The ideal targeted therapy - Radioiodine and the thyroid V Ralph McCready Royal Sussex County Hospital Brighton UK Institute of Cancer Research Sutton Surrey The ideal targeted therapy - Radioiodine and the thyroid History of radioiodine Benign thyroid disease Malignant thyroid disease Suggestions for research Radioactive iodine First human use was 75 years ago • 1936 Hertz wondered if I -131 could be made • 1937 He made studies on rabbits with I -128 and found that hyperplastic glands increased absorption • 1938 Iodine-131 (131I), was discovered by Glenn Seaborg and John Livingood at the University of California, Berkeley • 1941 January 1st, Saul Hertz administered cyclotron produced a I-130 - I-131 mixture as the first therapeutic dose to a human patient with Graves’ Dr Saul Hertz disease at Massachusetts General Hospital. • 1946 May published a series of 29 patients with radioactive Iodine in the study of thyroid physiology Hertz S, Roberts A, Salter WT. Radioactive iodine as an indicator in Hertz S, Roberts A 1946 Radioactive iodine in the study of thyroid thyroid physiology, IV: the metabolism of iodine in Graves’ disease. physiology. VII The use of radioactive iodine therapy in Journal of Clinical Investigation 1942;21:25-29. hyperthyroidism. JAMA 131:81–86 75th I 131 Anniversary – Barcelona EANM 2016 Barbara Hertz Daughter Saul Hertz The I-131 story starts with the discovery of Iodine-127 in 1811 Bernard Courtois in 1811. while routinely processing the ash from seaweed to recover sodium and potassium compounds, he released a curious violet vapour that condensed into attractive iodine crystals. Dr Romsai Suwanik, Siriaj Hospital Bangkok Wanted to overcome iodine deficiency in Thai people Showed villagers how to make clay pots using flip charts Studies on Iodine Nutrition in Thailand RICHARD H. FOLLIS, JR., KANCHANA VANPRAPA AND DIREK DAMRONGSAKDI Interdepartmental Committee on Nutrition for National Defense, Bethesda, Maryland, and the Department of Radiology, Siriraj Hospital,Bangkok, Thailand Produced clean water The search for the magic bullet Benign Disease I-131- Malignant Disease brunchnews.com 1949 Early successful 131I treatment of thyroid cancer 1949 +6 months 24 years later I.5 billion super yacht Eclipse Gibraltar 4th May 2017 D W Smithers Acta Radiologica vol XXXV January 1954 Thyroid hormones are the key to life Too much Marti Feldman Too little Oprah Winfrey Thyroid disease is no respecter of status! The Bush family had it Former US President George H. W. Bush was diagnosed with Graves' disease in 1991 and was treated with radioactive iodine. His wife, former First Lady Barbara Bush, was also diagnosed with Graves' disease around the same time— interestingly enough, so was their dog Millie. The disease is not known to be transmissible! Image by LehighValleyLive.com But not only dogs get thyrotoxicosis Common signs include: Hyperactivity Increased appetite and thirst Nervousness Rapid heart rate Lump in the neck (goitre) Risk factors include: Eating canned food x 3 Using litter trays x 3 Martin, K.M. et al.: Evaluation of dietary and environmental risk factors for hyperthyroidism in cats. JAVMA 217 (6):853-856; 2000. But not only dogs get thyrotoxicosis Mollie On Carbimazole since birth Iodine Metabolism Provides the basis for imaging and therapy Hypothalamus TRH Follicular Cells I* Ant Pituitary TSH Gut T3 T4 PBI Blood flow ~ 30 ml/min 20% extraction on first pass* * Sodium Iodide (131I) MHRA Product Licence 00221/0113 Iodine 131 and Benign Thyroid Disease Hyperthyroidism • Women 8 per 10,000 per year • Men negligible incidence • All the signs and symptoms are of being in love • (Or taking RCP/FRCR examinations) Whickham Survey UK population Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68 Overactive thyroid Diffuse toxic hyperplasia Autonomous (Grave’s disease) 84% functioning nodules 12% Radioiodine therapy versus antithyroid drugs in Graves' disease: A 2016 meta-analysis of randomized controlled trials Conclusion • Radioiodine therapy is associated with a higher hyperthyroid cure rate and lower relapse rate. • ‘we would recommend radioiodine therapy as the treatment of choice for patients with Graves' disease.’ Jungi Wang and Lan Qin DOI: http://dx.doi.org/10.1259/bjr.20160418MM, But what about the Radiation Risk? ‘No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking product Sodium Iodide (131I) solution for Injection, outweigh the risks; hence a Marketing Authorisation has been granted (to GE Healthcare)’. SODIUM IODIDE (131I) 74MBq & 925MBq SOLUTION FOR INJECTION MHRA PL 00221/0113 2016 American Guidelines – Hyperthyroid Therapy • ATA guidelines published last year • ‘Sufficient activity of radioactive iodine should be administered in a single application, typically a mean administered activity of 10–15 mCi (370-555 MBq), to render the patient with Graves’ Disease hypothyroid’ Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees S, Samuels M, Sosa JA, Stan MN, Walter M. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. Thyroid. 2016 Aug 12 [Epub ahead of print]. doi: 10.1089/thy.2016.0229. PMID: 27521067 2010 European Guidelines – Hyperthyroid Therapy • In patients with hyperthyroidism, the aim of treatment with 131I is to achieve a non-hyperthyroid status, which can be euthyroid • or hypothyroid, recompensated by T4 medication. If you ask the patients’ opinion they will say ‘Please can I be normal without medication’ Happy to spend their time in having extra measurements EANM procedure guidelines for therapy of benign thyroid disease M. P. M. Stokkel & Daria Handkiewicz Junak & Michael Lassmann & Markus Dietlein & Markus Luster Eur J Nucl Med Mol Imaging (2010) 37:2218–2228 It is unscientific to use a fixed administered activity A better approach is to aim at a thyroid absorbed dose that will make the patient euthyroid. What is the optimum dose to achieve euthyroidism? PET Dosimetry for the Treatment of Thyrotoxicosis by Using I -131 • Hyperthyroid patients with Grave’s disease were given a fixed (75 MBq) activity of 131I • Volume measured using 124I and PET • Doses to the thyroid were calculated • Patients were followed up and dose to achieve maximum probability of euthyroidism derived M A Flower et al Eur J Nucl Med (1994) 21:531-536 What is the optimum dose to achieve euthyroidism? Best chance of euthyroidism at two years was with an absorbed dose of 60-80 Gy M A Flower et al Eur J Nucl Med (1994) 21:531-536 European Guidelines - Hyperthyroidism In patients with Graves’ disease, the dose with the aim of restoring a euthyroid status is approximately 150 Gy So more needs to be done EANM procedure guidelines for therapy of benign thyroid disease Marcel P. M. Stokkel & Daria Handkiewicz Junak & Michael Lassmann & Markus Dietlein & Markus Luster Eur J Nucl Med Mol Imaging (2010) 37:2218–2228 Future research is needed to • Discover and analyze the range of doses received from fixed administered activities and investigate the reason for the variation. • The use of i.v. administration to eliminate one of the variables • Explore why the variation in time from administration to outcome • Discover the optimum time for retreatment Nodular Goitre 131I therapy • Studies using dosimetry have shown a success rate of 85 – 100% but with an incidence of hypothyroidism of 10–20%1 • But hypothyroidism (TMNG) can be up to to 64% at 24 years2 • Absorbed dose has been between 300-400 Gy • The problem of long term hypothyroidism may lie in the irradiation of normal thyroid tissue • How may this be avoided? 1. Reiners C, Schneider P. Radioiodine therapy of thyroid autonomy. 2. Holm LE, Lundell G, Israelsson A, Dahlqvist I 1982 Incidence Eur J Nucl Med. 2002;29 Suppl 2:S471–8. of hypothyroidism occurring long 75. Reinhardt M, Kim B, Wissmeyer M, Juengling F, Brockmann after iodine-131 therapy for hyperthyroidism. J Nucl Med 23:103-107. The answer could be direct I 131 injection Direct injection of the radioiodine into nodules would reduce hypothyroidism by protecting normal thyroid using normal tissue suppression with Thyroxine1 Radio frequency/ ultrasound ablation is already being used2 We should be using radioiodine. 1.McCready VR, Dizdarevic S, Aplin M. Interventional Nuclear Medicine Eur J Nucl Med Mol Imaging. 2013 May 2. Sung JY, Baek JH, Jung SL, Kim JH, Kim KS, Lee D, Kim WB, Na DG 2015 Radiofrequency ablation for autonomously functioning thyroid nodules: a multicenter study. Thyroid 25:112-117. Thyroid Cancer also affects famous people Musician and singer-songwriter Rod Stewart was diagnosed with thyroid cancer in 2000 - 16 years ago Rod Stewart 16 years later he is still doing well recently celebrated his 9th wedding anniversary Radioiodine really works Hello Magazine 23.08.2016 Rod Stewart and Penny Lancaster have just celebrated their ninth wedding anniversary there is no doubt that in Penny the once notorious womaniser has finally found a blonde worth being faithful to. Differentiated Thyroid Cancer Rare disease • 13 per 100,000 incidence in the USA (NCI) • 11,500 per 100,000 at autopsy 1 • So 11487 people have a thyroid carcinoma • they are unaware of • And it doesn’t kill them • So it could be a benign disease 1. Yong Sang Lee et al Papillary Thyroid Microcarcinomas Are Different from Latent Papillary Thyroid Carcinomas at Autopsy J Korean Med Sci. 2014 May; 29(5): 676– 679 Good Survival - RMH Series 1949 - 1991 100 With Total Thyroidectomy Ablation