1. Risk Adapted Management of Thyroid Cancer R Michael Tuttle, MD Professor of Medicine Endocrine Service Memorial Sloan Kettering Cancer Center New York, NY

2. Predicting Outcomes in Thyroid Cancer Common Staging Systems EORTCAGESAMESMACISOSUMSKCCTNM Age√√√√-√√ Gender√-√---- Size-√√√√√√ Multicen----√-- Grade-√---√- ETE√√√√√√√ LN----√√√ DM√√√√√√√ Resection---√--- Designed to predict death from disease, not recurrence Dean DS and Hay ID. Cancer Control, 2000; 7(3): p. 229-239.

3. Differentiated Thyroid Cancer Mazzaferri. JCEM 2001 0 10 20 30 40 50 60 02468 Age (yrs) at time of initial therapy Percent 5-910-19 20-2930-39 40-4950-5960-6970-95 Recurrence Death Distant Recurrence

4. Limitations  Current Staging systems Are designed to predict death, not recurrence Don’t adequately incorporate  Molecular findings  Histological subtyping Do not adjust to new data obtained during follow up Are not altered by duration of disease free survival  As clinicians Begin with initial risk stratification Obtain new data every 6 months Integrated into ongoing and updated risks of recurrence and death

5. Management Based on Risk Risk of DeathRisk of Recurrence Risk of Distant Metastases Risk of Not Responding to Therapy (Risk of Persistent Disease) What risk are we talking about?

6. Risk Adapted Management Risk of DeathRisk of Recurrence Guide Initial Treatment Recommendations (Extent of surgery, RAI ablation, EBRT etc)

7. MSKCC Strategy for Risk Stratification Age Gender Size Extent Grade Distantmets < 45 yrs Female < 4 cm Intraglandular Low Absent Low >45 yrs Male >4 cm Extraglandular High Present HighIntermediate Mixture of Features Shah,Shaha, MSKCC

8. Risk Stratification Age Gender Size Extent Grade Distantmets < 45 yrs Female < 4 cm Intraglandular Low Absent >45 yrs Male >4 cm Extraglandular High Present LowHighIntermediate Mixture of Features MSKCC Death Rate 40% <1% 38% 15% 22% 54% Shah,Shaha, MSKCC

9. Risk Stratification for Death from Thyroid Cancer Very LowLowIntermediateHigh Age Size Histology Resection LN DM Tuttle. Endocrine Practice 14: 764-774, 2008.

10. Risk Stratification for Death from Thyroid Cancer Very LowLowIntermediateHigh Age< 45 years Size Histology < 1 cm PTC* ResectionComplete LNNo DMNo *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

11. Risk Stratification for Death from Thyroid Cancer Very LowLowIntermediateHigh Age< 45 years Size Histology < 1 cm PTC* 1-4 cm PTC* ResectionComplete LNNo+/- DMNo *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

12. Risk Stratification for Death from Thyroid Cancer Very LowLowIntermediateHigh Age< 45 years >45 years PTC > 4 cm Size Histology < 1 cm PTC* 1-4 cm PTC* ?Other > 1-2 cm ResectionComplete Incomplete LNNo+/- DMNo Yes *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

13. Risk Stratification for Death from Thyroid Cancer Very LowLowIntermediateHigh Age< 45 years Young patients (<45 yrs)  Classic PTC > 4cm  Worrisome histology >45 years PTC > 4 cm Size Histology < 1 cm PTC* 1-4 cm PTC* Older patients (> 45 yrs)  Classic PTC < 4 cm  Worrisome histology ?Other > 1-2 cm ResectionComplete Incomplete LNNo+/- DMNo Yes *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

14. Risk of Recurrence of Thyroid Cancer LowIntermediateHigh Age Size Histology LN *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

15. Risk of Recurrence of Thyroid Cancer LowIntermediateHigh AgeAny age Size< 1 cm HistologyClassic PTC* LNNone apparent *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

16. Risk of Recurrence of Thyroid Cancer LowIntermediateHigh AgeAny age 60 yrs Size< 1 cm> 4 cm HistologyClassic PTC*Other Gross ETE Gross Vasc Inv LNNone apparentPresent *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

17. Risk of Recurrence of Thyroid Cancer LowIntermediateHigh AgeAny age20- 60 yrs 60 yrs Size< 1 cm1-4 cm> 4 cm HistologyClassic PTC*Classic PTC Minor ETE Minor Vasc Inv Other Gross ETE Gross Vasc Inv LNNone apparentPresent or absentPresent *Classic PTC, intrathyroidal Tuttle. Endocrine Practice 14: 764-774, 2008.

18. Risk Adapted Management of Low Risk Patients Very Low Age< 45 years Size Histology < 1 cm PTC* ResectionComplete LNNo DMNo Death Less than total thyroidectomy is acceptable RAI ablation not required Low AgeAny age Size< 1 cm HistologyClassic PTC* LNNone apparent Recurrence Tuttle. Endocrine Practice 14: 764-774, 2008.

19. Risk Adapted Management of High Risk Patients High Age>45 years PTC > 4 cm Size Histology Other > 1-2 cm ResectionIncomplete LN+/- DMYes High Age 60 yrs Size> 4 cm HistologyOther Gross ETE Gross Vasc Inv LNPresent Recurrence Death Total thyroidectomy RAI ablation Tuttle. Endocrine Practice 14: 764-774, 2008.

20. Risk Adapted Management Risk of DeathRisk of Recurrence Initial SurgeryRAI remnant ablation Very LowLowLobectomy or total thyroidectomy Not required LowLobectomy or total thyroidectomy Not required LowIntermediateTotal thyroidectomyFor selected patients* HighTotal thyroidectomyYes IntermediateTotal thyroidectomyFor most patients Intermediate HighTotal thyroidectomyYes IntermediateTotal thyroidectomyYes High Total thyroidectomyYes Tuttle. Endocrine Practice 14: 764-774, 2008.

21. Expected Benefit FactorsDescriptionDecrease risk of death Decrease risk of recurrence May facilitate initial staging and follow up T11cm or less, intrathyroidal 1-2 cm, intrathyroidal T2> 2 to 4 cm, intrathyroidal T3> 4cm < 45 yrs old > 45 yrs old Any size, any age, minimal extrathyroidal extension T4Any size with gross extrathyroidal extension Risk Adapted Management Based on TNM (AJCC) Staging RAI remnant ablation ATA Thyroid Cancer Guidelines, Revised 2009

22. Expected Benefit FactorsDescriptionDecrease risk of death Decrease risk of recurrence May facilitate initial staging and follow up T11cm or less, intrathyroidal 1-2 cm, intrathyroidal T2> 2 to 4 cm, intrathyroidal T3> 4cm < 45 yrs old > 45 yrs old Any size, any age, minimal extrathyroidal extension T4Any size with gross extrathyroidal extension Potential Benefits of RAI Ablation New Table in the Updated ATA Thyroid Cancer Guidelines No Yes NoConflicting DataYes NoConflicting DataYes No Yes No Conflicting Data Yes Inadequate Data Yes ATA Thyroid Cancer Guidelines, Revised 2009

23. Expected Benefit FactorsDescriptionDecrease risk of death Decrease risk of recurrence May facilitate initial staging and follow up Nx, N0No clinical or pathologic LN documented N1< 45 yrs old > 45 yrs old M1Distant metastasis present No Conflicting Data Yes No Yes Potential Benefits of RAI Ablation New Table in the Updated ATA Thyroid Cancer Guidelines ATA Thyroid Cancer Guidelines, Revised 2009

24. Proposed Language ATA Guidelines  Radioiodine ablation is recommended for all patients with known distant metastases, gross extrathyroidal extension of the tumor regardless of tumor size, or primary tumor size greater than 4 cm even in the absence of other higher risk features  Radioiodine ablation is recommended for selected patients with 1-4 cm thyroid cancers confined to the thyroid, documented lymph node metastases, or other higher risk features when the combination of age, tumor size, lymph node status and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer  Radioiodine ablation is not recommended for patients with unifocal cancer less than 1 cm without other higher risk features ATA Thyroid Cancer Guidelines, Revised 2009

25. Risk Adapted Management Risk of DeathRisk of Recurrence Guide Initial Treatment Recommendations (Extent of surgery, RAI ablation, EBRT etc) Guide Intensity and Timing of Follow up (Tg, US, RAI scans, PET scans, CT scans etc)

26. Risk Adapted Management First 2 years of follow up LowIntermediateHigh Supp Tg Stim Tg Neck US Dx WBS MRI, CT FDG PET Tuttle. Endocrine Practice 14: 764-774, 2008.

27. Risk Adapted Management First 2 years of follow up LowIntermediateHigh Supp TgQ 6 months Stim TgNot required Neck USQ year x2 Dx WBSNot required MRI, CTNot required FDG PETNot required Tuttle. Endocrine Practice 14: 764-774, 2008.

28. Risk Adapted Management First 2 years of follow up LowIntermediateHigh Supp TgQ 6 months Stim TgNot required1-2 years Neck USQ year x2 Dx WBSNot required1-2 years MRI, CTNot required FDG PETNot required Tuttle. Endocrine Practice 14: 764-774, 2008.

29. Risk Adapted Management First 2 years of follow up LowIntermediateHigh Supp TgQ 6 months Stim TgNot required1-2 years Neck USQ year x2 Dx WBSNot required1-2 years MRI, CTNot required If Tg elevated or high clinical suspicion FDG PETNot required If Tg elevated, RAI scan negative Response to Therapy Variables (Tg, US, RAI scans, PET scans, CT scans etc) Tuttle. Endocrine Practice 14: 764-774, 2008.

30. Response to Therapy Assessment Excellent response Acceptable Response Incomplete Response Supp Tg Stim Tg Trend in Tg Anti-Tg antibodies Not included in current risk stratification systems Tuttle. Endocrine Practice 14: 764-774, 2008.

31. Response to Therapy Assessment Excellent response Acceptable Response Incomplete Response Supp TgUndetectable Stim TgUndetectable Trend in Tg Remains undetectable Anti-Tg antibodies Absent Not included in current risk stratification systems Tuttle. Endocrine Practice 14: 764-774, 2008.

32. Response to Therapy Assessment Excellent response Acceptable Response Incomplete Response Supp TgUndetectableDetectable but < 1 ng/mL Stim TgUndetectable< 10 ng/mL Trend in Tg Remains undetectable Declining Anti-Tg antibodies AbsentAbsent or declining Not included in current risk stratification systems Tuttle. Endocrine Practice 14: 764-774, 2008.

33. Response to Therapy Assessment Excellent response Acceptable Response Incomplete Response Supp TgUndetectableDetectable but < 1 ng/mL > 1 ng/mL Stim TgUndetectable< 10 ng/mL> 10 ng/mL Trend in Tg Remains undetectable DecliningStable or rising Anti-Tg antibodies AbsentAbsent or decliningPersistent or rising Not included in current risk stratification systems Tuttle. Endocrine Practice 14: 764-774, 2008.

34. Response to Therapy Assessment Neck Ultrasonography ExcellentAcceptableIncomplete NED Tuttle. Endocrine Practice 14: 764-774, 2008.

35. Response to Therapy Assessment Neck Ultrasonography ExcellentAcceptableIncomplete NEDNon-specific changes in thyroid bed Probable inflammatory lymph nodes Stable millimeter sized cervical LN even if abnormal by US criteria Tuttle. Endocrine Practice 14: 764-774, 2008.

36. Response to Therapy Assessment Neck Ultrasonography ExcellentAcceptableIncomplete NEDNon-specific changes in thyroid bed Probable inflammatory lymph nodes Stable millimeter sized cervical LN even if abnormal by US criteria Evidence of structurally significant recurrent/persistent disease in the thyroid bed (> 1 cm) Cervical lymph nodes (> 1cm), particularly if structurally progressive or FDG avid Tuttle. Endocrine Practice 14: 764-774, 2008.

37. Secondary Risk Stratification 2 years after initial therapy Based on Accumulating Clinical Data ExcellentAcceptableIncomplete Lower our initial risk estimates Response to Therapy Tuttle. Endocrine Practice 14: 764-774, 2008.

38. Secondary Risk Stratification 2 years after initial therapy Based on Accumulating Clinical Data ExcellentAcceptableIncomplete Lower our initial risk estimates Little change in our initial risk estimates Response to Therapy Tuttle. Endocrine Practice 14: 764-774, 2008.

39. Secondary Risk Stratification 2 years after initial therapy Based on Accumulating Clinical Data ExcellentAcceptableIncomplete Lower our initial risk estimates Little change in our initial risk estimates Raise our initial risk estimates Response to Therapy Tuttle. Endocrine Practice 14: 764-774, 2008.

40. Risk Stratification An active, ongoing process Risk Assessment Treatment Plan Response to Therapy Follow up Strategy Tuttle. Endocrine Practice 14: 764-774, 2008.

41. Risk Adapted Management of Thyroid Cancer Individualized Recommendations Risk Appropriate Therapy Risk Appropriate Follow up Minimizes Unnecessary Treatments and Testing Maximizes Benefits of Therapy