1. Ronen Gurfinkel February 25, 2015
2014 American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer
Ronen Gurfinkel
February 25, 2015

2. Objectives Review guidelines and updates on Preoperative staging
Initial surgical management of DTC
Staging and risk stratification
Radioiodine therapy
Assessing response to therapy
Long term Follow-up

3. ATA Guidelines
Thyroid nodule and DTC treatment guidelines first developed 1996
Revised in 2006 and 2009
Draft update released 2014
Endorsed by AACE, American College of Endocrinology, BAHNO, ENDO Society, EACMFS, EANM, ESES, ESPE

4. 2009 Guidelines

5. 2015 Guidelines

6. 2015 Guidelines

7. 2015 ATA Guidelines - Organization
Thyroid nodule guidelines
Recommendations 1-31
DTC: Initial management guidelines
Recommendations 32-61
DTC: Long-term management guidelines and advanced cancer management guidelines
Recommendations
Directions for future research

8. Preoperative Assessment

9. Preoperative Staging Role of preop neck U/S?
20-50% of DTC patients have cervical LN mets
Preop U/S identifies suspicious LN in 20-31%
Can confirm LN mets with U/S-guided FNA
Measuring Tg in FNA needle washout fluid may be helpful if select cases
Cystic LN
Inadequate cytology
Discordant U/S and cytology results
Up to 90% may have micromets
Half of mets missed by U/S

10. Preoperative Staging Recommendation 32
Preop neck US (central + lateral compartments) (Strong/Moderate)
US-guided biopsy of suspicious LNs (≥ 8-10 mm) if would change management (Strong/Moderate)
(NEW) FNA-Tg washout appropriate in select patients, but ? difficult to interpret (Weak/Low)
No change in A&B except size
Added C

11. Preoperative Staging
2009 guidelines recommended against routine preop CT, MRI, or PET
Choi et al (2009)
299 PTC patients, compared U/S vs CT
U/S better for ETE, multifocal/bilobar disease
U/S more accurate for staging
Lesnick et al (2014)
U/S + CT better than U/S alone for lateral LN
MRI and PET have poor sensitivities for LNs (30-40%)
Cross-sectional imaging is better for locally invasive tumours

12. Preoperative Staging Recommendation 33 (CHANGED)
Cross-section imaging (CT, MRI) with contrast recommend as adjunct to U/S if suspicious for advanced disease (Strong/Low)
Routine preop FDG-PET no recommended (Strong/Low)
33 - CT previously not recommended

13. Preoperative Staging
Preop Anti-Tg Ab do not predict stage, disease-free survival
No data that preop Tg impact on management or outcomes
Recommendation 34
Routine preop Tg and Anti-Tg Ab are not recommended (Weak/Low)
33 - CT previously not recommended

14. Initial Surgical Management

15. Surgery for Biopsy Proven DTC
2009 guidelines
TC > 1 cm  total or near-total thyroidectomy
TC < 1 cm  lobectomy (unifocal, no other RFs)
Based on retrospective data that bilateral surgery
Improved survival
Decreased recurrence
Allowed for routine RAI
Facilitated follow-up

16. 52,173 patients in National Cancer Data Base (1985-1998)
Bilimoria et al, Ann Surg 2007

17. 52,173 patients in National Cancer Data Base (1985-1998)
Bilimoria et al, Ann Surg 2007

18. Surgery for Biopsy Proven DTC
Recent data showed similar outcomes between unilateral vs. bilateral surgery (in selected patients)
Unilateral surgery  less LT4 Rx and less complications
2015 guidelines use RAI more selectively and RAI scans used less in follow-up

19. Lobectomy vs Total Thyroidectomy
Mendelsohn et al, Arch Otolaryngol Head Neck Surg 2010
22,724 PTC patients
SEER
No survival difference

20. 1,810 patients in MSKCC database (1986-2005)
Nixon et al, Surgery 2012

21. Surgery for Biopsy Proven DTC
Recommendation 35 (CHANGED)
Total or near-total thyroidectomy if
TC > 4cm
Gross extrathyroidal extension
Clinically apparent LN mets (cN1)
Clinicaly apparent distant mets (cM1)
(Strong/Moderate)
Either lobectomy or thyroidectomy if TC 1-4 cm AND cN0
“Thyroid lobectomy alone may be sufficient initial treatment for low risk papillary and follicular carcinomas; however, the treatment team may choose total thyroidectomy to enable RAI therapy or to enhance follow-up based upon disease features and/or patient preferences.”
Lobectomy if TC < 1cm (no ETE, cN0, no other RFs)

22. Lymph Node Dissection Recommendation 36
Therapeutic central neck dissection (CND) for cN1 (Strong/Moderate)
Consider prophylactic CND for PTC with cN0 but T3 or T4, cN1b, or if info will change management (Weak/Low)
No prophylactic CND may be appropriate for noninvasive T1 or T2 tumours, cN0, and most follicular cancer (Strong/Moderate)

23. Lymph Node Dissection Recommendation 37
Therapeutic lateral LN dissection in biopsy-proven lateral cervical LN mets (Strong/Moderate)

24. Completion Thyroidectomy
Recommendation 38
Offer if bilateral thyroidectomy would have been recommended if diagnosis was available before initial surgery. Therapeutic CND if cN1 (Strong/Moderate)
RAI in lieu of completion thyroidectomy not recommended (except select cases)
(Weak/Low)

25. Staging and Risk Stratification

26. Postoperative Staging
Recommendation 47
AJCC/UICC staging for all DTC patients, based on utility in predicting mortality, and its requirement in cancer registries
(Strong/Moderate)

27. ATA Initial Risk Stratification
AJCC stage unable to predict recurrence
2009 guidelines introduced the Initial Risk Stratification system

28. Retrospective validation on 3 continents
Need prospective data
Still suboptimal in predicting recurrence (explains little proportion of variance)

29. ATA Initial Risk Stratification
Risk in each category can vary based on other features
Histology
Multifocality
Extent of vascular invasion
Extent of LN mets
Genetic markers

30. Figure 4. Risk of structural disease recurrence in patients without structurally identifiable disease after initial therapy.

31. Modified Initial Risk Stratification System
Figure 4. Risk of structural disease recurrence in patients without structurally identifiable disease after initial therapy.

34. BRAF V600E Mutation
BRAF V600E shown to predict higher risk, but is also linked to other clinico-pathologic features
Tufano et al, Medicine 2012
Meta-analysis 14 studies, 2,470 PTC patients
Higher recurrence in BRAF V600E compared to wild type (24.9% vs 12.6%)
Sensitivity to detect recurrence was 65%
But PPV 25%

35. Postoperative Risk Stratification
Recommendation 48 (CHANGED)
ATA 2009 Initial Risk Stratification system for postop DTC patients based on utility in predicting risk of recurrence/persistence (Strong/Moderate)
May use additional prognostic variables in Modified Initial Risk Stratification System; incremental benefit not established (Weak/Low)
BRAF testing not routinely recommended for initial postop risk stratification (adds little incremental prognostic value) (Weak/Moderate)

36. Dynamic Risk Assessment
Initial staging and risk assessments provide single point estimates and can be used to guide initial therapy
No current system modifies initial risk estimate using follow-up data
Systems that incorporate response to therapy have improved ability to predict long term outcomes
Limitations
Not validated in certain subgroups (eg no RAI, lobectomy)
Lack of prospective data
Inconsistency between authors in defining significant Tg levels or imaging findings

37. Vaisman et al, Clin Endocrinol 2012

38. Validation of Dynamic Risk Assessment
Tuttle et al, Thyroid 2010

39. Dynamic Risk Assessment
Excellent response:
no clinical, biochemical or structural evidence of disease
Biochemical incomplete response:
abnormal thyroglobulin or rising anti-thyroglobulin antibody levels in the absence of localizable disease
Structural incomplete response:
persistent or newly identified loco-regional or distant metastases
Indeterminate response:
non-specific biochemical or structural findings which cannot be confidently classified as either benign or malignant. This includes patients with stable or declining anti-thyroglobulin antibody levels without definitive structural evidence of disease

44. Incomplete Biochemical Incomplete Structural
Response to Treatment
ATA Risk
Excellent
Incomplete Biochemical
Incomplete Structural
Indeterminate
Low
86-91%
11-19%
2-6%
12-29%
Intermediate
57-63%
21-22%
19-28%
8-23%
High
14-16%
16-18%
67-75%
0-4%

45. Postoperative Risk Assessment
Recommendation 49
Initial recurrence risk estimates should be continually modified during follow-up, because the risk of recurrence and disease specific mortality can change over time as a function of the clinical course of the disease and the response to therapy (Strong/Low)

46. Postoperative Radioactive Iodine Therapy

47. Decision for RAI Therapy
2009 guidelines recommended postop RAI therapy mainly on the basis of tumour pathology (esp size)
Postoperative disease status is an important consideration
No RCTs comparing strategies for RAI therapy decision making

48. Decision for RAI Therapy - Tg
Tg reaches nadir 3-4 weeks postop
Level influenced by amount of residual thyroid cancer and/or normal thyroid tissue
Postop Tg is independent predictor or persistent/recurrent diseases
risk increases as Tg increases
Can also predict success of RAI ablation and mortality risk
Uncertain what Tg level (stim or non-stim) should prompt therapy

49. Postop Tg in Risk Assessment
Low risk patients, Tg < 1 ng/ml confirms low risk status
Intermediate risk patients, Tg < 1 ng/ml is reassuring, but does not completely rule out small mets
Postop Tg > ng/ml increase likelihood of poor outcomes
Thus, postop Tg may be useful to select low/intermediate risk patients for RAI therapy, but unlikely to alter decision in high risk patients

50. Decision for Adjuvant Rx
Recommendation 50 (NEW)
Postop disease status should be considered when deciding additional therapy (Strong/Low)
Postop Tg can be helpful is assessing persisting disease/remnant and predicting recurrence (Strong/Moderate)
Optimal Tg cut-off to guide decision-making for RAI therapy not known (No rec/Insuff)
Postop RAI scan may be useful to determine extent of remnant, or if results would alter treatment decision/dose used (Weak/Low)
Stim Tg + U/S –> high NPV for intermed/high risk patients

51. Postop RAI Recommendation 51 (CHANGED)
RAI remnant ablation not routinely recommended for ATA low risk (Weak/Low)
RAI remnant ablation not routinely recommended for unifocal papillary microca (if no other adverse features) (Strong/Moderate)
RAI remnant ablation not routinely recommended for multifocal papillary microca (if no other adverse features) (Weak/Low)
RAI should be considered in ATA intermediate risk (Weak/Low)
RAI is recommended in ATA high risk (Strong/Moderate)
Table 14

55. Postop RAI Recommendation 52 (NEW)
The role of molecular testing in guiding postop RAI has yet to be established (No rec/Insuff)

56. RAI (Dx or Rx) – Preparation
Recommendation 53 (Slightly CHANGED)
If using thyroid hormonal withdrawal, LT4 should be stopped for 3-4 weeks, with/without T3 in initial weeks. Measure TSH prior to giving RAI (Strong/Mod)
Goal TSH > 30 generally adopted, but there is uncertainty relating optimum level and improvement in outcomes (Weak/Low)

57. rhTSH (Thyrogen) for RAI Rx?
Recommendation 54 (CHANGED)
rhTSH acceptable for low/intermediate risk patients without extensive LN involvement (T1-3, N0/x/1a, M0) (Strong/Mod)
rhTSH may be considered in intermediate risk with extensive LNs without distant mets (Weak/Low)
Cannot recommend rhTSH in high risk patients (No rec/Insuff)
Consider rhTSH in any risk patient with co-morbidity that precludes withdrawal (Strong/Low)

58. RAI Rx Dosing – 2009 Guidelines
RECOMMENDATION 36
The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B
RECOMMENDATION 37
If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma), then higher activities (100–200 mCi) may be appropriate. Recommendation rating: C

59. RAI Rx Dosing – 2015 Guidelines
Recommendation 55 (CHANGED)
If RAI remnant ablation is performed after total thyroidectomy for low/intermediate risk with lower risk features (ie. low volume central neck LNs with no other known gross residual disease nor any other adverse features), low administered dose activity of approximately of 30 mCi (1.1 GBq) is generally favored over higher administered dose activities (Strong/High)

60. RAI Rx Dosing – 2015 Guidelines
Recommendation 56 (CHANGED)
When RAI is used for initial adjuvant therapy to treat suspected/documented microscopic residual disease in intermediate/high risk patients, administered activities of mCi are generally recommended (in absence of known distant metastases). Routine use of higher administered activities in this setting does not appear to reduce structural disease recurrence for T3 and N1 disease (Weak/Low)

61. Low iodine diet for RAI? Recommendation 57
Consider low iodine diet 1-2 weeks before RAI (Weak/Low)

62. Posttherapy Scan? Recommendation 58
A post-therapy whole-body scan +/- SPECT-CT is recommended after RAI post ablation/treatment (Strong/Mod)

63. Initial TSH Suppression
Recommendation 59 (CHANGED)
High risk patients, initial TSH suppression < 0.1 mU/L is recommended. (Strong/Mod)
Intermediate risk patients, initial TSH suppression mU/L is recommended. (Weak/Low)
Low risk post ablation patients with low Tg levels, TSH 0.1–0.5 mU/L, while continuing surveillance for recurrence. Similar for non-ablated low risk patients (but Tg levels may higher) and continued surveillance for recurrence applies. (Weak/Low)
Low risk patients +/- RAI with undetectable Tg levels, TSH 0.5–2 mU/L, while continuing surveillance for recurrence (Weak/Low)
? Evidence for change??

64. Adjuvant Therapy Recommendation 60 Recommendation 61
No role for routine external beam radiation (Strong/Low)
Recommendation 61
No role for routine systemic adjuvant therapy (Strong/Low)

65. Long Term DTC Follow-up

66. Role of Tg During Follow-up
Recommendation 62 (CHANGED)
Tg should be measured by assay that calibrated against the CRM457 standard. Ideally, Tg should be assessed longitudinally in the same lab using the same assay. Tg Abs should be quantitatively assessed with every Tg measurement (Strong/High)
During initial follow-up, serum Tg on LT4 should be measured every 6-12 months. More frequent Tg measurements may be appropriate for high risk patients (Strong/Moderate)
In low/intermediate risk patients with excellent response, utility of subsequent Tg testing is not established. Time interval between serum Tg measurements can be lengthened to at least months (Weak/Low)
TSH should be measured at least every 12 months in all patients on thyroid hormone therapy (Strong/Moderate)
High risk patients and all patients without excellent response should have Tg measured at least every 6-12 months for several years. (Weak/Low)

67. Role of Tg During Follow-up
Recommendation 63 (CHANGED)
Low/intermediate risk post ablation patients with negative cervical US, serum Tg should be measured at 6-18 months on LT4 in a sensitive Tg assay or after TSH stimulation to verify excellent response (Strong/Moderate)
Repeat TSH stimulated Tg testing is not recommended for low/intermediate risk patients with an excellent response (Weak/Low)
Subsequent stim Tg testing may be considered in patients with an indeterminate or biochemical/structural incomplete response after additional therapies or spontaneous decline in Tg values to reassess response to therapy (Weak/Low)

68. Tg In Follow-up of Non-ablated Patients
Recommendation 64
Periodic Tg measurements on LT4 and neck US should be considered during follow-up in
Patients with less than total thyroidectomy
Patients post total thyroidectomy but not RAI ablation
Specific cutoff Tg level that optimally distinguish normal residual thyroid tissue from persistent thyroid cancer are unknown
Rising Tg values over time are suspicious for growing thyroid tissue or cancer.
(Strong/Low)

69. Cervical US During Follow-up
Recommendation 65
Following surgery, cervical US should be performed at 6–12 months and then periodically, depending on the patient’s risk for recurrent disease and Tg status (Strong/Moderate)
If a positive result would change management, US suspicious LNs > 8-10 mm in the smallest diameter should be biopsied with Tg needle washout measurement (Strong/Low)
Suspicious LNs < 8-10 mm in smallest diameter may be followed without biopsy with consideration for FNA/intervention if there is growth or if the node threatens vital structures (Weak/Low)
Low-risk patients post ablation with negative cervical US, low Tg (<0.2 ng/ml on LT4 or <1ng/ml after TSH-stimulation) can be followed primarily with clinical examination and Tg measurements on thyroid hormone replacement (Weak/Low)

70. Diagnostic RAI WBS During Follow-up
Recommendation 66
After first post RAI treatment WBS, low/intermediate risk excellent response to therapy do not require routine diagnostic WBS during follow-up (Strong/Moderate)
Recommendation 67
Diagnostic WBS 6–12 months after ablation can be useful in the follow-up of patients with high or intermediate risk (higher risk features) of persistent (Strong/Low)
SPECT/CT radioiodine imaging is preferred over planar (Weak/Moderate)

71. TSH Suppression During Follow-up
Recommendation 70 (CHANGED)
Patients with structural/biochemical incomplete response, TSH < 0.1 mU/L indefinitely if no contraindications. (Strong/Moderate)
Patients with excellent/indeterminate response, but presented with high risk disease, consider maintaining TSH 0.1–0.5 mU/L for up to 5 years after which degree of TSH suppression can by reduced (Weak/Low)
Patients with excellent/indeterminate response, especially those at low risk for recurrence, TSH 0.5–2 mU/L (Strong/Moderate)
Patients not ablated, with excellent/indeterminate response (normal neck US and low/undetectable suppressed Tg, and Tg or TgAb that are not rising) TSH 0.5–2 mU/L (Weak/Low)

73. Low Risk
Figure 5. Clinical decision making and management recommendations in ATA low risk differentiated thyroid cancer patients that have undergone total thyroidectomy. R – Recommendation in text.

74. Low Risk
Figure 6. Clinical decision making and management recommendations in ATA low risk differentiated thyroid cancer patients that have undergone less than total thyroidectomy (lobectomy or lobectomy with isthmusectomy). R – Recommendation in text.

75. Intermediate
Risk
Figure 7. Clinical decision making and management recommendations in ATA intermediate risk differentiated thyroid cancer patients that have undergone total thyroidectomy. R – Recommendation in text.

76. High Risk
Figure 8. Clinical decision making and management recommendations in ATA high risk differentiated thyroid cancer patients that have undergone total thyroidectomy and have no gross residual disease remaining in the neck. R – Recommendation in text.

77. Take Home Messages
2015 ATA guidelines have made significant changes based on new studies
Modified initial risk stratification +/- Tg may guide decision for RAI treatment
Shift towards less aggressive treatment
Less surgery for low/intermediate risk patients
More selective RAI use and lower dosing
Less aggressive TSH suppression
Dynamic risk assessments may guide further follow-up and treatment

78. QUESTIONS?