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2015
2014 American Thyroid Association
Management Guidelines for Patients
with Thyroid Nodules and
Differentiated Thyroid Cancer
Ronen Gurfinkel
February 25, 2015
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
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
2009 Guidelines
2015 Guidelines
2015 Guidelines
2015 ATA Guidelines - Organization
A. Thyroid nodule guidelines
– Recommendations 1-31
B. DTC: Initial management guidelines
– Recommendations 32-61
C. DTC: Long-term management guidelines and
advanced cancer management guidelines
– Recommendations 33-101
D. Directions for future research
Preoperative Assessment
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
Preoperative Staging
• Recommendation 32
A. Preop neck US (central + lateral compartments)
(Strong/Moderate)
B. US-guided biopsy of suspicious LNs (≥ 8-10 mm)
if would change management
(Strong/Moderate)
C. (NEW) FNA-Tg washout appropriate in select
patients, but ? difficult to interpret (Weak/Low)
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
Preoperative Staging
• Recommendation 33 (CHANGED)
A. Cross-section imaging (CT, MRI) with contrast
recommend as adjunct to U/S if suspicious for
advanced disease (Strong/Low)
B. Routine preop FDG-PET no recommended
(Strong/Low)
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)
Initial Surgical Management
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
• 52,173 patients in National Cancer Data Base
(1985-1998)
Bilimoria et al, Ann Surg 2007
• 52,173 patients in National Cancer Data Base
(1985-1998)
Bilimoria et al, Ann Surg 2007
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
Lobectomy vs Total Thyroidectomy
• Mendelsohn et al, Arch Otolaryngol Head
Neck Surg 2010
– 22,724 PTC patients
– SEER 1988-2001
– No survival difference
• 1,810 patients in MSKCC database (19862005)
Nixon et al, Surgery 2012
Surgery for Biopsy Proven DTC
• Recommendation 35 (CHANGED)
A.
Total or near-total thyroidectomy if
•
•
•
•
B.
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 followup based upon disease features and/or patient preferences.”
(Strong/Moderate)
C.
Lobectomy if TC < 1cm (no ETE, cN0, no other RFs)
(Strong/Moderate)
Lymph Node Dissection
• Recommendation 36
A. Therapeutic central neck dissection (CND) for
cN1 (Strong/Moderate)
B. Consider prophylactic CND for PTC with cN0 but
T3 or T4, cN1b, or if info will change
management (Weak/Low)
C. No prophylactic CND may be appropriate for
noninvasive T1 or T2 tumours, cN0, and most
follicular cancer (Strong/Moderate)
Lymph Node Dissection
• Recommendation 37
– Therapeutic lateral LN dissection in biopsy-proven
lateral cervical LN mets (Strong/Moderate)
Completion Thyroidectomy
• Recommendation 38
A. Offer if bilateral thyroidectomy would have been
recommended if diagnosis was available before
initial surgery. Therapeutic CND if cN1
(Strong/Moderate)
B. RAI in lieu of completion thyroidectomy not
recommended (except select cases)
(Weak/Low)
Staging and Risk Stratification
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)
ATA Initial Risk Stratification
• AJCC stage unable to predict recurrence
• 2009 guidelines introduced the Initial Risk
Stratification system
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
Modified Initial Risk
Stratification System
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%
Postoperative Risk Stratification
• Recommendation 48 (CHANGED)
A. ATA 2009 Initial Risk Stratification system for postop
DTC patients based on utility in predicting risk of
recurrence/persistence (Strong/Moderate)
B. May use additional prognostic variables in Modified
Initial Risk Stratification System; incremental benefit
not established (Weak/Low)
C. BRAF testing not routinely recommended for initial
postop risk stratification (adds little incremental
prognostic value) (Weak/Moderate)
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
Vaisman et al, Clin Endocrinol 2012
Validation of Dynamic Risk Assessment
Tuttle et al, Thyroid 2010
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
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%
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)
Postoperative Radioactive Iodine
Therapy
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
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
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 > 10-30 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
Decision for Adjuvant Rx
• Recommendation 50 (NEW)
A. Postop disease status should be considered when
deciding additional therapy (Strong/Low)
B. Postop Tg can be helpful is assessing persisting
disease/remnant and predicting recurrence
(Strong/Moderate)
C. Optimal Tg cut-off to guide decision-making for RAI
therapy not known (No rec/Insuff)
D. Postop RAI scan may be useful to determine extent
of remnant, or if results would alter treatment
decision/dose used (Weak/Low)
Postop RAI
• Recommendation 51 (CHANGED)
A. RAI remnant ablation not routinely recommended for
ATA low risk (Weak/Low)
B. RAI remnant ablation not routinely recommended for
unifocal papillary microca (if no other adverse features)
(Strong/Moderate)
C. RAI remnant ablation not routinely recommended for
multifocal papillary microca (if no other adverse
features) (Weak/Low)
D. RAI should be considered in ATA intermediate risk
(Weak/Low)
E. RAI is recommended in ATA high risk (Strong/Moderate)
Postop RAI
• Recommendation 52 (NEW)
– The role of molecular testing in guiding postop RAI
has yet to be established (No rec/Insuff)
RAI (Dx or Rx) – Preparation
• Recommendation 53 (Slightly CHANGED)
A. 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)
B. Goal TSH > 30 generally adopted, but there is
uncertainty relating optimum level and
improvement in outcomes (Weak/Low)
rhTSH (Thyrogen) for RAI Rx?
• Recommendation 54 (CHANGED)
A. rhTSH acceptable for low/intermediate risk patients
without extensive LN involvement (T1-3, N0/x/1a,
M0) (Strong/Mod)
B. rhTSH may be considered in intermediate risk with
extensive LNs without distant mets (Weak/Low)
C. Cannot recommend rhTSH in high risk patients (No
rec/Insuff)
D. Consider rhTSH in any risk patient with co-morbidity
that precludes withdrawal (Strong/Low)
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
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)
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 30-150 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)
Low iodine diet for RAI?
• Recommendation 57
– Consider low iodine diet 1-2 weeks before RAI
(Weak/Low)
Posttherapy Scan?
• Recommendation 58
– A post-therapy whole-body scan +/- SPECT-CT is
recommended after RAI post ablation/treatment
(Strong/Mod)
Initial TSH Suppression
• Recommendation 59 (CHANGED)
A. High risk patients, initial TSH suppression < 0.1 mU/L is
recommended. (Strong/Mod)
B. Intermediate risk patients, initial TSH suppression 0.10.5 mU/L is recommended. (Weak/Low)
C. 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)
D. Low risk patients +/- RAI with undetectable Tg levels, TSH
0.5–2 mU/L, while continuing surveillance for recurrence
(Weak/Low)
Adjuvant Therapy
• Recommendation 60
– No role for routine external beam radiation
(Strong/Low)
• Recommendation 61
– No role for routine systemic adjuvant therapy
(Strong/Low)
Long Term DTC Follow-up
Role of Tg During Follow-up
• Recommendation 62 (CHANGED)
A.
B.
C.
D.
E.
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 12-24 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)
Role of Tg During Follow-up
• Recommendation 63 (CHANGED)
A. Low/intermediate risk post ablation patients with
negative cervical US, serum Tg should be measured at 618 months on LT4 in a sensitive Tg assay or after TSH
stimulation to verify excellent response
(Strong/Moderate)
B. Repeat TSH stimulated Tg testing is not recommended
for low/intermediate risk patients with an excellent
response (Weak/Low)
C. 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)
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)
Cervical US During Follow-up
• Recommendation 65
A.
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)
B. 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)
C. 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)
D. 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)
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
A. 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)
B. SPECT/CT radioiodine imaging is preferred over
planar (Weak/Moderate)
TSH Suppression During Follow-up
• Recommendation 70 (CHANGED)
A.
Patients with structural/biochemical incomplete response,
TSH < 0.1 mU/L indefinitely if no contraindications.
(Strong/Moderate)
B. 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)
C. Patients with excellent/indeterminate response, especially
those at low risk for recurrence, TSH 0.5–2 mU/L
(Strong/Moderate)
D. 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)
Low Risk
Low Risk
Intermediate
Risk
High Risk
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
QUESTIONS?