1. Focus on endocrine neoplasia July 9, 2010 Rome Furio Pacini Dipartimento di Medicina Interna e Scienze Endocrino-Metaboliche Università di Siena Differentiated thyroid carcinoma: Treatment and follow-up

2. Thyroid cancer incidence and mortality in USA (1973-2002) and Italy (1988-2002) Italian Network of Cancer Registries, 2006 Italy USA APC: USA 3.8% Italy 4.0%

3. Thyroid cancer incidence in USA (1973-2002) and Italy (1988-2002) Italy USA Italian Network of Cancer Registries, 2006

4. Trend incidence of papillary thyroid cancer by size in USA (1988-2002)

6. CRITICAL STEPS IN THE MANAGEMENT OF DTC Surgery 131 I therapy Short term follow up Long term follow up

7. ATA and ETA Differentiated thyroid cancer guidelines: Surgery for cytology diagnostic of malignancy Preoperative ultrasound for the contralateral lobe and cervical lymph nodes (central and bilateral) is recommended for all patients undergoing thyroidectomy for suspicious cytology Near total or total thyroidectomy should be the initial procedure in any malignancy discovered before surgery. Thyroid lobectomy alone may be sufficient treatment for small, isolated, intrathyroidal papillary carcinomas in the absence of cervical nodal metastases, that have been diagnosed at final histology when the surgical procedure had been performed for other indications.

8. POST-SURGICAL RADIOIODINE ABLATION Rationale: –Ablation: eradication of normal thyroid remnants –Treatment: irradiation of persistent disease –Total body scan a few days later –Diagnostic scan useless –The combination of serum Tg, post-therapy WBS and neck ultrasound is a strong predictor of the future outcome.

9. Metanalysis of radioiodine effectiveness ( Sawka et al, J Clin Endocrinol Metab, 2004) SeriesNFollow-up (yr) 131 I Effectiveness cancer mortality 131 I Effectiveness cancer recurrence Ohio State151016.6P<0.0001P<0.016 UCSF18710.6NSP<0.0001 Hong Kong5879.2NS Toronto38210.8NS Illinois Reg22826.5NS Gundersen1777.2NS Anderson159911P<0.001 Gustave R.2737.3NS Mexico2295NS Pisa96412NSP<0.001

10. Does post-surgical 131-I decrease DTC recurrence and mortality rates? European Consensus (Pacini et al. EJE 153:1-10, 2005) Very low-risk patients: Benefit unifocal T1 <1 cm N0 M0no evidence Low-risk patients: T1 >1 cm N0 M0may decrease recurrence T2 N0 M0but evidence not definitive High-risk patients: any T3 and T4evidence of decreased any T N1recurrence and mortality M1rate

11. 100 mCi; hypo vs rhTSHrhTSH; 50 vs 100 mCi

15. On l-T4 therapy: Measurements of Serum Tg and anti-Tg antibodies Thyroid hormones and TSH: to assess the appropriate dose of l-T4 FOLLOW-UP: 3 months after ablation

16. FOLLOW-UP: 8-12 MONTHS AFTER ABLATION Clinical examination: poorly sensitive Neck ultrasonography Serum Tg determination following TSH stimulation ( 131 I-total body scan)

17. Follow-up of differentiated thyroid carcinoma after surgery and radioiodine ablation Options 1. After thyroid hormone withdrawal or after rhTSH ?? 2. based on stimulated serum Tg measurement alone or in combination with 131-I WBS ??

18. SERUM Tg DETERMINATION Serum Tg is a marker of disease (Van Herle, 1975), not a disease Measurement: –Immunometric assay (IMA) –Standardization: CRM-457 –Functional sensitivity < 1ng/mL. Supersensitive methods (<0.1ng/mL): improved sensitivity but decreased specificity. –Search for interferences: Measurement of anti-Tg antibodies.

19. DETECTABLE Tg LEVEL AFTER THYROID ABLATION. Eustatia-Rutten, Clin Endocrinol, 61: 61, 2004 The sensitivity of serum Tg determination is improved by 15-20% following TSH stimulation.

20. SIGNIFICANCE OF DETECTABLE Tg/TSH AT 1 YEAR Haugen 2002 Mazzaferri 2002 Robbins 2002 Torlontano 2003 Pacini 2003 Baudin 2003 n8310710992294256 Tg/TSH >1 ng/ml(%) 17191715 14 Disease detected 68.48.23.37.83.5 Neck / Distant 4.8/1.23.7/4.74.6/3.73.3/06.1/1.71.9/1.6 NED9.610.39.2127.110.9

21. J Clin Endocrinol Metab. 2002, 87:1499-501

23. SeriesPatients (n) StimulusFalse neg. Tg (WBS+/Tg-) False neg. WBS (WBS-/Tg+) Robbins366rhTSH54/175 (31%) 75/191 (39%) Pacini315hypo0/315 (0%)Not included Cailleux256hypo0/210 (0%)46/46 (100%) Mazzaferri107rhTSH0/68 (0%)39/39 (100%) Torlontano99rhTSH0/78 (0%)21/21 (100%) Pacini72rhTSH0/41 (0%)20/31 (64.5%) All121554/887 (6.1%) 201/328 (61.2%) Metanalysis of the rate of false negative stimulated Tg and WBS

24. DETECTION OF NECK RECURRENCES DETECTION OF NECK RECURRENCES Combination of neck US and Tg/TSH determination.

25. USE OF rhTSH. The benefits in terms of QOL of rhTSH over withdrawal are obvious. Is the sensitivity of serum Tg similar following rhTSH and withdrawal?

26. 0 10 20 30 40 50 60 70 80 90 100 Percent rhTSH Testing: Metastatic Cancer Detection Rate 100 77 100 97 80 88 67 57 2 105 Serum Thyroglobulin (ng/mL) rhTSH whole-body scan and Tg rhTSH Tg Tg on thyroid hormone therapy Haugen BR, Pacini F, Reiners C, et al: J Clin Endocrinol Metab. 1999;84:3877

27. 1 10 100 Peak rhTSH Tg Hypo Tg Tg ng/ml p= 0.001 Correlation between peak rhTSH-Tg and hypo-Tg (31 patients, Department of Endocrinology, Pisa )

28. CONCLUSION: ELEVATED SERUM Tg LEVELS. Some months after initial treatment, detectable serum Tg (<5-10ng/mL) may be produced by: –irradiated cells that will disappear in 2/3 of cases (Baudin, Pacini, Torlontano, Toubeau), and serum Tg will decrease –neoplastic cells that will progress, and serum Tg will increase. A control TSH-stimulated Tg obtained some months (or years) later will differentiate these two groups of patients. The most relevant parameter is the trend of Tg level, rather than its level.

29. LOW RISK PATIENTS: UNDETECTABLE STIMULATED SERUM Tg AT 8-12 MONTHS False negative results are rare (excellent NPV) LT4 dose can be decreased to achieve a low- normal serum TSH level (0.5-2.5 µU/mL) Patients are followed up on a yearly basis on replacement L-T4 treatment. In the absence of abnormalities, no other testing is warranted.

30. ETAATA Persistent diseaseTSH <0.1 mU/L Evidence of remission low riskreplacement high risksuppressive duration3-5 years ETA and ATA guidelines: l-T4 therapy suppressive vs replacement

31. CONCLUSIONS Follow up based on neck US and Tg/TSH is all we need for nearly 80% of the patients (the low risk) Other diagnostic and treatment modalities in selected cases at risk of recurrence or metastases.