Recent advances in the diagnosis and treatment for benign and

malignant thyroid disease

Professor Steven Boyages

The University of Sydney

Westmead Hospital

May 2015

Nutrition Related DisordersNutrition Related Disorders

MicronutritionMicronutritionUndernutrition PCMUndernutrition PCM

Minerals and VitaminsMinerals and VitaminsFolic AcidFolic Acid

Vitamin D deficiencyVitamin D deficiencyVitamin A deficiencyVitamin A deficiency

Fe deficiencyFe deficiencySelenium deficiencySelenium deficiency

Iodine deficiencyIodine deficiency

MicronutritionMicronutritionUndernutrition PCMUndernutrition PCM

Minerals and VitaminsMinerals and VitaminsFolic AcidFolic Acid

Vitamin D deficiencyVitamin D deficiencyVitamin A deficiencyVitamin A deficiency

Fe deficiencyFe deficiencySelenium deficiencySelenium deficiency

Iodine deficiencyIodine deficiency

MacronutritionMacronutritionObesityObesity

HyperlipidemiaHyperlipidemiaInsulin ResistanceInsulin Resistance

DiabetesDiabetesAlcoholAlcohol

MacronutritionMacronutritionObesityObesity

HyperlipidemiaHyperlipidemiaInsulin ResistanceInsulin Resistance

DiabetesDiabetesAlcoholAlcohol

Iodine Deficiency DisordersIodine Deficiency DisordersSIGNIFICANCESIGNIFICANCE

One of the commonest nutritional disordersOne of the commonest nutritional disorders Over 1 billion people live in deficient Over 1 billion people live in deficient

environmentsenvironments Affects primarily the thyroid but secondarily may Affects primarily the thyroid but secondarily may

impact on brain developmentimpact on brain development Most preventable cause of mental Most preventable cause of mental disabilitydisability Not limited to developing countriesNot limited to developing countries Principles of food fortification to populationsPrinciples of food fortification to populations Structural basis of scientific thinking (Kuhn)Structural basis of scientific thinking (Kuhn)

Early recognition of goitre with Early recognition of goitre with impaired mental abilityimpaired mental ability

"Hence while travelling in a "Hence while travelling in a certain region in the County certain region in the County Tyrol, under the jurisdiction of Tyrol, under the jurisdiction of the Bishop of Gurk, I was the Bishop of Gurk, I was astonished at the very large astonished at the very large number of number of madmen, fools and madmen, fools and doltsdolts; but when I considered ; but when I considered the frigidity and the humidity the frigidity and the humidity of the air, and also perceived of the air, and also perceived the crudity of the waters from the crudity of the waters from the very frequent occurrence the very frequent occurrence of of goitregoitre... all astonishment ... all astonishment ceased entirely." ceased entirely."

EUSTACHIUS RUDIUS, A EUSTACHIUS RUDIUS, A PHYSICIAN FROM UTRECHTPHYSICIAN FROM UTRECHT

(1551-1611)(1551-1611)

Thyroid PhysiololgyThyroid Physiololgy

Thyroid Function TestsThyroid Function Tests

TSH, direct measure of thyroid TSH, direct measure of thyroid hormone actionhormone action– Different types of thyroid hormone Different types of thyroid hormone

receptorsreceptors Free T4, estimatesFree T4, estimates Free T3, estimatesFree T3, estimates

Iodine is essential for normal Iodine is essential for normal thyroid hormone synthesisthyroid hormone synthesis

Na Iodide TransporterNa Iodide Transporter

What is normal intake?What is normal intake?Too little and Too much can be Too little and Too much can be

a problema problem

Recommended intakesRecommended intakes

The American Thyroid Association has recently recommended that all women receive 150 µg iodine supplements above their dietary intake during pregnancy and lactation, and that the iodine content in all prenatal vitamins should be standardized at 150 µg

The American Thyroid Association has recently recommended that all women receive 150 µg iodine supplements above their dietary intake during pregnancy and lactation, and that the iodine content in all prenatal vitamins should be standardized at 150 µg

Sources of iodineSources of iodine

SaltSalt MilkMilk BreadBread Other foods, eg kelp, seaweed, laverOther foods, eg kelp, seaweed, laver MedicationsMedications

Sources of iodineSources of iodine Dietary iodine Daily intake (µg)Dietary iodine Daily intake (µg) Dairy products Dairy products 5252 GrainsGrains 7878 Meat Meat 3131 Mixed dishes Mixed dishes 2626 Vegetables Vegetables 2020 Desserts Desserts 2020 Eggs Eggs 1010 Iodized salt Iodized salt 380380 Other iodine sourcesOther iodine sources(µg)(µg) Vitamin/mineral prep (per tablet) Vitamin/mineral prep (per tablet) 150150 Amiodarone (per tablet) Amiodarone (per tablet) 75,00075,000 Povidone iodine (per mL) Povidone iodine (per mL) 10,00010,000 Ipodate (per capsule) Ipodate (per capsule) 308,000308,000

Endemic GoitreEndemic Goitre

Change in incidence rates of cancer 1991-2009

Top 10 cancers and Top 10 cancer deaths

Trends in incidence (1982-2009) and death rates (1968-2007)

Mortality and incidence ratio

Thyroid-Cancer Incidence and Related Mortality in South Korea, 1993–2011.

Ahn HS et al. N Engl J Med 2014;371:1765-1767.

Penetration of Thyroid-Cancer Screening (2008–2009) and Incidence of Thyroid Cancer (2009) in the 16 Administrative Regions of South Korea.

Ahn HS et al. N Engl J Med 2014;371:1765-1767.

Rising incidence of thyroid cancer

Over the past few decades an increase in the incidence of thyroid cancer has been recorded in many countries around the world, and has been particularly marked in the Australian state of New South Wales (NSW).

The reasons for this increase remain unclear, but heightened medical surveillance and increased technological sensitivity could be contributing to greater detection of asymptomatic disease.

Objective

To describe the pathways to diagnosis of thyroid cancer for a cohort of newly diagnosed patients in NSW and compare these pathways in groups of people defined by age, gender, place of residence, ethnic background and medical insurance status.

Pathways to the diagnosis of thyroid cancer in New South Wales: a population-based cross-sectional study.Kahn C, Simonella L, Sywak M, Boyages S, Ung O, O'Connell D.Cancer Causes Control. 2012 Jan; 23(1):35-44. Epub 2011 Oct 15

Methods

Newly diagnosed cases of thyroid cancer (n=452) were identified and recruited through the population-based NSW Central Cancer Registry.

Participants completed a questionnaire and diary of doctor visits and investigations that led to their diagnosis.

Tumour characteristics were obtained from pathology reports.

Pathways to cancer paperrecruitment

Results

60% of patients had their cancer discovered serendipitously, while 40% initially presented to their doctor with a lump or symptom specific to thyroid cancer.

The pathways to diagnosis varied significantly with tumour size (p=0.001) and also by age in men and place of residence in women (p=0.008 and p=0.05 respectively).

 

 

 

Pathways of detection for thyroid cancer NSW

  Men n=108 Women n=344 Total n=452 Weighted

Pathway n % n % n % %*

Patient detected 39 36.1 140 40.7 179 39.6 38.8

Doctor detected 23 21.3 49 14.2 72 15.9 16.4

Imaging 22 20.4 28 8.1 50 11.1 10.9

After benign disease 14 13 104 30.2 118 26.1 26.2

Other 10 9.3 23 6.7 33 7.3 7.6

Table 3: Pathways to the diagnosis of thyroid cancer in men and women in NSW, Australia* Weighted to population distribution by place of residence

Factors associated with pathways to diagnosis

The pathways to diagnosis varied significantly by age group (p=0.009), sex (p<0.001), tumour size (p<0.001), spread of cancer at diagnosis (p=0.006), treatment for another disease at time of diagnosis (p=0.02), and current work status (p=0.001).

Variables that were not statistically significantly associated with the pathways to diagnosis included health insurance status, education level, smoking, alcohol consumption, number of other illnesses, previous cancer, family history of thyroid cancer, time from last pregnancy for women, and cancer type.

Multi-regression model

After adjusting for all factors in the model the only factor that differed significantly across the pathway groups was tumour size (p=0.001).

The odds of a patient with a large tumour (>3cm) being initially detected by a doctor (vs patient detected) were 66% (OR=0.34, 95% CI 0.1, 0.9) lower than a patient with a small tumour (<1cm).

Patients with large tumours also had 60% (OR=0.4, 95% CI 0.2, 0.9) lower odds of being detected after treatment for benign thyroid disease (vs patient detected) than patients with a tumour less than 1cm.

Patients with tumours between 2 and 3 cm had 6.85 greater odds (95% CI 2.3, 20.7) of being diagnosed as an incidental finding of imaging (vs patient detected) than patients with a tumour less than 1cm.

Conclusion

As the majority of participants had serendipitous diagnoses, the reported incidence of thyroid cancer is likely to be influenced by diagnostic technology and medical surveillance practices.

Thyroid-Cancer Incidence and Related Mortality in South Korea, 1993–2011.

Ahn HS et al. N Engl J Med 2014;371:1765-1767.

Penetration of Thyroid-Cancer Screening (2008–2009) and Incidence of Thyroid Cancer (2009) in the 16 Administrative Regions of South Korea.

Ahn HS et al. N Engl J Med 2014;371:1765-1767.

Dilemma

Nodular thyroid disease is common and the incidence of thyroid cancer is rising

Increasing cost of over-investigation leading to the potential for unnecessary surgery and unnecessary aggressive treatment for thyroid cancer

Implications for Diagnosis; Surgery; and radioactive iodine therapy

Thyroid cancer models

Original Article Preoperative Diagnosis of Benign Thyroid

Nodules with Indeterminate Cytology

Erik K. Alexander, M.D., Giulia C. Kennedy, Ph.D., Zubair W. Baloch, M.D., Ph.D., Edmund S. Cibas, M.D., Darya Chudova, Ph.D., James Diggans, Ph.D., Lyssa

Friedman, R.N., M.P.A., Richard T. Kloos, M.D., Virginia A. LiVolsi, M.D., Susan J. Mandel, M.D., M.P.H., Stephen S. Raab, M.D., Juan Rosai, M.D., David L. Steward, M.D., P. Sean Walsh, M.P.H., Jonathan I. Wilde, Ph.D., Martha A.

Zeiger, M.D., Richard B. Lanman, M.D., and Bryan R. Haugen, M.D.

N Engl J MedVolume 367(8):705-715

August 23, 2012

Study Overview

• A significant fraction of fine-needle aspirates obtained from thyroid nodules are read as indeterminate.

• A new molecular test accurately predicts whether a cytologically indeterminate nodule is benign 93% of the time, permitting a conservative approach to management.

The Afirma Thyroid FNA Analysis Process

Results

Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59).

The negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance,” “follicular neoplasm or lesion suspicious for follicular neoplasm,” or “suspicious cytologic findings” were 95%, 94%, and 85%, respectively.

Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule.

Algorithm for Evaluating Thyroid Nodules.

Jameson JL. N Engl J Med 2012;367:765-767.

Conclusions

• These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results.

Types of thyroid surgery

Type of surgery

Should Prophylactic Central (Level 6) Lymph Node Dissections be Performed?

There is agreement that therapeutic central and lateral lymph node dissections should be performed at the time of total thyroidectomy when lymph nodes are suspicious or proved to harbor cancer by sonographic appearance or by FNA analyses preoperatively or when suspicious lymph nodes are found at operation. Prophylactic lateral lymph node dissections were common in the past, but have been abandoned for several decades or longer.

Recently, Delbridge and his group and others have proposed that unilateral or bilateral prophylactic central lymph node dissections (level 6 dissections) with parathyroid autotransplantation be performed in all cases of papillary thyroid cancer at the time of total thyroidectomy. This, they state, might decrease mortality from thyroid cancer, would greatly decrease recurrence of cancer, and would further clarify who needs radioiodine therapy postoperatively. Some studies by very experienced surgeons demonstrate no increase in hypoparathyroidism or recurrent laryngeal nerve injuries after this procedure, while other equally competent surgeons have found an increase in permanent hypoparathyroidism.

We and others do not routinely perform this procedure because of the increased risk of hypoparathyroidism, but reserve it for cases in which ipsilateral central lymph nodes are clearly involved with tumor. 27d

Minimally invasive thyroidectomy

• No visible neck scar

Axillae, Chest

• Smaller scar

Video assisted endoscopic approach

• Robotic transaxillary thyroidectomy

Original Article Strategies of Radioiodine Ablation in Patients with

Low-Risk Thyroid Cancer

Martin Schlumberger, M.D., Bogdan Catargi, M.D., Ph.D., Isabelle Borget, Pharm.D., Ph.D., Désirée Deandreis, M.D., Slimane Zerdoud, M.D., Boumédiène Bridji, M.D.,

Ph.D., Stéphane Bardet, M.D., Laurence Leenhardt, M.D., Ph.D., Delphine Bastie, M.D., Claire Schvartz, M.D., Pierre Vera, M.D., Ph.D., Olivier Morel, M.D.,

Danielle Benisvy, M.D., Claire Bournaud, M.D., Françoise Bonichon, M.D., Catherine Dejax, M.D., Marie-Elisabeth Toubert, M.D., Sophie Leboulleux, M.D., Marcel

Ricard, Ph.D., Ellen Benhamou, M.D., for the Tumeurs de la Thyroïde Refractaires Network for the Essai Stimulation Ablation Equivalence Trial

N Engl J MedVolume 366(18):1663-1673

May 3, 2012

Study Overview

• This trial compared two thyrotropin-stimulation methods and two 131I doses for postoperative ablation in patients with low-risk thyroid cancer.

• Rates of ablation were similar in all treatment groups.

• Doses lower than those currently recommended may be adequate for this condition.

Randomization and Follow-up of the Study Patients.

Schlumberger M et al. N Engl J Med 2012;366:1663-1673

Initial Characteristics of the 752 Randomized Patients, According to Thyrotropin-Stimulation Method and 131I Dose.

Schlumberger M et al. N Engl J Med 2012;366:1663-1673

Follow-up Testing of Thyroid Ablation 6–10 Months after 131I Administration in the 684 Patients Who Could Be Evaluated, According to Thyrotropin-Stimulation Method and 131I Dose.

Schlumberger M et al. N Engl J Med 2012;366:1663-1673

Adverse Events, According to Thyrotropin-Stimulation Method and 131I Dose.

Schlumberger M et al. N Engl J Med 2012;366:1663-1673

Conclusions

• The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer.

Original Article Ablation with Low-Dose Radioiodine and

Thyrotropin Alfa in Thyroid Cancer

Ujjal Mallick, F.R.C.R., Clive Harmer, F.R.C.P., Beng Yap, F.R.C.P., Jonathan Wadsley, F.R.C.R., Susan Clarke, F.R.C.P., Laura Moss, F.R.C.P., Alice Nicol, Ph.D., Penelope M. Clark, F.R.C.Path., Kate Farnell, R.C.N., Ralph

McCready, D.Sc., James Smellie, M.D., Jayne A. Franklyn, F.Med.Sci., Rhys John, F.R.C.Path., Christopher M. Nutting, M.D., Kate Newbold, F.R.C.R., Catherine Lemon, F.R.C.R., Georgina Gerrard, F.R.C.R., Abdel Abdel-Hamid, F.R.C.R., John

Hardman, F.R.C.R., Elena Macias, M.D., Tom Roques, F.R.C.R., Stephen Whitaker, M.D., Rengarajan Vijayan, F.R.C.R., Pablo Alvarez, M.Sc., Sandy

Beare, Ph.D., Sharon Forsyth, B.Sc., Latha Kadalayil, Ph.D., and Allan Hackshaw, M.Sc.

N Engl J MedVolume 366(18):1674-1685

May 3, 2012

Study Overview

• In this trial, low-dose radioiodine was as effective as high-dose radioiodine in patients with differentiated thyroid tumors, and recombinant human thyrotropin (thyrotropin alfa) was as effective as thyroid hormone withdrawal.

Days of Hospital Isolation, According to Radioiodine Dose.

Mallick U et al. N Engl J Med 2012;366:1674-1685

Baseline Characteristics of the Patients.

Mallick U et al. N Engl J Med 2012;366:1674-1685

Symptoms Reported by Patients during the 4 Weeks before Ablation.

Mallick U et al. N Engl J Med 2012;366:1674-1685

Conclusions

• Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events.

RAI resistance

The cure rates for DTC are generally high when patients are treated with surgery or RAI. However, between 5% and 15% of patients develop RAI resistance, and these patients typically have an expected survival of 2.5 to 3.5 years.

No standard therapy exists for patients who experience disease progression.

New agents that either induce sodium iodide symporter activity or that inhibit tyrosine kinase inhibitor

o Sorafenibo Selumetinib

Inhibitors of kinase signalling pathways in tumour cells and vascular

endothelial cells

Sorefenib

Sorafenib, a tyrosine kinase inhibitor, inhibits multiple kinases, including the Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET, which are associated with tumor cell proliferation and angiogenesis.

The drug is currently approved by the FDA to treat unresectable hepatocellular carcinoma and advanced renal cell carcinoma.

Original Article Selumetinib-Enhanced Radioiodine Uptake in

Advanced Thyroid Cancer

Alan L. Ho, M.D., Ph.D., Ravinder K. Grewal, M.D., Rebecca Leboeuf, M.D., Eric J. Sherman, M.D., David G. Pfister, M.D., Desiree Deandreis, M.D., Keith S. Pentlow,

M.Sc., Pat B. Zanzonico, Ph.D., Sofia Haque, M.D., Somali Gavane, M.D., Ronald A. Ghossein, M.D., Julio C. Ricarte-Filho, Ph.D., José M. Domínguez, M.D., Ronglai Shen, Ph.D., R. Michael Tuttle, M.D., Steve M. Larson, M.D., and James A. Fagin,

M.D.

N Engl J MedVolume 368(7):623-632

February 14, 2013

Inhibitors of kinase signalling pathways in tumour cells and vascular

endothelial cells

Study Overview

• Inhibition of mitogen-activated protein kinase resulted in an increase in expression of the sodium–iodide symporter in 12 of 20 patients, 8 of whom had sufficient uptake to warrant treatment with radioiodine.

• Five patients had a response, and 3 had stable disease.

Protocol Design and Changes in Iodine Uptake.

Ho AL et al. N Engl J Med 2013;368:623-632

Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses.

Ho AL et al. N Engl J Med 2013;368:623-632

Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine.

Ho AL et al. N Engl J Med 2013;368:623-632

Conclusions

• Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.

Original Article Lenvatinib versus Placebo in Radioiodine-

Refractory Thyroid Cancer

Martin Schlumberger, M.D., Makoto Tahara, M.D., Ph.D., Lori J. Wirth, M.D., Bruce Robinson, M.D., Marcia S. Brose, M.D., Ph.D., Rossella Elisei, M.D., Mouhammed Amir Habra, M.D., Kate Newbold, M.D., Manisha H. Shah, M.D., Ana O. Hoff, M.D., Andrew G. Gianoukakis, M.D., Naomi Kiyota, M.D., Ph.D., Matthew H. Taylor, M.D.,

Sung-Bae Kim, M.D., Ph.D., Monika K. Krzyzanowska, M.D., M.P.H., Corina E. Dutcus, M.D., Begoña de las Heras, M.D., Junming Zhu, Ph.D., and Steven I.

Sherman, M.D.

N Engl J MedVolume 372(7):621-630

February 12, 2015

Study Overview

• In a phase 3, placebo-controlled study, lenvatinib was associated with a significant increase in progression-free survival (18.3 months vs. 3.6 months).

• Toxic effects with lenvatinib were substantial and included hypertension, diarrhea, and unexplained death.

Enrollment, Randomization, and Treatment.

Schlumberger M et al. N Engl J Med 2015;372:621-630

Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population.

Schlumberger M et al. N Engl J Med 2015;372:621-630

Baseline Characteristics in the Intention-to-Treat Population.

Schlumberger M et al. N Engl J Med 2015;372:621-630

Efficacy Measures.

Schlumberger M et al. N Engl J Med 2015;372:621-630

Adverse Effects.

Schlumberger M et al. N Engl J Med 2015;372:621-630

Conclusions

• Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131–refractory thyroid cancer.

• Patients who received lenvatinib had more adverse effects.

Inhibitors of kinase signalling pathways in tumour cells and vascular

endothelial cells