1. Update in Thyroid Cancer Management
Paul W. Ladenson, MD
Lebanese Society of Endocrinology, Diabetes & Lipids
Beirut
June 30, 2017 3

2. Thyroid Cancer New Dimensions in Management
Ultrasonography and molecular testing in differential diagnosis of cytologically indeterminate nodules
Thyroid nodules
Refinements in the uses of radioiodine and intense TSH suppressive therapies
Benign lesions
Thyroid cancers
Tumor genotyping to guide thyroid cancer treatment and monitoring
Thyroidectomy + 131I
Recombinant TSH to avoid morbidity of hypothyroidism in treatment and monitoring
T4 Therapy &
Monitoring
New tyrosine kinase inhibitors to stabilize disease and restore iodine-avidity in patients with non-iodine avid metastases
Cure / Remission
Recurrence & Retreatment 3

3. Treatment Decisions to be Made
Thyroid Cancer Management
Treatment Decisions to be Made
Whether to perform lobectomy or bilateral thyroidectomy (or completion when lobectomy initially done)
Whether to perform central neck dissection with initial thyroidectomy
Whether to give postoperative 131I to ablate remnant thyroid tissue
How intensively to suppress serum TSH 3

4. Monitoring Decisions to be Made
Thyroid Cancer Management
Monitoring Decisions to be Made
Whether to perform TSH-stimulated serum thyroglobulin +/- RAI scanning, and how often
Whether to use cervical sonography
Whether to biopsy sonographically indeterminate lymph nodes 3

5. Modulating Therapy & Monitoring with
Classic Risk Factors for Recurrence & Death
Older age (>45 years)
Larger tumor (>2-4 cm)
Extrathyroidal invasion
Cervical node metastases, esp. if extensive
Distant (extracervical) metastases
Aggressive histological subtypes
Tall & columnar cell & insular PTC variants
Angioinvasive FTC 3

6. Disease-Free Survival
Performance of Classical Staging Risk Factors
National Thyroid Cancer Registry Study
Overall Survival
Disease-Free Survival
Among the 4941 DTC patients in the overall cohort, 88% had PTC, 8% had FTC, and 4% had HCC. Median follow-up duration was 6 years (range, 0–25 y) with a total of person-years of documented follow-up. Only 94 patients, 1.9% of the cohort, lacked any follow-up information. The overall cohort characteristics are summarized in Table 1. The median follow-up time in years (range) by stage was as follows: stage I, 6.6 (0–25.0); stage II, 6.0 (0–24.3); stage III, 6.5 (0–23.0); and stage IV, 4.2 (0.1–24.0). Among the 3649 patients considered disease-free after initial therapy, 933 (26%) were diagnosed with structural recurrent disease occurring a median of 1.2 years (range, 0.2–21) after diagnosis, either detected by imaging or confirmed by pathology report. Local or regional recurrence accounted for 74% of recurrences (60% regional, 14% local), and distant metastases accounted for 11% of recurrences. In 16% of patients reported to have recurrence, the site was not specified. Five-year OS after recurrence was 91% for either local or regional recurrent disease, as compared with 81% after recurrence as distant metastases.
4,941 patients (88% PTC, 8% FTC, 4% HCC) acquired
Median follow-up 6 years (range, 0–25 y; overall 34,631 person-yrs)
26% had structural recurrence among 3,649 initially disease-free
Carhill, et al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis J Clin Endocrinol Metab. 2015;100: 3

7. Enhanced Risk Factors for Recurrence
Modulating Therapy & Monitoring
Enhanced Risk Factors for Recurrence
Older age (>45 years)
Larger tumor (>2-4 cm)
Extrathyroidal invasion
Cervical node metastases, esp. if extensive
Distant (extracervical) metastases
Aggressive histological subtypes
Tumor gene mutations 3

8. Association with Lymph Node Metastasis
BRAF mutation in PTC
Association with Lymph Node Metastasis
Study
Nikiforova et al, 2003
Namba et al, 2003
Xu et al, 2003
Puxeddu et al, 2004
Fugazzola et al, 2004
Kim et al, 2004
Sedliarou et al, 2004
Xing et al, 2005
Trovisco et al, 2005
Kim et al, 2005a
Kim et al, 2005b
Liu et al, 2005
Adeniran et al, 2006
Riesco-Eizaguirre et al, 2006
Kim et al, 2006a
Kim et al, 2006b
Lee et al, 2006
Jin et al, 2006
Park et al, 2006
Jo et al, 2006
Sapio et al, 2006
Abrosimo et al, 2007
Mitsiades et al, 2007
Durante et al, 2007
Lupi et al, 2007
Rodolico et al, 2007
Kebebew et al, 2007
Wang et al, 2007
All Studies 2 4 6 8 10 12 14 16 18 20
Odds Ratio

9. Association with Extra-thyroidal Invasion*
BRAF mutation in PTC
Association with Extra-thyroidal Invasion*
Study
Nikiforova et al, 2003
Namba et al, 2003
Xu et al, 2003
Puxeddu et al, 2004
Fugazzola et al, 2004
Kim et al, 2004
Sedliarou et al, 2004
Xing et al, 2005
Trovisco et al, 2005
Kim et al, 2005a
Kim et al, 2005b
Liu et al, 2005
Adeniran et al, 2006
Riesco-Eizaguirre et al, 2006
Kim et al, 2006a
Kim et al, 2006b
Lee et al, 2006
Jin et al, 2006
Park et al, 2006
Jo et al, 2006
Sapio et al, 2006
Abrosimo et al, 2007
Mitsiades et al, 2007
Durante et al, 2007
Lupi et al, 2007
Rodolico et al, 2007
Kebebew et al, 2007
Wang et al, 2007
All Studies 2 4 6 8 10 12 14 16 18 20 22
Odds Ratio

10. Xing, et al. J Clin Endocrinol Metab 2005;90:6373-9.
BRAF Mutation in Papillary Thyroid Cancer
Predicting Recurrence
1.0
0.8
BRAF-
0.6
Recurrence-Free Probability
BRAF+
p = 0.04
0.4
In stage I or II patients, BRAF mutation was associated with higher recurrence risk (OR 11.6; 95% CI, 2.2–62.6; p=0.004).
Figure 2. Kaplan-Meier estimate of cancer recurrence-free probability in BRAF mutation-positive and –negative PTC. Short vertical lines indicate censored observations (months of follow-up for those that have not had a recurrence). (Log-rank test; chi-square = 4.0, p=0.04)
0.2
0.0 12 24 36 48 60 72 84 96
108
120
Months
Xing, et al. J Clin Endocrinol Metab 2005;90:

11. Xing, et al. J Clin Oncol. 2014;32:2718-26
Telomerase Reverse Transcriptase Mutation
Predicting PTC Recurrence
This retrospective multicenter study investigated the relationship of BRAFV600E mutation with PTC-related mortality and the impact from conventional clinicopathological risk factors in 1,849 PTC patients from 13 centers in 7 countries.
Xing, et al. J Clin Oncol. 2014;32:

12. Xing, et al. J Clin Oncol. 2014;32:2718-26
BRAF & TERT Mutation in Papillary Thyroid Cancer
Predicting Recurrence
screened 17 benign thyroid adenomas and 265 TC samples
from patients in the Middle East for these mutations by PCR and direct sequencing using DNA
isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored
TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations,
including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC,
9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular
TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265
(2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two
mutations were mutually exclusive. TERT promoter mutations were significantly more
common in older (R45 years) than younger patients and were associated with larger tumour
size, vascular invasion, higher TNM stage (stage III and IV), BRAFV600E mutation and
persistent/recurrent disease at 6–12 months after initial treatment and at the last follow up.
These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients
from Middle East demonstrates that TERT promoter mutations are relatively common,
especially in the non-CPTC, and are associated with more aggressive histopathological
Xing, et al. J Clin Oncol. 2014;32:

13. Postulated Use in Guiding Management
Mutational Analyses in Papillary Thyroid Cancer
Postulated Use in Guiding Management
Issue
BRAF+/TERT+
BRAF-/TERT-
Completion thyroidectomy
Yes No
Central neck dissection
Postop. 131-I
Target TSH <0.1 mU/L
TSH-stimulated Tg monitoring

14. Benefits of Postoperative 131-I Therapy
National Thyroid Cancer Registry Study
In stage IV patients, 131-I therapy was associated with improved overall survival.
In stage III patients, 131-I therapy after total/near-total thyroidectomy was associated with improved overall survival.
Carhill, et al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis J Clin Endocrinol Metab. 2015;100: 3

15. Benefits of Postoperative 131-I Therapy
National Thyroid Cancer Registry Study
In stage IV patients, 131-I therapy was associated with improved overall survival.
In stage III patients, 131-I therapy after total/near-total thyroidectomy was associated with improved overall survival.
In stage II patients, 131-I was not associated with reduced disease-free or overall survival.
In stage 1 patients, more extensive surgery and 131-I was paradoxically associated with worse disease-free survival -- probably because they facilitated Tg detection of more minimal residual cervical disease.
Carhill, et al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis J Clin Endocrinol Metab. 2015;100: 3

16. 131-I Use Recommended by 2015 ATA Guideline
ATA Risk Category
Characteristics
131-I Recommendation
Low
Intrathyroidal DTC with no extrathyroidal extension, vascular invasion, or metastases
Not routinely recommended
(Weak recommendation, Low-quality evidence)
Intermediate
Microscopic extrathyroidal extension, cervical node metastases, RAI-avid neck disease outside thyroid bed, vascular invasion, or aggressive histology
Should be considered
High
Gross extrathyroidal extension, incomplete tumor resection, distant metastases, or inappropriate postoperative serum thyroglobulin
Routinely recommended
(Strong recommendation, moderate-quality evidence)
2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133. 3

17. TSH Suppressive Thyroid Hormone Therapy
( - ) 3

18. Benefits of TSH Suppression
National Thyroid Cancer Registry Study
Stage 3 Patients
Stage 4 Patients
overall survival improved significantly when the TSH was suppressed to
Undetectable levels in patients with NTCTCSG stage III or IV disease
In patients with stage III or IV disease, overall survival improved significantly when TSH was suppressed to undetectable levels.
Carhill, et al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis J Clin Endocrinol Metab. 2015;100: 3

19. Benefits of TSH Suppression
National Thyroid Cancer Registry Study
Stage 1 Patients
Stage 2 Patients
In stage II patients disease, overall survival improved when TSH was suppressed to the subnormal to undetectable range, but there was no incremental benefit of suppressing TSH to undetectable.
In stage 1 patients, TSH suppression no degree of TSH suppression proved to be beneficial. 3

20. TSH Suppression Recommended by 2015 ATA Guideline
ATA Risk Category
Characteristics
TSH Suppression Recommendation
Low
Intrathyroidal DTC with no extrathyroidal extension, vascular invasion, or metastases
TSH may be maintained at the lower end of the ref. range (0.5–2.0 mU/L).
(Weak recommendation, Low-quality evidence)
Intermediate
Microscopic extrathyroidal extension, cervical node metastases, RAI-avid neck disease outside thyroid bed, vascular invasion, or aggressive histology
TSH suppression to 0.1–0.5 mU/L is recommended.
High
Gross extrathyroidal extension, incomplete tumor resection, distant metastases, or inappropriate postoperative serum thyroglobulin
TSH suppression to <0.1 mU/L is recommended.
(Strong recommendation, moderate-quality evidence)
 (C) For low-risk patients who have undergone remnant ablation
and have undetectable serum Tg levels, TSH may be
maintained at the lower end of the reference range (0.5–
2mU/L) while continuing surveillance for recurrence. Similar
recommendations hold for low-risk patients who have
not undergone remnant ablation and have undetectable serum
Tg levels.
(Weak recommendation, Low-quality evidence)
 (D) For low-risk patients who have undergone remnant
ablation and have low-level serum Tg levels, TSH may be
maintained at or slightly below the lower limit of normal
(0.1–0.5 mU/L) while surveillance for recurrence is continued.
Similar recommendations hold for low-risk patients
who have not undergone remnant ablation, although
serum Tg levels may be measurably higher and continued
surveillance for recurrence applies.
 (E) For low-risk patients who have undergone lobectomy,
TSH may be maintained in the mid to lower reference
range (0.5–2 mU/L) while surveillance for recurrence is
continued. Thyroid hormone therapy may not be needed if
patients can maintain their serum TSH in this target range.
2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133. 3

21. Postoperative Thyroid Remnant Ablation and Monitoring Options
Limitations
Hypothyroidism
Tumor growth
Lack of TSH rise 3

22. Quality of Life Impact rTSH versus Withdrawal
*p<0.05, **p<0.02, ***p<0.0001
N.S. *
***
*** ** *
SF-36 Scores vs. Postoperatively
difference in the mean change scores Week 4 SF-36 scores for the between the two treatmentHypothyroid groups were statistically significantly reduced from the time of screening (Baseline) for the following quality of life domains: [CHS1]Physical Functioning, Role Physical, Vitality, Social Functioning, and Mental Health. No statistically significant differences were found for Bodily Pain and General Health.  [CHS1]MCS is also statistically significant 3

23. Schlumberger M, et al. New Engl J Med 2012;366:1663
Radioiodine Therapy in Low-Risk Thyroid Cancer Efficacy of TSH Stimulation Methods & 131-I Doses
Schlumberger M, et al. New Engl J Med 2012;366:1663

24. Thyroid Cancer Approach to Diagnosis & Management
Thyroid nodules
Benign lesions
Thyroid cancers
Thyroidectomy + 131I
Managing the patient with non-iodine avid metastases
T4 Therapy &
Monitoring
Cure / Remission
Recurrence & Retreatment 3

25. Schlumberger M et al. N Engl J Med 2015;372:621-630.
Chemotherapy for Differentiated Thyroid Cancer Lenvatinib Phase III Trial: Prog.-Free Survival
Schlumberger M et al. N Engl J Med 2015;372:

26. Brose M et al. J Clin Oncol 2019 (June 14);71:6472.
Chemotherapy for Differentiated Thyroid Cancer Lenvatinib Phase III Trial: Overall Survival
Lenvatinib
Placebo
Brose M et al. J Clin Oncol 2019 (June 14);71:6472.

27. Re-differentiating Chemotherapy for Non-iodine Avid Metastatic Disease
Selumetinib used in 20 patients with minimally or non- iodine avid metastatic papillary thyroid cancers
dose of 75 mg given orally
twice daily for 4 weeks.
Patients were required to have differentiated thyroid
carcinoma of follicular-cell origin, or its respective
variants, histopathologically confirmed
at the MSKCC. Patients also had to meet at least
one of the following criteria for radioiodine-refractory
disease: an index metastatic lesion that
was not radioiodine-avid on diagnostic radioiodine
scanning performed up to 2 years before
enrollment; a radioiodine-avid metastatic lesion
that remained stable in size or progressed despite
radioiodine treatment 6 months or more
before entry into the study; and 18F-fluorodeoxyglucose
(FDG)–avid lesions on PET scanning
(FDG avidity is indicative of less differentiated
thyroid tumors with impaired iodine uptake20
and resistance to radioiodine,21 which are associated
with a poor prognosis22).
Ho AL, et al. N Engl J Med 2013;368:

28. Re-differentiating Chemotherapy for Non-iodine Avid Metastatic Disease
Selumetinib increased 124I uptake in 12 (60%), incl. 4/9 patients with BRAF & 5/5 NRAS mutant tumors
8 reached the dosimetry threshold for 131I therapy
5 had partial responses and 3 had stable disease
All 8 patients decreased Tg at 2 mos. (mean -89%)
dose of 75 mg given orally
twice daily for 4 weeks.
Patients were required to have differentiated thyroid
carcinoma of follicular-cell origin, or its respective
variants, histopathologically confirmed
at the MSKCC. Patients also had to meet at least
one of the following criteria for radioiodine-refractory
disease: an index metastatic lesion that
was not radioiodine-avid on diagnostic radioiodine
scanning performed up to 2 years before
enrollment; a radioiodine-avid metastatic lesion
that remained stable in size or progressed despite
radioiodine treatment 6 months or more
before entry into the study; and 18F-fluorodeoxyglucose
(FDG)–avid lesions on PET scanning
(FDG avidity is indicative of less differentiated
thyroid tumors with impaired iodine uptake20
and resistance to radioiodine,21 which are associated
with a poor prognosis22).

29. Chemotherapy for Differentiated Thyroid Cancer Adverse Events During Treatment
Axitinib
Motesanib
Sorafenib
Sunitinib
Fatigue
50%
46%
80%
79%
Diarrhea
48%
59%
73%
56%
Nausea
33%
28%
30% 10
Weight loss
25%
40%
Hypertension
42%
Rash
15%
<10%
70%
- - -
Pain
57%
Hand-Foot Syndrome
83%
53%
AE Grade >3
63%
62% ?
Lenvatinib was associated with 1%-4% drug-related fatal AEs.

30. Advances in Thyroid Cancer Management Conclusions
Guidelines for postoperative radioiodine use and TSH suppression therapy have been refined, consistent with the timely concept of Precision Medicine.
Mutation analysis (e.g., BRAF) can enhance traditional demographic and histopathological staging criteria to predict recurrence and survival risk in apparently low risk patients.
Recombinant TSH lessens morbidity and offers equal efficacy for postoperative 131-I thyroid remnant ablation.
ABSTRACT
PURPOSE: To prospectively assess the impact of recombinant TSH (rhTSH) administration on PET/CT imaging for differentiated thyroid cancer (DTC) in patients who, after primary treatment had a serum thyroglobulin >10 ng/mL, normal radioiodine whole body scan and limited disease
PATIENTS-METHODS: PET/CT was performed before (basal PET) and hours after rhTSH administration (rhTSH-PET) in the 63 patients who completed the study Images were analyzed by 2 readers, initially independently and then together for consensus reading. Proposed treatment plan was prospectively assessed before basal and rhTSH-PET and after rhTSH-PET
RESULTS: One hundred and eight lesions were detected in 48 organs, in 30 patients. Basal PET and rhTSH PET were equally sensitive for detecting patients with lesions (49% vs. 54%, P=0.42). rhTSH PET was more sensitive than basal PET for the detection of distinct lesion (81% vs. 95%, P=0.001) and tended to be more sensitive for the detection of involved organ (79% vs. 94%, P=0.054). Changes in treatment management plan occurred in 18% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in 6 patients among which 5 were proved to be true-positive findings on pathology (8%), a rate under the 10% rate expected to reach significancy.
CONCLUSION: The use of rhTSH for FDG PET/CT imaging increases the number of lesions detected. Its added value on our cohort of 63 patients is however limited without significant benefit neither on the per-patient analysis nor on the changes in treatment management plan.

31. Advances in Thyroid Cancer Management Conclusions
Novel tyrosine kinase inhibitors can often stabilize non-iodine avid metastatic disease, and in some patients, prolong overall survival and restore iodine avidity.
ABSTRACT
PURPOSE: To prospectively assess the impact of recombinant TSH (rhTSH) administration on PET/CT imaging for differentiated thyroid cancer (DTC) in patients who, after primary treatment had a serum thyroglobulin >10 ng/mL, normal radioiodine whole body scan and limited disease
PATIENTS-METHODS: PET/CT was performed before (basal PET) and hours after rhTSH administration (rhTSH-PET) in the 63 patients who completed the study Images were analyzed by 2 readers, initially independently and then together for consensus reading. Proposed treatment plan was prospectively assessed before basal and rhTSH-PET and after rhTSH-PET
RESULTS: One hundred and eight lesions were detected in 48 organs, in 30 patients. Basal PET and rhTSH PET were equally sensitive for detecting patients with lesions (49% vs. 54%, P=0.42). rhTSH PET was more sensitive than basal PET for the detection of distinct lesion (81% vs. 95%, P=0.001) and tended to be more sensitive for the detection of involved organ (79% vs. 94%, P=0.054). Changes in treatment management plan occurred in 18% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in 6 patients among which 5 were proved to be true-positive findings on pathology (8%), a rate under the 10% rate expected to reach significancy.
CONCLUSION: The use of rhTSH for FDG PET/CT imaging increases the number of lesions detected. Its added value on our cohort of 63 patients is however limited without significant benefit neither on the per-patient analysis nor on the changes in treatment management plan.