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Controversies in Thyroid Cancer
R Michael Tuttle, MD
Professor of MedicineEndocrine Service
Memorial Sloan Kettering Cancer CenterNew York, NY
Which Controversies?
Papillary Thyroid Cancer
Management ofMinimal Residual
Disease
When to treat,when to observe
How to know whenRIA quits working
Clinical Dilemma38 yr old male, total thyroidectomy
2.8 cm PTC, 8/13 positive LN’s
7 days after150 mCi RAI
Diagnostic WBS
1 yearlater
Thyroglobulin1.8 ng/mL 23 ng/mL
Scan negative, Tg positiveDilemma
Clinical Dilemma38 yr old male, total thyroidectomy
2.8 cm PTC, 8/13 positive LN’s
7 days after150 mCi RAI
Diagnostic WBS
1 yearlater
Thyroglobulin1.8 ng/mL 23 ng/mL
15 ng/mL
5 ng/mL
1 ng/mL
Stimulated Thyroglobulin
Detection of Recurrent DiseaseMajor Paradigm Shift
Papillary Thyroid Cancer
1950’s RAI Scanning
1980’s Thyroglobulin
1990’s Neck ultrasound
2000 FDG PET scan
Tg positive, Scan negative
Major Paradigm ShiftApproach to Detection of Recurrent Disease
Away from routine WBS
A move toward
Thyroglobulin Neck US
Modern Technologies
Increased Detection ofPersistent Disease
Improved Localizationof Persistent Disease
Additional Therapy
Effect on Outcomes?
Curing Patients?
Causing More Harm Than Good?
Scan Negative, Tg Positive
NegativeDiagnostic WBS
Elevated Tg
RAI as a diagnostic tool
Post-TherapyWBS
100-150 mCi
Improved DiseaseLocalization
Disease Localization with Post-therapy Scan
20
(41%)
839Lung
15
(31%)
474Lymph
nodes
15
(31%)
663Thyroid
Bed
40/49
(81%)
18/2516/1716/17Positive
TotalSchlumberger
1988
Pineda
1995
Pacini
1987
Tg positive, RAI scan negative patients
Scan Negative, Tg Positive
NegativeDiagnostic WBS
Post-TherapyWBS
Elevated Tg
100-150 mCi
Follow up after total thyroidectomy and RAI ablation
Post-therapy scan was less likely to be positive inpatients with stimulated Tg < 10 ng/mL
Disease Localization
Non-RAI avidPoorly Differentiated Tumors
Making Tg poorly
Small volumeWell Differentiated Tumors
Making Tg very well
Scan Negative, Tg Positive
NegativeDiagnostic WBS
Post-TherapyWBS
Elevated Tg
100-150 mCi
Follow up after total thyroidectomy and RAI ablation
Consider high dose empiric RAI to localize disease inscan negative patients with stimulated Tg values
greater than 10 ng/mL
Scan Negative, Tg Positive43 year old female, papillary thyroid cancer, presented with sacral mass
s/p total thyroidectomy and 249mCi RAI ablation, 201mCi Rx
Stim Tg38 ng/mL
400mCi
TherapeuticBenefit?
Scan negative, Tg positiveEmpiric RAI therapy
Clinically Important Outcomes
Disease Specific Mortality Disease Free Survival
Follow Up WBS
Serum Thyroglobulin on Suppression
Serum Thyroglobulin after TSH Stimulation
Scan negative, Tg positiveObservation vs Empiric RAI therapy
77 patients s/p total thyroidectomy and RAI ablationTg positive, Dx scan negative, no structural evidence of disease
28 patientsObserved
Before 198412 yr follow upMedian Tg 9.5
42 patientsRAI therapyAfter 1984
7 yr follow upMedian Tg 55
30 patientsPositive post-Rx scan
Repeat RAI Rx
12 patientsNegative post-Rx scan
No more RAIPacini JCEM 2001
Tg positive, Scan negativeTg 4-207 ng/mL, mean 7 yrs follow up
Once
Multiple
Empiric
RAI Rx
07/12
(58%)
2/12
(17%)
Post-Rx
Negative
11/30
(37%)
9/30
(30%)
10/30
(33%)
Post-Rx
Positive
WBS pos
Tg pos
WBS neg
Tg lower
WBS neg
Tg neg
Pacini JCEM 2001
Scan negative, Tg positiveObservation vs Empiric RAI therapy
77 patients s/p total thyroidectomy and RAI ablationTg positive, Dx scan negative, no structural evidence of disease
28 patientsObserved
Before 198412 yr follow upMedian Tg 9.5
42 patientsRAI therapyAfter 1984
7 yr follow upMedian Tg 55
12/42 (30%) Undetectable Stim Tg
Pacini JCEM 2001
19/28 (68%) Undetectable Stim Tg
Scan Negative, Tg positive28 patients observed without therapy for 12 yrs
1/14
(7%)
6/14
(43%)
7/14
(50%)
Stim Tg >10
2/14
(14%)
12/14
(86%)
Stim Tg 3-10
3/28
11%
6/28
(21%)
19/28
(68%)
Total
No change -
increase Tg
Decreased
Stim Tg
Undetectable
Stim Tg
Pacini JCEM 2001
Scan negative, Tg positive256 consecutive patients, total thyroidectomy and RAI ablation
37 with negative Dx WBS, and elevated Tg (mean 6 ng/mL)Observation alone for 5 yrs
14/37 (38%)Stim Tg was lower
Stim Tg 1-5 ng/mL8/12 (75%)
Undetectable Stim Tg
Stim Tg >10 ng/mL3/12 (25%)
Undetectable Stim Tg
Baudin JCEM 2003
Scan negative, Tg positive178 consecutive patients, total thyroidectomy and RAI ablation
105 evaluable 53 with negative Dx WBS, and elevated Tg (mean 36ng/mL)
42/53Observed
Median 6 yrs
Stim Tg < 2ng/mL31/42 (74%)
11/53Treated, multimodality
Median 8 yrs
Stim Tg < 2 ng/mL4/11 (36%)
Stim Tg > 2ng/mLStable, Persistent
11/42 (26%)
Stim Tg > 2 ng/mL7/11 (64%)
2 deaths
Alzahrani et al, J Endocrinol Invest, 2005
Initial Therapyn = 110
Total thyroidectomyRAI Ablation
Initial Follow upNegative Dx WBS
Stimulated Tg 0.6 to 10 ng/mL
1 year later
Study EndpointsStimulated Tg
Dx WBS
1-2 years later
Study Time Line
Intervention18: RAI therapy92: Observation
Stimulated Tg undetectable at follow up
0
20
40
60
80
100
Per
cent
Stim Tg lower Stim Tg undetectable
Initial Stimulated Tg2.1 - 10 ng/mL
71%
42%
n = 98 paired samples
29%
3%
Initial Stimulated Tg0.6 - 2 ng/mL
p < 0.001
Results of follow up stimulated Tg
0
20
40
60
80
100
Per
cent
Observed (n=25) RAI Therapy (n=11)
Lower Unchanged Higher
40%
12%
48%
n = 36 paired samples
Initial stimulated Tg 2.1 - 10 ng/mLNegative Diagnostic Scan
45%
18%
36%
Initial Therapyn = 110
Total thyroidectomyRAI Ablation
Initial Follow upNegative Dx WBS
Stimulated Tg 0.6 to 10 ng/mL
1 year later
Study EndpointsStimulated Tg
Dx WBS(95% negative)
1-2 years later
Study Time Line
Clinical Outcomes91% NED
9% Clinical Recurrence(50% cervical, 50% pulmonary)
3-5 years after Dx
Scan Negative, Tg Positive
Role of Empiric RAI Dosing
Helpful in localizing diseaseStimulated Tg >10 ng/mL
Therapeutic Effect?Much less clear
Observation EffectLow level Tg’s, without structural evidence
of disease, frequently resolve withobservation alone over many years
Common Clinical QuestionCommon Clinical Question
How can I make this thyroglobulinHow can I make this thyroglobulinnumber go to zero?number go to zero?
DonDon’’t I need more surgery?t I need more surgery?
34 year old female34 year old femalePalpable lymph nodes in the neckPalpable lymph nodes in the neck
Total thyroidectomyTotal thyroidectomy
•• Tumor scrapped off of the right RLNTumor scrapped off of the right RLN
•• All gross disease was removedAll gross disease was removed
HistologyHistology
•• 2.9 cm moderately differentiated PTC2.9 cm moderately differentiated PTC
•• 8/13 lymph nodes positive8/13 lymph nodes positive
Post Post ––op right VC paralysisop right VC paralysis
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Diagnostic WBS (131I)
150 mCi 131IPost-therapy scan is the same
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Normal post-op thyroid bed
1.1 x 0.5 x 0.5 cmcystic lymph node
Serum Tg fell from 22 ng/mL beforeRAI ablation to 5-6 ng/ml with a TSHof 0.1 mIU/L over the next 12 months
No abnormal blood flow
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Tg 6.2 ng/mL baselineTg 26 ng/mL stimulated
Diagnostic WBS (5mCi 131I)
Negative WBS
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Chest CT was entirely normalChest CT was entirely normal
Empiric Dose of RAI? 200 mCi 131I
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
18 FDG PET Scan
Negative PET0
20
40
60
80
100
RAI Positive FDG PET Positive
Well Moderate Poorly Undiff
Degree of Tumor Differentiation
Per
cent
Pos
itiv
e Sc
ans
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Normal post-op thyroid bed
1.1 x 0.5 x 0.5 cmcystic lymph node
Serum Tg for the next year was about 3 ng/mL
Follow-up Neck Ultrasound
34 year old female34 year old female2.9 cm moderately diff PTC, invasion into right RLN2.9 cm moderately diff PTC, invasion into right RLN
Serum Tg for the next year was about 3 ng/mL
Sought a second opinionUS FNA positive for PTC in the cystic lymph node
and a 3 mm paratracheal lymph node
Left Modified Radical Neck Dissection5/50 lymph nodes positive for PTC
6 months after surgery
Ongoing follow upSerial US, chest CT, PET scan
Serum Tg was 2.3 ng/mL
Small Cervical Lymph Nodes Tg Positive
Role of Additional Surgery
We usually consider surgery ifAbnormal LN > 1 cm
Evidence of structural disease progressionEspecially if PET positive
Always FNA LN prior to surgical resectionCompartment oriented resection
Otherwise, cautious observations is recommendedSerial neck US
64 year oldFollicular Thyroid Cancer, presented as a painful hip met
18 FDG PET Scan
Anterior Posterior
Diagnostic RAI WBS
200 mCi, once a year for 3 yearsNo clinical benefit
When to stop treating with RAI?
♦ Even if
The patient is not cured
The Tg is not zero
The patient has progressive disease
The post-therapy scan is still positive
The patient is dying of thyroid cancer
When additional administered activities are unlikely to produce a
significant clinical benefit.
23 year old females/p total thyroidectomy
3.5 cm PTC, 18/26 lymph nodes positiveHer first diagnostic WBS in preparation for RRA
CXRRAI
Durante et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroidcarcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006 Aug;91(8):2892-9.
Brain and bone metastases tend to be very refractory to cure with RAI.
CT RAI Fused
35 year old female, metastatic FTC
CT RAI Fused
When to stop treating with RAI?
♦ Individual features: age, histology, site of disease
♦ Diagnostic whole body RAI scan
♦ 18 FDG PET scan
♦ Previous objective evidence of benefit
How do we determine if additional RAI is likely to produce a
significant clinical benefit?
When to stop treating with RAI?
♦ Before stopping RAI treatment, make sure the previousattempts were done correctly.
♦ Admitting RAI is no longer effective does not mean that wehave nothing to offer the patient.
♦ Multidisciplinary teams are critical in these RAIrefractory patients
A few important caveats
Which Controversies?
Papillary Thyroid Cancer
Management ofMinimal Residual
Disease
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