – offer consultation service Villagelin, D. et al. Outcomes in Relapsed Graves' Disease Patients Following • Best practice – offer to consult and manage Radioiodine or Prolonged Low Dose of patients after RAIT Methimazole Treatment. Thyroid 2015. DOI: 10.1089/thy.2015.0195

Pre-RAIT Work-Up: Educate Patients (and Referring 99m − 131 TcO4 Scan + 24-Hr I Uptake Doctors) About RAIT at Consultation Document Etiology Chin • Minimized dietary (LID) and medical Iodine • Go over radiation precautions, pt. should come for RAIT unescorted, etc. • Assure pts. – they will leave the facility SSN Anterior Dominant Cold Nodule? Anterior - generally feeling the same as on arrival 99m - Document Benign Cause! TcO4 Thyroid Uptake = 2.45% (Normal 0.36-1.6%) • Review meds, provide guidance (monitor HR for beta blocker adjustments, etc.) • Explain RAIT comes as a capsule (pediatric Measure Uptake: cap. or liquid, if swallowing difficulties) • It doesn’t cause nausea – but expectation RAO LAO ±4 Hr. & 24 Hr. and/or nervousness sure could! Mild (Early) Graves’ Disease 24-Hr 131I uptake = 43%

Mark Tulchinsky, MD, FACNM, CCD 3 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

RAIT for Thyrotoxicosis HYPERTHYROIDISM: General Considerations TREATMENT GOAL • Absolute contraindication – Pregnancy and • RAIT Goals other*, document pregnancy test results  Euthyroidism – futile in Graves’ & hypothetically may increase carcinogenic risk – not recommended • Treating a very toxic patient may result in  Ablation – predictable, time-saver for pts & dead cells thyroid storm – pretreat with MZ (4-6 wks.) don’t turn cancerous – recommended (1) • Stop ATD’s for 2 d. (48 hrs), start uptake • Approach to Ablation day 3, measure uptake, scan & RAIT day 4  Fixed dose (15 mCi) – simple, but not as predictable • Beta-blocker can be continued, HR guided  Radiation dose (cGy) based – multiday dosimetry makes • Re-starting ATDT post-RAIT, optional it impractical, simplified is same as below • Iodine (lithium) loading post-RAIT is  Delivered activity per g of thyroid, normalized to 24hr uptake – simple, practical and rational optional, practiced rarely 1. Bahn RS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management *Contraindications: pregnancy, lactation, known or suspected thyroid guidelines of the American Thyroid Association and American Association of Clinical cancer, individuals unable to comply with radiation safety guidelines. Endocrinologists. Endocr Pract 2011;17:456-520.

Relationship between thyroid radiation dose and Grave’s Disease RAIT: hypothyroidism rate in patients who were <18 years old mCi/g of Thyroid @ 24 hrs. • Most give 0.12-0.20 mCi of 131I/g of thyroid, normalized to 24 hr. uptake • Ablation activity (AA) coefficient at PSU is 0.24 mCi/g (developed empirically) • AA = (gland weight in g x 0.24 mCi/g) / 24 hr. uptake fraction (i.e. 0.5 for 50% uptake) • Gland weight: cannot palpate it for sure – 30 g; can palpate, but cannot see it – 40 g; can see it when pt. walks in – ≥ 60 g • “Fudge Factor” – give more to pts. who are older, on anti-thyroid meds, MNG, severe HT, Scott A. Rivkees, et al. Influence of iodine-131 dose on the outcome of hyperthyroidism rapid 131I turnover, larger glands in children. Pediatrics 2003;111:745-749.

Response to 131I Therapy in Graves’: 0.24 mCi per gm of Thyroid Treatment Complications: Early (PSU Experience) • Typically None • Thyroiditis (sore throat) is the most common 1:40  Occurs 1-3 days post therapy  Rarely needs medication  Responds well to NSAIDs

25 75 300

Mark Tulchinsky, MD, FACNM, CCD 4 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

Treatment Complications: Early Late Complication of RAIT • Exacerbation of thyrotoxicosis (~1%)  Rare in ATD-pretreated, self limited • Ageusia – water swish/swallow after RAI  Increase/start β-blockers and ± ATD’s • Very Rare complications – • Thyroid storm (0.3%) – ATD pretreatment Sialadenitis/Xerostomia diminishes risk • Hypoparathyroidism is extremely rare  Key manifestation is fever • Hyperparathyroidism (parathyroid 131  Mean time to onset 6 days adenoma) – questionable relation to I  Treatment of the thyroid storm: • There is no evidence of increased

 Thermoregulation, physiologic support secondary primary malignancy incidence

 Iodine (30 drops of SSKI a day) • No evidence of congenital defects  PTU (900-1200 mg a day)  Avoid conception for 6-12 months  β-adrenergic blockade (, atenolol, etc.)

Graves’ Orbitopathy (GO), aka What Do We Know About Risk of GO Graves Ophthalmopathy, Thyroid-Associated Orbitopathy (TAO), Thyroid Eye Disease (TED) as Relevant to Therapy of GD? • Known risk factors = remove whichever Clinical Incidence: ~ 20% of GD possible, i.e. smoking, post RAIT TSH elevation/hypo (replace early) Imaging Reveals: > 60% of GD 1 year • Higher the T3, the greater GO occurrence- Severe in ≤ 5% progression probability for all treatments (especially for RAIT) = pretreat with ATD’s Predisposing factors: • Higher the TSH-R-Ab & inflammation in Smoking thyroid, the greater GO risk => suppress Older age autoimmune response with steroids Progression is the Male sex natural course of GO Diabetes • GO progression after RAIT starts early => Hypothyroidism after RAIT preventive measures must start early

Initial Experience: Basics Choice of Primary Treatment in GD RAI Group – 39 pts, initial dose Lesson 1: “Gentle” RAIT is 120 Gy → 13/39 worsening / de rough on the eye! Ablate Case Presentation Case Presentation novo GO, 18/39 were given more with single administration! without GO with mild GO than 1 dose, 12/18 developed >1RAIT, 67% → ↑GO worsening (10) or de novo (2) GO 1 RAIT, 5% → ↑GO

2011 Survey of Clinical Practice Patterns in the Management of Graves' Disease J Clin Endocrinol Metab. 2012;97(12):4549-4558. doi:10.1210/jc.2012-2802 Tallstedt L, et al. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Engl J Med. 1992;326:1733-1738. Abbreviations: GD = Graves’ disease; CS = corticosteroids

Mark Tulchinsky, MD, FACNM, CCD 5 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

Grading Exophthalmos Prevention of Post-RAIT GO: Three-tier, Risk-adjusted Approach • No signs of GO • No GO findings, no risk factors → no prophylaxis • Mild GO (no proptosis, but has some inflammatory scleral redness, etc. • No GO findings or Mild GO, + risk factor(s) • Mod. GO: proptosis 21 - 24 mm  Prednisone 0.2 mg/kg/d, tapered over the 4-5 • Severe GO: proptosis > 24 mm weeks, starting on the day of RAIT • Mild to Moderate GO, + risk factor(s) If any sign of GO –  Prednisone 0.4-0.5 mg/kg/d, tapered over 3 months, starting on the day of RAIT refer to ophthalmology • Moderate to Severe GO → no RAIT for exophthalmometry Shiber S, et al. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Thyroid. 2014;24:1515-1523. DOI: 10.1089/thy.2014.0218

Autonomously Functioning Solitary RAIT of Autonomous Solitary Toxic Thyroid Nodules Nodules • They are 7 - 16 times more common among • An ideal case for 131I treatment. The normal women and can occur at any age tissue is suppressed and endogenously • True adenoma, colloid nodules or local protected hyperplasia. Up to 4% may harbor occult cancer • Formerly, 30-60 mCi doses were used, which that is of doubtful clinical significance resulted in high incidence of needless • Nontoxic (euthyroid) or toxic (usually mild) hypothyroidism • Usually 1 - 3 cm in diameter, can enlarge quickly if • Usually, a 160-240 µCi/gm dose is internal hemorrhage occurs administered (about 10 mCi on average)  ≤2 cm size usually doesn’t make enough TH to • Expect euthyroidism in 91% by 6 months, and cause hyperthyroidism or suppress normal thyroid 93% by 1 year. 7% may need more than one dose. Hypothyroidism would be very unusual.  At ~ 2.5 cm extra-nodular thyroid tissue function is • If a nodule edema is a concern (compression), suppressed, ± subclinical hyperthyroidism TU pre-treat and/or administer steroids and/or  At ~ 3 cm hyperthyroidism is expected recommend surgery.

RAIT of Multiple Autonomous Toxic Multiple Hyper-Functioning Nodules Nodules: Multinodular Goiter – Toxic Multinodular Goiter

• Somewhat more resistant to 131I treatment. Anterior with Markers Anterior • The dose is greater than for Graves’, 30 mCi dose is usually given (fudge factors – thyroid weight & uptake) Chin • The hypothyroidism is less common following the treatment  Functioning nodules get ablative dose, then spared suppressed tissue becomes active, it SSN may provide adequate euthyroid function • Poor iodine uptake is common and may 24 hrs. 131I uptake = 38% require stimulation or higher 131I activities Treated with 30 mCi, euthyroid 1 year later

Mark Tulchinsky, MD, FACNM, CCD 6 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

Toxic Multi-Nodular Goiter on US 131 Huysmans, MD et al. Large, Compressive Goiters Treated with Radioiodine. with Low I Uptake Ann Intern Med. 1994;121(10):757-762. doi:10.7326/0003-4819-121-10-199411150-00005

Anterior Anterior Could this gland with low 131I uptake be ablated? Yes, if it is stimulated first! 24 hrs. 131I uptake = 10.5% 24 hrs. 131I uptake = 58%

Patient 17 before (A) and 1 year (B) after treatment with 5.6 GBq (150 mCi) of Iodine-131. Note the What was the uptake stimulant? distended neck veins and edematous face as signs of compression of the superior vena cava before 4 weeks of Methimazole (MZ), stopped for 2 days, therapy (A) and their improvement 1 year after therapy (B). Published with permission of the patient. uptake capsule, day 3 measured/scanned/RAIT-ed Copyright © American College of Physicians. All rights reserved.

Thyroid Uptake Stimulation: Uptake (24 hr) Improvement Thioureas Pre-Treatment Following Stimulation PSU Experience 80%

Thioureas for minimum of 4 wks. 70%

60% Day 0 Day 1 Day 2 Day 3 Stop Start I-131 50% Uptake Dose Drug 40% 43.6% All 19 patients, 100%, were cured from 30% hyperthyroidism in pre-treated patients. 20% 70.5% of control group patients were cured. 10% 13.8% The difference was statistically significant.

Tulchinsky, M. et al. Stimulating Low Uptake Multinodular Goiter with Anti-thyroid Tulchinsky, M. et al. Stimulating Low Uptake Multinodular Goiter with Anti-thyroid Drugs Prior to I-131 Therapy: A Better Therapeutic Response? Abstract Presented at Drugs Prior to I-131 Therapy: A Better Therapeutic Response? Abstract Presented at 2002 SNM Annual Meeting. 2002 SNM Annual Meeting.

Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. ATD’s pre- and post-RAIT Pretreatment Lowers the 131I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J • Discontinuation of ATD’s for 2 days after Clin Endocrinol Metab, June 2015, 100(6):2261–2267 ≥2-3 mo. of treatment or pre-treatment • Included: 22 pts with MNG, subclinical HT,  Boosts RAIU, especially important in MNG RAIU < 50%, no compressive symptoms, with low baseline uptake random group assignment: • Kyrilli A, Tang BN, Huyge V, et al.  10 pts low iodine diet (LID) group (age 70.7±7 y, 8 F) Thiamazole Pretreatment Lowers the (131)I  12 pts Thiamazole (MTZ) group (age 66.5±14 y, 10 F) Activity Needed to Cure Hyperthyroidism in  MTZ continued for 42 d, stopped for 3 days before Patients With Nodular Goiter. J Clin start of RAIU re-measurement Endocrinol Metab 2015;100:2261-2267. • Authors: “The MTZ-enhanced RAIU led to a 31% decrease in the required median 131I activity needed to 24-hr 42d. on/3d. off ADT LID treat the patients, from 16.0 mCi (Interquartile range: 12.3–34.5) at baseline to 11.0 mCi (Interquartile RAIU (%) 32±10* 63±18 37 ±7* 39 ±10 range: 8.3–14.0) after treatment (p<0.001)” * Baseline - before intervention

Mark Tulchinsky, MD, FACNM, CCD 7 Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018

Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Lowers the 131I Activity Needed to Cure Hyperthyroidism in Patients With Thiamazole Pretreatment Lowers the 131I Activity Needed Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6):2261–2267 to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6):2261–2267

• The most important finding should be this:

7%

10% 18%

10%

±

± ±

±

37

32 63 39

Stimulation with Recombinant Human Amiodarone-Induced Thyrotoxicosis (AIT): Thyroid-Stimulating Hormone (rhTSH) Type 2, Normalized off Amiodarone • Single dose of 0.01 – 0.03 mg IM • n = 15 pts, withdrawal period, 5-147 • Iodine is given 24 hours later (33±34) mo., all had RAIU > 10% @24hrs • Uptake improves by about 2 fold • Aim, prevent recurrent AIT All euthyroid • Pros before RAIT  Quick prep • I-131, 10-20 (15.6±5) mCi • Cons • Outcome, 14 hypo- and 1 euthyroid  High prevalence of HT CV side effects • Early, mild hyper in 2 pts  High Cost • Amiodarone reintroduced in 14 pts  This is not an FDA approved use of rhTSH • 12 pts had arrhythmia controlled Hermida JS, Jarry G, Tcheng E, et al. Radioiodine ablation of the thyroid to allow the Romao R, et al. High prevalence of side effects after recombinant human thyrotropin- reintroduction of amiodarone treatment in patients with a prior history of amiodarone- stimulated radioiodine treatment with 30 mCi in patients with multinodular goiter and induced thyrotoxicosis. Am J Med. 2004;116:345-348. subclinical/clinical hyperthyroidism. Thyroid 2009;19:945-51.

Amiodarone-Induced Thyrotoxicosis (AIT): Type 2, on Amiodarone Conclusions: • RAIT is safe and effective initial therapy for hyperthyroidism, including Graves’ disease, • n = 4 pts, only 1 was withdrawn, RAIU <4% multi-nodular toxic goiter, etc. @24hrs • RAIT has lower mortality than ATD • Aim – ablation. All thyrotoxic at RAIT • RAIT induced Graves’ Orbitopathy is • Thyroid volume by Ultrasound, 1 g/mL → g preventable • RAI activity, 0.08 mCi/g/24hr-RAIU-ratio • RAIT is effective and safe in reducing the size of toxic and substernal goiter, but it may • I-131: 29, 35, 50, 80 mCi require iodine uptake stimulation • Outcome, 3 hypo- and 1 euthyroid • The most cost-effective and the safest stimulation maneuver to raise RAIU is thioureas pre-treatment Gursoy A, Tutuncu NB, Gencoglu A, Anil C, Demirer AN, Demirag NG. Radioactive iodine in the treatment of type-2 amiodarone-induced thyrotoxicosis. J Natl Med Assoc. 2008;100:716-719. Thank you for your attention!

Mark Tulchinsky, MD, FACNM, CCD 8