This presentation summarises new information on the diagnosis and treatment of thyroid cancer

1. Recent advances in the diagnosis
and treatment for thyroid cancer
Professor Steven Boyages
The University of Sydney
Westmead Hospital

3. Change in incidence rates of
cancer 1991-2009

4. Top 10 cancers and Top 10 cancer
deaths

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

6. Mortality and incidence ratio

7. 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.

8. 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

9. 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.

10. Pathways to cancer paper
recruitment

11. 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).

12. Pathways of detection for thyroid
cancer NSW
Pathway
Patient
detected
Doctor
detected
Men n=108
Women n=344
Total n=452
Weighted
n
%
n
%
n
%
%*
39
36.1
140
40.7
179
39.6
38.8
23
21.3
49
14.2
72
15.9
16.4
Imaging
After benign
disease
22
20.4
28
8.1
50
11.1
10.9
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

13. 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.

14. 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.

15. 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.

16. 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

18. 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 Med
Volume 367(8):705-715
August 23, 2012

19. 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.

20. The Afirma Thyroid FNA Analysis
Process

21. 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.

22. Algorithm for Evaluating Thyroid Nodules.
Jameson JL. N Engl J Med 2012;367:765-767.

23. 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.

24. Types of thyroid surgery

25. Type of surgery

27. 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

28. Minimally invasive thyroidectomy
• No visible neck scar
Axillae, Chest
• Smaller scar
Video assisted endoscopic approach
• Robotic transaxillary thyroidectomy

29. 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 Med
Volume 366(18):1663-1673
May 3, 2012

30. 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.

31. Randomization and Follow-up of the Study Patients.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

32. 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

33. 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

34. Adverse Events, According to Thyrotropin-Stimulation Method and 131I Dose.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

35. 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.

36. 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 Med
Volume 366(18):1674-1685
May 3, 2012

37. 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.

38. Days of Hospital Isolation, According to Radioiodine Dose.
Mallick U et al. N Engl J Med 2012;366:1674-1685

39. Baseline Characteristics of the Patients.
Mallick U et al. N Engl J Med 2012;366:16741685

40. Symptoms Reported by Patients during the 4 Weeks before Ablation.
Mallick U et al. N Engl J Med 2012;366:1674-1685

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

42. 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 Sorafenib
o Selumetinib

44. 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.

45. 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 Med
Volume 368(7):623-632
February 14, 2013

46. 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.

47. Protocol Design and Changes in Iodine Uptake.
Ho AL et al. N Engl J Med 2013;368:623-632

48. 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

49. 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

50. 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.