controversies in thyroid cancer - montpellier · 2016-02-19 · controversies in thyroid ......

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