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

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1 RADIOACTIVE IODINE THERAPY FOR HYERTHYROIDISM Mark Tulchinsky, MD, FACNM, CCD Professor of Radiology and Medicine Division of Nuclear Medicine Penn State University Hospital I Love What I do, i.e. Nuclear Medicine No other relevant disclosures or conflicts of interest Learning Objectives Treatment Options Medications Surgery 131 I Treatment (RAIT) Graves Disease w/o Orbitopathy Graves Disease with Orbitopathy Toxic Adenoma Multinodular Toxic Goiter Intermittent (recurrent) Thyroiditis Amiodarone Thyrotoxicosis Radioactive Iodine (RAI) Administration for Graves Disease: Birthplace of Radiotheranostics Saul Hertz, M.D. (April 20, 1905 July 28, 1950) The first to study RAI in an animal model of hyperthyroidism March 31 st, 1941, at the age of 35 y, administered the first RAI treatment (RAIT) to a patient with Grave s disease The first to use RAI uptake to inform RAIT, i.e. radiotheranostic principle Conditions Amenable to RAIT Condition Graves disease (~80%) Toxic Multinodular Goiter Toxic Adenoma Hashimoto s Thyroiditis in productive phase ( Hashitoxicosis, overlaps Graves ) Intermittent/recurrent Thyroiditis* Amiodarone thyroiditis Etiology TSH-R-Ab stimulation of thyrocyte mutation TSH-R-Ab activation autonomous function autoimmune disease - a variety of cell- and antibody-mediated immune processes Unknown Multifactorial *RAIT in recovery phase, prevents recurrences Abbreviations: TSH-R-Ab = thyroid stimulating hormone receptor autoantibobdy, RAIT = RAI treatment Therapeutic Options for Productive Hyperthyroidism Antithyroid Drug therapy (ATDT) Symptomatic control with beta blockers Thioureas, aka Thionamides, Anti- Thyroid Drugs (ATD s) Corticosteroids Stable Iodine (SSKI, etc.) Rituximab Radioactive Iodine Treatment (RAIT) Alone or with adjuncts (steroids ± other DT) Surgery Mark Tulchinsky, MD, FACNM, CCD 1

2 Hyperthyroidism Drug Therapy Thioureas: Propylthiouracil (PTU) & Methimazole (MZ) Hyperthyroidism Drug Therapy Propylthiouracil (PTU) & Methimazole (MZ) PTU ATD s & MZdivert oxidized PTU iodide & MZ away from thyroglobulin, effectively ceasing thyroid hormone biosynthesis Inhibition of hormone synthesis depletes existing stores of iodinated thyroglobulin as the protein is hydrolyzed and hormone released, depleting thyroid hormone stores ATD s bind intrathyroidal iodide and facilitate its clearance from the thyroid, depleting thyroid iodine content PTU inhibits peripheral T4 to T3 conversion ATD s do NOT block I - trapping X = the site of biochemical block by thioureas Major Minor Rare (0.2% 0.5%) Common (1% 5%) Agranulocytosis Urticaria or other rash Very rare (<0.1%) Arthralgia Thrombocytopenia Fever Aplastic anemia Transient granulocytopenia Vasculitis, lupus-like syndrome Uncommon (<1%) Hypoglycemia (anti-insulin Ab) (MZ) Gastrointestinal upset Cholestatic hepatitis (MZ) Abnormalities of taste and smell Fulminant hepatitis (PTU) Arthritis Hypoprothrombinemia (PTU) 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) multiple, fixed or calculated SMALL activities Hypothyroid goal (Ablation) Fixed activity (15 mci), over & under treat a lot Radiation dose to thyroid, prolonged dosimetry Activity per g of thyroid, simple & fewest failures The Thyrotoxicosis Therapy Follow-up Study, assembled in 1961, comprises 35,000 subjects treated for hyperthyroidism at over 20 medical centers in the US and 1 in the UK between 1946 and This is the largest group of hyperthyroid patients that has been followed up for subsequent cancer and other health outcomes. Thyrotoxicosis Therapy Follow-up Study Typical Approach to GD in the USA: First Decade of 21 st 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: Mark Tulchinsky, MD, FACNM, CCD 2

3 RAIT n=102 pts MMI n=114 pts Abbreviation: MMI = Methimazole Between 1995 and 2013, Brazil (Campinas & São Paulo): Reviewed 15 mci Villagelin, D. et al. Outcomes in Relapsed Graves' Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment. Thyroid DOI: /thy Worsened Unchanged RAIT Improved group MZ group What NM Docs Should Know? Be proactive in confronting GO concerns Post RAIT Hypothyroidism minimize Practice RAIT that has predictable outcome Guide referring about timing for TH replacement Selective steroid prophylaxis Be proactive in improving symptoms before, during, and after RAIT Pre-treat with ATDT, beta blockers Good practice offer consultation service Best practice offer to consult and manage patients after RAIT RAO Pre-RAIT Work-Up: 99m TcO 4 Scan + 24-Hr 131 I Uptake SSN Document Etiology Chin Dominant Cold Nodule? Document Benign Cause! Mild (Early) Graves Disease LAO - 99m TcO 4- Thyroid Uptake = 2.45% (Normal %) Measure Uptake: ±4 Hr. & 24 Hr. 24-Hr 131 I uptake = 43% Educate Patients (and Referring Doctors) About RAIT at Consultation Minimized dietary (LID) and medical Iodine Go over radiation precautions, pt. should come for RAIT unescorted, etc. Assure pts. they will leave the facility generally feeling the same as on arrival Review meds, provide guidance (monitor HR for beta blocker adjustments, etc.) Explain RAIT comes as a capsule (pediatric cap. or liquid, if swallowing difficulties) It doesn t cause nausea but expectation and/or nervousness sure could! Mark Tulchinsky, MD, FACNM, CCD 3

4 RAIT for Thyrotoxicosis General Considerations Absolute contraindication Pregnancy and other*, document pregnancy test results Treating a very toxic patient may result in thyroid storm pretreat with MZ (4-6 wks.) Stop ATD s for 2 d. (48 hrs), start uptake day 3, measure uptake, scan & RAIT day 4 Beta-blocker can be continued, HR guided Re-starting ATDT post-rait, optional Iodine (lithium) loading post-rait is optional, practiced rarely *Contraindications: pregnancy, lactation, known or suspected thyroid cancer, individuals unable to comply with radiation safety guidelines. HYPERTHYROIDISM: TREATMENT GOAL RAIT Goals Euthyroidism futile in Graves & hypothetically may increase carcinogenic risk not recommended Ablation predictable, time-saver for pts & dead cells don t turn cancerous recommended (1) Approach to Ablation Fixed dose (15 mci) simple, but not as predictable Radiation dose (cgy) based multiday dosimetry makes it impractical, simplified is same as below Delivered activity per g of thyroid, normalized to 24hr uptake simple, practical and rational 1. Bahn RS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract 2011;17: Relationship between thyroid radiation dose and hypothyroidism rate in patients who were <18 years old Scott A. Rivkees, et al. Influence of iodine-131 dose on the outcome of hyperthyroidism in children. Pediatrics 2003;111: Grave s Disease RAIT: mci/g of 24 hrs. Most give mci of 131 I/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, rapid 131 I turnover, larger glands Response to 131 I Therapy in Graves : 0.24 mci per gm of Thyroid (PSU Experience) Treatment Complications: Early Typically None Thyroiditis (sore throat) is the most common 1:40 Occurs 1-3 days post therapy Rarely needs medication Responds well to NSAIDs Mark Tulchinsky, MD, FACNM, CCD 4

5 Treatment Complications: Early Exacerbation of thyrotoxicosis (~1%) Rare in ATD-pretreated, self limited Increase/start β-blockers and ± ATD s Thyroid storm (0.3%) ATD pretreatment diminishes risk Key manifestation is fever Mean time to onset 6 days Treatment of the thyroid storm: Thermoregulation, physiologic support Iodine (30 drops of SSKI a day) PTU ( mg a day) β-adrenergic blockade (propranolol, atenolol, etc.) Late Complication of RAIT Ageusia water swish/swallow after RAI Very Rare complications Sialadenitis/Xerostomia Hypoparathyroidism is extremely rare Hyperparathyroidism (parathyroid adenoma) questionable relation to 131 I There is no evidence of increased secondary primary malignancy incidence No evidence of congenital defects Avoid conception for 6-12 months Graves Orbitopathy (GO), aka Graves Ophthalmopathy, Thyroid-Associated Orbitopathy (TAO), Thyroid Eye Disease (TED) What Do We Know About Risk of GO as Relevant to Therapy of GD? 1 year Progression is the natural course of GO Clinical Incidence: ~ 20% of GD Imaging Reveals: > 60% of GD Severe in 5% Predisposing factors: Smoking Older age Male sex Diabetes Hypothyroidism after RAIT Known risk factors = remove whichever possible, i.e. smoking, post RAIT TSH elevation/hypo (replace early) Higher the T3, the greater GO occurrenceprogression probability for all treatments (especially for RAIT) = pretreat with ATD s Higher the TSH-R-Ab & inflammation in thyroid, the greater GO risk => suppress autoimmune response with steroids GO progression after RAIT starts early => preventive measures must start early Initial Experience: Basics RAI Group 39 pts, initial dose 120 Gy 13/39 worsening / de novo GO, 18/39 were given more than 1 dose, 12/18 developed worsening (10) or de novo (2) GO Lesson 1: Gentle RAIT is rough on the eye! Ablate with single administration! >1RAIT, 67% GO 1 RAIT, 5% GO Choice of Primary Treatment in GD Case Presentation without GO Case Presentation with mild GO Tallstedt L, et al. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Engl J Med. 1992;326: Survey of Clinical Practice Patterns in the Management of Graves' Disease J Clin Endocrinol Metab. 2012;97(12): doi: /jc Abbreviations: GD = Graves disease; CS = corticosteroids Mark Tulchinsky, MD, FACNM, CCD 5

6 Grading Exophthalmos No signs of GO Mild GO (no proptosis, but has some inflammatory scleral redness, etc. Mod. GO: proptosis mm Severe GO: proptosis > 24 mm If any sign of GO refer to ophthalmology for exophthalmometry Prevention of Post-RAIT GO: Three-tier, Risk-adjusted Approach No GO findings, no risk factors no prophylaxis No GO findings or Mild GO, + risk factor(s) Prednisone 0.2 mg/kg/d, tapered over the 4-5 weeks, starting on the day of RAIT Mild to Moderate GO, + risk factor(s) Prednisone mg/kg/d, tapered over 3 months, starting on the day of RAIT Moderate to Severe GO no RAIT Shiber S, et al. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Thyroid. 2014;24: DOI: /thy Autonomously Functioning Solitary Thyroid Nodules They are 7-16 times more common among women and can occur at any age True adenoma, colloid nodules or local hyperplasia. Up to 4% may harbor occult cancer that is of doubtful clinical significance Nontoxic (euthyroid) or toxic (usually mild) Usually 1-3 cm in diameter, can enlarge quickly if internal hemorrhage occurs 2 cm size usually doesn t make enough TH to cause hyperthyroidism or suppress normal thyroid At ~ 2.5 cm extra-nodular thyroid tissue function is suppressed, ± subclinical hyperthyroidism At ~ 3 cm hyperthyroidism is expected RAIT of Autonomous Solitary Toxic Nodules An ideal case for 131 I treatment. The normal tissue is suppressed and endogenously protected Formerly, mci doses were used, which resulted in high incidence of needless hypothyroidism Usually, a µci/gm dose is administered (about 10 mci on average) Expect euthyroidism in 91% by 6 months, and 93% by 1 year. 7% may need more than one dose. Hypothyroidism would be very unusual. If a nodule edema is a concern (compression), TU pre-treat and/or administer steroids and/or recommend surgery. RAIT of Multiple Autonomous Toxic Nodules: Multinodular Goiter Somewhat more resistant to 131 I treatment. The dose is greater than for Graves, 30 mci dose is usually given (fudge factors thyroid weight & uptake) The hypothyroidism is less common following the treatment Functioning nodules get ablative dose, then spared suppressed tissue becomes active, it may provide adequate euthyroid function Poor iodine uptake is common and may require stimulation or higher 131 I activities Multiple Hyper-Functioning Nodules Toxic Multinodular Goiter with Markers Chin SSN 24 hrs. 131 I uptake = 38% Treated with 30 mci, euthyroid 1 year later Mark Tulchinsky, MD, FACNM, CCD 6

7 Toxic Multi-Nodular Goiter on US with Low 131 I Uptake Huysmans, MD et al. Large, Compressive Goiters Treated with Radioiodine. Ann Intern Med. 1994;121(10): doi: / hrs. 131 I uptake = 10.5% Could this gland with low 131 I uptake be ablated? Yes, if it is stimulated first! 24 hrs. 131 I uptake = 58% What was the uptake stimulant? 4 weeks of Methimazole (MZ), stopped for 2 days, uptake capsule, day 3 measured/scanned/rait-ed Patient 17 before (A) and 1 year (B) after treatment with 5.6 GBq (150 mci) of Iodine-131. Note the distended neck veins and edematous face as signs of compression of the superior vena cava before therapy (A) and their improvement 1 year after therapy (B). Published with permission of the patient. Copyright American College of Physicians. All rights reserved. Thyroid Uptake Stimulation: Thioureas Pre-Treatment PSU Experience Thioureas for minimum of 4 wks. Uptake (24 hr) Improvement Following Stimulation 80% 70% 60% Day 0 Stop Thiourea Drug Day 1 Day 2 Start Uptake All 19 patients, 100%, were cured from hyperthyroidism in pre-treated patients. 70.5% of control group patients were cured. The difference was statistically significant. Day 3 I-131 Dose 50% 40% 30% 20% 43.6% 10% 13.8% 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 2002 SNM Annual Meeting. 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 2002 SNM Annual Meeting. ATD s pre- and post-rait Discontinuation of ATD s for 2 days after 2-3 mo. of treatment or pre-treatment Boosts RAIU, especially important in MNG with low baseline uptake Kyrilli A, Tang BN, Huyge V, et al. Thiamazole Pretreatment Lowers the (131)I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab 2015;100: hr 42d. on/3d. off ADT LID RAIU (%) 32±10* 63±18 37 ±7* 39 ±10 * Baseline - before intervention Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131 I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6): Included: 22 pts with MNG, subclinical HT, RAIU < 50%, no compressive symptoms, random group assignment: 10 pts low iodine diet (LID) group (age 70.7±7 y, 8 F) 12 pts Thiamazole (MTZ) group (age 66.5±14 y, 10 F) MTZ continued for 42 d, stopped for 3 days before start of RAIU re-measurement Authors: The MTZ-enhanced RAIU led to a 31% decrease in the required median 131 I activity needed to treat the patients, from 16.0 mci (Interquartile range: ) at baseline to 11.0 mci (Interquartile range: ) after treatment (p<0.001) Mark Tulchinsky, MD, FACNM, CCD 7

8 37±7% 32±10% 39±10% 63±18% Optimal 131 I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018 Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131 I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6): Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131 I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6): The most important finding should be this: Stimulation with Recombinant Human Thyroid-Stimulating Hormone (rhtsh) Single dose of mg IM Iodine is given 24 hours later Uptake improves by about 2 fold Pros Quick prep Cons High prevalence of HT CV side effects High Cost This is not an FDA approved use of rhtsh Romao R, et al. High prevalence of side effects after recombinant human thyrotropinstimulated radioiodine treatment with 30 mci in patients with multinodular goiter and subclinical/clinical hyperthyroidism. Thyroid 2009;19: Amiodarone-Induced Thyrotoxicosis (AIT): Type 2, Normalized off Amiodarone n = 15 pts, withdrawal period, (33±34) mo., all had RAIU > Aim, prevent recurrent AIT All euthyroid before RAIT I-131, (15.6±5) mci Outcome, 14 hypo- and 1 euthyroid Early, mild hyper in 2 pts Amiodarone reintroduced in 14 pts 12 pts had arrhythmia controlled Hermida JS, Jarry G, Tcheng E, et al. Radioiodine ablation of the thyroid to allow the reintroduction of amiodarone treatment in patients with a prior history of amiodaroneinduced thyrotoxicosis. Am J Med. 2004;116: Amiodarone-Induced Thyrotoxicosis (AIT): Type 2, on Amiodarone n = 4 pts, only 1 was withdrawn, RAIU Aim ablation. All thyrotoxic at RAIT Thyroid volume by Ultrasound, 1 g/ml g RAI activity, 0.08 mci/g/24hr-raiu-ratio I-131: 29, 35, 50, 80 mci Outcome, 3 hypo- and 1 euthyroid 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: Conclusions: RAIT is safe and effective initial therapy for hyperthyroidism, including Graves disease, multi-nodular toxic goiter, etc. RAIT has lower mortality than ATD RAIT induced Graves Orbitopathy is preventable RAIT is effective and safe in reducing the size of toxic and substernal goiter, but it may require iodine uptake stimulation The most cost-effective and the safest stimulation maneuver to raise RAIU is thioureas pre-treatment Thank you for your attention! Mark Tulchinsky, MD, FACNM, CCD 8