The ideal targeted therapy - Radioiodine and the

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. . 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

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 ()

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 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 Ablation Dose 3 GBq 131I 90 Therapy Doses 5.5 GBq 131I 80 70 Female 60 % 50 40 Male 30 Papillary Follicular 20 Hurthle 10 0 0 5 10 15 20 25 30 Years Survival - Year of Presentation

100 With Total Thyroidectomy Ablation Dose 3 GBq 131I 90 Therapy Doses 5.5 GBq 131I 80 1972 - 91 70 60 % 50 1949- 1972 40

30 Reason : Fixed activity but better surgery lower volume residual tissue results in higher absorbed dose 20 10 Years 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 The subject for debate is the post surgery administered activity

• 100 mCi (3.7 GBq) ablation has been very successful • But 10-15% develop distant metastases • Once metastases develop the outlook is poor

100 90 80 70 60 50 40 Lung 30 20 10 Other 0 0 1 2 3 4 5 6 7 8 9 10 Years The subject for debate Post surgery administered activity

• 100 mCi 3.7 GBq ablation has been very successful • But 10-15% develop distant metastases • Once metastases develop the outlook is poor

• Now we use 30 mCi (1.1 GBq) • 30 mCi was not a scientific decision • Does use of 30 mCi increase the risk of recurrence over 30 years?

100 • If it does will the recurrence at 30 years come from 90 80 the under-dosed micro disease that was present at 70 the time of ablation? 60 50 40 Lung 30 20 10 Other 0 0 1 2 3 4 5 6 7 8 9 10 Years Does reducing the radioiodide ablation activity to 30 mCi fixed activity affect the outcome?

• Median follow-up was 24 (range, 4-34) years. • 49% successful ablation with one 3.7 GBq administered activity • Disease free survival at 30 years 95% • 51% required more activity • Disease free survival at 30 year 81% • So did the need for more activity mean that the doses to the residual tissue and potential metastases was too low? • One argument is to minimise the risk of second primary malignancy

J Clin Endocrinol Metab. 2013 May;98(5):1819-25. doi: 10.1210/jc.2013-1197. Epub 2013 Mar 14. Long-term outcomes following low-dose radioiodide ablation for differentiated thyroid cancer. Welsh L1, Powell C, Pratt B, Harrington K, Nutting C, Harmer C, Newbold K. Radiation induced secondary primary malignancies

• Second Primary Malignancies were diagnosed in 9% of I 131- treated patients and 10.5% of non-I 131-treated patients.

• Does not support the argument for reducing ablation activity to minimise secondary malignancy

Thyroid. 2016 Aug;26(8):1110-6. doi: 10.1089/thy.2016.0037. Epub 2016 Jul 22. Hirsch D Nevertheless a better approach is to deliver the correct absorbed dose - whatever that is?

600

500 A better approach is to 400 deliver an known ablative 300 dose 200

Remnant asorbed dose (Gy) (Gy) dose asorbed Remnant 100

0 Failed ablation Successful ablation

Maximum voxel radiation dose

Significant correlation (p=0.03) Glenn Flux et al EJNMMI 2010 Feb;37(2):270-5. Suggestions for future research

• More research is required to discover the correct absorbed dose to ablate normal thyroid tissue and micro DTC metastases • More research is required to discover the relation between administered activity and the absorbed dose to normal remnants • Would require i.v. administration to reduce variable gut absorption? • Is the appropriate dose to ablate remnants sufficient to ablate occult disease within and outside the thyroid remnant? Conclusions

• Radioiodine therapy started by Saul Hertz is the success story of Nuclear Medicine • It is the model for molecular radiotherapy but why is it so successful? • After 76 years we are still trying to explain the reasons for its success

• Hyperthyroidism • We should aim for euthyroidism • Investigate further the absorbed dose/administered activity required • Differentiated Thyroid Cancer • Still a discussion on the appropriate administered activity for post surgical ablation (and ablation of occult metastases) • Requires a 30 year follow up to be certain of the success of any alternative approach to the original high activity ablation The encore is at 16.15! However

Figure 3. Increasing second primary malignancy (SPM) rates with time for all malignancies and leukemias are illustrated in patients with well differentiated thyroid cancer (WDTC). The horizontal line indicates a standardized incidence ratio (SIR) of 1.0; error bars indicate 95% confidence intervals.

N. Gopalakrishna Iyer et al Cancer October 1, 2011 4439 Is there a long term risk in not administering I 131 to patients with favourable prognosis? Iodine Or Not study

There may be no risk of radiation induced new primary malignancy? Can a recurrence be treated as successfully as ablation with an initial high activity? It requires a 30 year study to confirm the hypothesis The search for the magic bullet for disease especially cancer Is Iodine 131 the magic bullet?

I-131- So how low can we reduce the administered activity to minimise induction of second primary malignances? • Twenty-three patients received 3,000 MBq radioiodine following near-total thyroidectomy. • Maximum absorbed doses to thyroid remnants ranged from 7 to 570 Gy. • Eighteen of the 23 patients had a successful ablation. • A significant difference was seen between the absorbed doses delivered to thyroid remnants, blood, and red marrow for those patients that had a successful ablation compared to those with a failed ablation (p = 0.030, p = 0.043 and p = 0.048, respectively). • Questions • What dose should be aimed for? • How can this be achieved? • If we can deliver the optimum dose can we guarantee that all occult metastases have been ablated

Eur J Nucl Med Mol Imaging. 2010 Feb;37(2):270-5. doi: 10.1007/s00259-009-1261-3. Epub 2009 Sep 4. A dose-effect correlation for radioiodine ablation in differentiated thyroid cancer. Flux GD1, Haq M, Chittenden SJ, Buckley S, Hindorf C, Newbold K, Harmer CL. In patients followed for ≥2 years, SPMs were diagnosed in 9% of RAI-treated patients and 10.5% of non-RAI-treated patients. (Follow up 9 years) Annual incidence from bta 2008

• 5.1 per 100,000 female • 1.9 % per 100,000 male

• 10 year survivial 80-90% • 10-15% distant mets Conclusions

• Radioiodine therapy is the success story of Nuclear Medicine • Model for molecular radiotherapy

• Differentiated Thyroid Cancer therapy • 100+ mCi has given excellent outcomes • So far no risk to long term survival with the reduction of 100 mCi to 30 mCi (less residual tissue post surgery) • No definite proof of excess radiation induced second primary malignancy so why risk low dose • Even so should we reduce the ablation activity further? – requires a 30 year follow up – no quick publications – For treatment of Basedow disease: 40-80 Gy – For treatment of hyperfunction adenoma: 300-400 Gy – For treatment of non-immunogen, diffuse goitre: 150- 200 Gy 90% of I-131-sodium-iodide introduced into the body gets to the blood within an hour and 100% of it within 4 hours.

Iodine circulates within the blood as iodide (I-). It is actively transported into the follicular cells by an Na+/I- symport in the basal membrane. This pump concentrates iodine in the colloid at a level up to 250x greater than the plasma level. This process is known as iodide trapping All national and regional radiation protection rules regarding RAI treatment should be followed (104,105). In the , the treating physician must ensure and document that no adult member of the public is exposed to 0.5 mSv (500 milli-roentgen equivalent in man [mrem]) when the patient is discharged with a retained activity of 33 mCi (1.22 GBq) or greater, or emits ≥ 7 mrem/h (70 μSv/h) at 1 m. Thyroid Iodide Extraction

• Blood iodide is actively transported into the follicular cells by an Na+/I- symport in the basal membrane. This pump concentrates iodine in the colloid at a level up to 250x greater than the plasma level. • The thyroid gland iodine uptake depends upon the iodine level in the blood and the thyroid blood flow (30-100 ml/min) • In hyperthyroidism the blood flow is increased • Following injection, about 20 % of blood iodide is extracted in a single passage through the thyroid gland * • Differentiated thyroid cancer also extracts 131I but less efficiently

* SODIUM IODIDE (131I) 74MBq & 925MBq SOLUTION FOR INJECTION MHRA PL 00221/0113 Thyroid Blood Flow

• My blood volume = 4.7 litres

• Thyroid euthyroid blood flow is 31 ml/min > 109 ml/min

• Cardiac output = 5 litres per minute so about 0.6% of the C.O passes through the thyroid per minute

• 2.5 hours for my total blood volume to pass through the thyroid

• 20% extracted in a single passage

• 50% of maximum uptake is at 5 hours

• Peak at 25% – 24-48 hours

• Half life in the thyroid is 6 days - once there stays there Does reducing to 30 mCi the radioiodide ablation activity affect the outcome?

•RESULTS: • Median follow-up was 24 (range, 4-34) years. Low-dose RAI TRA was successful in 26 (49%) patients (successful ablation [SA] group), whereas 27 (51%) patients required further treatment (unsuccessful ablation [UA] group). Thirty-year disease-free survival was 92% in the SA group vs 87% in the UA group (P = .601). Thirty-year overall survival was 81% in the SA group vs 62% in the UA group (P = .154). Nine (17%) patients developed second malignancies (4 in the SA group and 5 in the UA group). Predictors of failure to achieve TRA with low-dose RAI were male sex and stage pT4 disease. 30 mCi ablation There is no evidence from long term follow up of our cohort that treatment outcomes are compromised for patients that fail TRA with low-activity and subsequently receive high activity 131I J Clin Endocrinol Metab. 2013 May;98(5):1819-25. doi: 10.1210/jc.2013-1197. Epub 2013 Mar 14. Long-term outcomes following low-dose radioiodide ablation for differentiated thyroid cancer. Welsh L1, Powell C, Pratt B, Harrington K, Nutting C, Harmer C, Newbold K. Multinodular Goitre RAI therapy

• The response is 50–60% by 3 months, and 80% by 6 months • Hypothyroidism was 3% at 1 year and 64% at 24 years (250). more common among patients under 50 years of age, • More recent study, the prevalence of hypothyroidism was 4% at 1 year and 16% at 5 years • At 1 year, the investigators noted a 7.6% prevalence, • 28% at 5 years, • 46% at 10 years, and • 60% at 20 years • Is this due to irradiation of the normal thyroid tissue? • So how might that be achieved?? • Answer = Ablate only the abnormal hyperfunctioning tissue Comments • Fixed activity gives a range of doses • It takes 18 months for the therapy to work • The optimum dose in this study is 80 Gy but some patients become euthyroid on 40 Gy • So what should the recommended dose be? • Does it vary from patient to patient? • If so why? • Does the 131I ablate a fraction of the cells in the thyroid? • Then how can that dose be achieved? Radiother Oncol. 1993 Jul;28(1):16-26. Radiation dose assessment in radioiodine therapy. Dose-response relationships in differentiated thyroid carcinoma using quantitative scanning and PET. O'Connell ME1, Flower MA, Hinton PJ, Harmer CL, McCready VR. Author information Abstract Dose-response charts have been constructed to determine the tumouricidal dose for differentiated thyroid carcinoma metastases and thus enable precise activities of radioiodine to be prescribed in order to maximise tumour kill and minimise morbidity. Tumour and normal residual thyroid absorbed doses from radioiodine-131 have been determined with increased precision using a dual-headed whole-body rectilinear scanner with special high-resolution low-sensitivity collimators. Improved accuracy in the estimation of functioning tumour mass has been achieved using positron emission tomography (PET) with a low-cost large area PET camera. Dose-response data have been obtained for 33 patients. Following near-total thyroidectomy and 3.0 GBq 131I, a mean absorbed dose of 410 Gy achieved complete ablation of thyroid remnants in 75% of patients. Patients who had persistent uptake in the thyroid region on subsequent radioiodine scanning had received a mean dose of only 83 Gy. Cumulative absorbed doses in excess of 100 Gy were found to eradicate cervical node metastases. Patients with bone metastases, who generally have a poor prognosis, were found to have received doses of the order of only 20 Gy to the tumour deposits. The dose-response data explain the spectrum of clinical responses to fixed activities of radioiodine. In future, they will enable precise prescription of radioiodine to achieve tumouricidal doses whilst avoiding the morbidity and expense of ineffective therapy. The success of RAI therapy in GD strongly depends on the administered activities. In patients without adjunctive ATD, randomized controlled trials found 61% success with 5.4 mCi (200 MBq) (92), Page 26 of 272 Thyroid 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis (doi: 10.1089/thy.2016.0229) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Thyroid 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis (doi: 10.1089/thy.2016.0229) This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. 69% with 8.2 mCi (302 MBq) (93), 74% with 10 mCi (370 MBq) (94), 81% with 15 mCi (555 MBq) (94) and 86% with 15.7 mCi (580 MBq) (95) RAI. Due to the high rate of patients requiring retreatment, RAI therapy with low activities is generally not recommended In either toxic or nontoxic multinodular goitre, radioiodine doses have been empirically established. Currently, an absorbed radiation dose of 100–150 Gy is recommended requiring about 3.7–5.5 MBq per gram of thyroid Majority of patients receiving 400–600 MBq.

Evidence shows that to achieve a hypothyroid state, >150 μCi/g (5.55 MBq/g) needs to be delivered (88-90). Alternately, a more detailed calculation can be made to deposit a specific radiation dose (in rad or Gy) to the thyroid. Using this approach, it is also necessary to know the effective half-life of RAI (88). This requires additional time and computation and, because the outcome has not shown to be better, this method is seldom used in the United States. Evidence shows that to achieve a hypothyroid state, >150 μCi/g (5.55 MBq/g) needs to be delivered (88-90). Patients who are on dialysis or who have jejunostomy or gastric feeding tubes require special care and management when being administered RAI treatment (91). ATA guideleines 2016

RECOMMENDATION 8 Sufficient activity of RAI should be administered in a single application, typically a mean dose of 10–15 mCi (370-555 MBq), to render the patient with Graves Disease hypothyroid. Strong recommendation, moderate-quality evidence. The goal of RAI therapy in GD is to control hyperthyroidism by rendering the patient hypothyroid; this treatment is very effective, provided sufficient radiation dose is deposited in the thyroid. This can be accomplished equally well by either administering a fixed activity or by calculating the activity based on the size of the thyroid and its ability to trap RAI (85). The first method is simple, while the second method requires two unknowns to be determined: the uptake of RAI and the size of the thyroid. The therapeutic RAI activity can then be calculated using these two factors and the quantity of radiation (μCi or Bq) to be deposited per gram (or cc) of thyroid (e.g., activity (μCi) = gland weight (g)×150-200 μCi/g×[1/24 hour uptake in % of administered activity]). The activity in μCi or Bq is converted to mCi or MBq by dividing the result by 1000. by which time about 8% of the orally administered activity is in the thyroid gland

Peak uptake 24 hours so 12 TBV through the thyroid

Orally 2 hours 5.5%+/-1.8% (range: 2.3-12.0) 24 hours 16.2+/-4.8% (range: 6.5-30.1)

Journal of Endocrinological Investigation July 1981, Volume 4, Issue 3, pp 335-341 First online: 04 April 2014 Thyroid blood flow rate in man. Electromagnetic flowmetry during operation in euthyroid normal gland, nontoxic goiter, and hyperthyroidism Lennart Tegler Direct injection of I 131- Unknowns

• Volume of injectate compared with volume of nodule (interstitial space) • What is the required absorbed dose • The speed of injection • The local uptake and retention compared with 20% extraction from the blood. First human studies of I - 131

• 1941 Hertz administered cyclotron produced I 130- I 131 as a therapeutic dose at MGH to a patients with Grave’s disease. • First successful treatment of humans with artificially produced radioactive • May 1946 series of 29 patients in Radioactive Iodine in the study of thyroid physiology,

Hertz S, Roberts A, Salter WT. Radioactive iodine as an indicator in thyroid physiology, IV: the metabolism of iodine in Graves’ disease. Journal of Clinical Investigation 1942;21:25-29. Dr Romsai Suwanik Dept Radiology Siriaj Hospital

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 Imaging the Thyroid

Radionuclide Half Life Principal Emission

• I 123 13 hours 160 kev • I 124 4 days 510 kev positron • I 131 8.04 days 364 kev beta • Tc 99m 6 hours 140kev Thyroid 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis (doi: 10.1089/thy.2016.0229) 30 mCi I 131 not scientific!

• All national and regional radiation protection rules regarding RAI treatment should be followed (104,105). In the United States, the treating physician must ensure and document that no adult member of the public is exposed to 0.5 mSv (500 milli-roentgen equivalent in man [mrem]) when the patient is discharged with a retained activity of 33 mCi (1.22 GBq) or greater, or emits ≥ 7 mrem/h (70 μSv/h) at 1 m. • 42 patients with thyroid nodules suspicious for papillary carcinoma or classified as malignant on cytology examination without suspicion of lymph node metastases by clinical and ultrasound examinations were recruited from a single public medical ins • Approximately 2 hours after lymphoscintigraphy, the patients were submitted to intraoperative rSLNB using a handheld gamma probe. All SLNs identified were removed alongside with non-SLNs from the same compartmentitution. Overall, T stage was as follows: T1, 23 patients (62.2%); T2, 8 patients (21.6%); and T3, 6 patients (16.2%) Thyroid Cancer

• Rare disease 3-10 per 100,000 p.a. • 6-10% in routine autopsies • Female:Males ratio 1.5:1 to 4:1 • Females 12 per 100,000 Iceland 1 per 100,000 U.K. • Mortality decreasing • Incidence increasing Thyroid Cancer - Aetiology

• Follicular in areas of endemic goitre • Papillary in areas without endemic goitre • Radiation in childhood (Papillary) • High TSH (in Animals) Belarus – Minsk Radiation in Childhood

Paediatric Thyroid Carcinoma

1987 4 1988 5 1989 29 1990 59 1992 66 1993 79 Marti Feldman • This is less than in most earlier reports.

• The relativeTBF was 1.2 (0.4–3.8) ml/min/g thyroid tissue in normal thyroid tissue • and 0.6 (0.1–3.7) ml/min/g in nontoxic nodular goiter (p<0.001). • Patients with hyperthyroidism had a higher total TBF 54 (15–197) ml/min (p<0.001), despite preoperative treatment giving euthyroidism. Survival Following Metastasis

100 90 So crucial to eliminate 80 metastases at the first 70 therapy % 60 50 40 Lung 30 20 10 Other 0 0 1 2 3 4 5 6 7 8 9 10 Years . 100 .. . Cell . . Diameters . . Cytoplasm

0.81 Mev beta (gamma) 153Sm 0.6 Mev beta 131I 1.07 MeV beta (gamma) 186Re

1.49 MeV beta 89Sr

0.001 0.01 0.1 1 10 100 Particle Range in mm in Tissue Oprah Winfrey

Daytime talk show diva Oprah Winfrey announced her thyroid problems in 2007. Before she was diagnosed with hypothyroidism, she struggled with weight gain and felt exhausted all the time. Image provided by SuperiorPics.com. Two negative feedback loops exist in the control of thyroid hormone secretion. (1) shows the loop between the TSH-producing cells of the anterior pituitary and the thyroid. (2) Increased levels of T4 and T3 in the blood cause a reduction Papillary Carcinoma

• 50% spread to cervical lymph nodes • Often multifocal • Initially 1% metastases • Later 4 - 25% metastases • 90% of radiation induced cancers are this histology WHO Classification Thyroid Tumours

Epithelial tumours Non-epithelial tumours Benign Follicular adenoma Malignant Lymphomas Miscellaneous tumours Others Secondary tumours Malignant Unclassified tumours Follicular Carcinoma Tumour - like lesions Medullary Carcinoma Undifferentiated Others Follicular Carcinoma

• Incidence 15 - 20% • Often in a long standing goitre • Rare under the age of 30 years • Metastases may not appear for years Presentation

With Total Thyroidectomy Without Total Thyroidectomy

Ablation Dose 3 GBq 131I Surgery

Abnormal Diagnostic Scan

3 month cycle Normal Diagnostic Scan

T3 Therapy Dose 5.5 GBq 131I T4

Abnormal Scan Normal Tg > 1 ng/ml Annual Follow Up T4 Ablation of Normal Thyroid

• To check for secondaries • Multifocal primary disease Thyroglobulin

• High Molecular weight glycoprotein • Sensitivity 80 - 85% (in the absence of Ab) • Antibodies may be present in up to 13%

• Should be less than 10 ng/ml on T4 • I -131 + Thyroglobulin = 95% sensitivity Discovery of I 131

• Iodine-131 (131I), was discovered by Glenn Seaborg and John Livingood in 1938 at the University of California, Berkeley Differentiated Thyroid Cancer Royal Marsden Hospital Series 1949 - 1991

• Most patients from the South East of England • 33% from Malta, Gibraltar, Turkey and Greece • Often surgery at referring institution • Often referred because of recurrence • Histology according to WHO • TNM as per UICC 1987 • Staging as per UICC 1987 Differentiated Thyroid Cancer Royal Marsden Hospital Series 1949 - 1991

Papillary Follicular Follicular 27% Hurthle Hurthle 3%

Papillary 70% TNM Classification

T N

T0 T1 T2 T3 T4 N1a N1b

1cm <4cm >4cm outside ipsilat. bilatl. capsule

M metastases Differentiated Thyroid Cancer Royal Marsden Hospital Series 1949 - 1991

Papillary 458 cases (70%) Follicular 177 cases (27%) Hurthle 14 cases (2%) Total 649 Age Distribution by Sex

120

Females

100 Males

80 . No patients 60

40

20

0 10 20 30 40 50 60 70 80 90 100 Age in years Survival - Sex

90 male female 80 70 60 50 40 30 20 10 0 5 10 15 20 25 30 Years Survival - Histology

100 90

80 70 Papillary 60 % 50 Follicular + 40 Hurthle 30 20

10 0 0 5 10 15 20 25 30 Years Survival - Histology

• Survival is better with Papillary Ca Histology • Progressive difference in survival from 2 years to 30 years Survival - Histology

• Papillary diagnosis offers improved survival from 2 years until 30 years • Papillary - 68% alive at 20 years • Follicular - 38% alive at 20 years Survival - Histological Grade

100 90 80 Moderately 70 differentiated 60 % 50 40 Well-differentiated 30 20 Poorly differentiated 10 0 0 5 10 15 20 25 30 Years Survival - Histological Grade

• Little difference in survival between moderately and well differentiated • Poor survival in patients with poorly differentiated histology - 24% at 10 years • After 10 years stable survival I 131 Treatment of Thyroid cancer

First patient at the Royal Cancer Hospital 1949. Survived to be a grandmother Survival - Age

100 90 < 40 80 70 60 40 - 49 % 50 40

30 50 - 59 20 60 - 69 10 0 0 5 10 15 20 25 30

Years % Survival - after presentation

% Surviving on reaching age 50 55 60 65 70 75 years

40 100% >95% >92% >92% >85%

45 98% 92% 72% 62% 58% 48%

55 88% 72% 72% 40%

65 65% 38% Survival - Staging ( < 45 yrs )

100 Stage I 90 80 70 60 Stage II % 50 40 30 20 10 0 0 5 10 15 20 25 30

Years Survival - Staging ( < 45 yrs )

Stage I Any size of tumour With/ without nodal spread No metastases

Stage II Any size of tumour With/without nodal spread Metastases present Survival - Staging ( > 45 yrs )

100 Stage I 90 80 70 % 60 50 40

30 Stage III 20 Stage IV 10 Stage II 0 0 5 10 15 20 25 30 Years Survival - Staging ( > 45 yrs )

Stage I Tumour 1 cm Stage II Tumour 1 -4 cm Stage III Tumour outside capsule Regional Nodal Spread Stage IV Any size tumour Any Nodal spread Metastases Survival - Nodal Status ( Papillary )

100 90 80 70 N 1a % 60 N 1b 50 40 N 0 30 20 10 0 0 5 10 15 20 25 30 Years Survival - Nodal Status ( Follicular)

100 90 % 80 70 60 50 40 30 N 1a 20 N 0 N 1 bilateral 10 0 0 5 10 15 20 25 30 Years Survival - Effect of Surgery

100 90

80 Total thyroidectomy 70 60 Near-total thyroidectomy % 50 Lobectomy or 40 hemithyroidectomy 30 20 Biopsy or 10 resection 0 0 5 10 15 20 25 30 Years Survival - Effect of Surgery

• Near total, lobectomy, are nearly equally effective until 15 years post presentation • Marked difference in survival at 30 years i.e. in the younger patients • Lumpectomy or biopsy only is followed by a dramatically reduced survival but this may be because the tumour was invasive and removal difficult Differentiated Thyroid Carcinoma - Stage

<45 years >45 years

Stage I TAny NAny M0 T1 N0 M0

Stage II TAny NAny M1 T2 N0 M0

T3 N0 M0

Stage III T4 N0 M0

Tany N1 M0

Stage IV Tany Nany M1 Histology and Grade

Histology Grade Number Papillary 1 369 2 59 3 30 Follicular 1 98 2 45 3 34 Hurthle 1 11 2 1 3 2 Total 649 Initial Surgical Treatment

Primary Tumour Neck Nodes

Tumour Cases Biopsy LE TL NT TT ND SNE

Papillary 458 37 39 199 82 99 87 91

Follicular 177 9 23 91 23 31 7 16

Hurthle 14 5 2 5

LE Lumpectomy TL Lobectomy NT Near Total TT Total ND Neck Dissection Metastases from Thyroid Cancer

Site Follicular Papillary

lymph node 28% 47% distant 14% 3% lung 20/47 4/10 bone 29/37 2/10 viscera 4/27 4/10

EORTC 1978 unpublished data Differentiated Thyroid Carcinoma Variable Hazard Ratio p-value Age <30 1.00 <0.001* 30-39 4.50 40-49 14.90 50-59 25.90 >60 34.06 Grade I,II 1.00 III 2.81 <0.01* Stage T0,T1,T2 1.00 <0.001* T3 1.78 T4 3.13 Metastases None 1.00 <0.001 Lung Only 3.41 Other 10.10 Differentiated Thyroid Carcinoma Univariate Analysis

Variable Hazard Ratio p-value Sex Male 1.00 p=0.01 Female 0.66

Histology Papillary 1.00 p<0.001 Follicular 2.07

Grade I 1.00 p<0.01 II 1.10 III 4.43

T Stage T1 1.00 p<0.001 T2 2.20 T3 3.37 T4 6.10 Derivation of Prognostic Index Based on Log Hazard Ratio Using Cox’s Regression

Age Grade T-Stage Distant Mets

<30 +0 I,II +0 T1,2 +0 None +0 30-39 +1.5 III +1 T3 +0.5 Lung +1 40-49 +2.5 T4 +0.1 Any +2 50-59 +3.5 >60 +4.0 Follow up Sensitivity

• Thyroglobulin 85% • Therapy Scan (5000MBq) 77% • Diagnostic Scan (200 MBq) 57% • Tl Scan (74 MBq) 55% • Sestamibi • Myoview Conclusions

• 30 year survival has been presented • Hazard ratios have been calculated • Useful in giving prognosis and determining treatment • Adverse factors include: • Increasing age • Increasing stage • Metastases Tumour Dose

• Uptake of the radioactivity • Mass (Volume) • Effective half life Thyroid Cancer

• Persistent disease 69 Gy • Complete ablation 384 Gy Thyroid Carcinoma Dosimetry

• Iodine 124 • Multiwire proportional chamber • Tomography gives volume • Measure uptake and half life