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Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based Approach Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong.

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Presentation on theme: "Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based Approach Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong."— Presentation transcript:

1 Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based Approach Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong

2 Welcome and introduction Dr June-Key Chung Professor of Nuclear Medicine Seoul National University Hospital, Korea

3 Programme Welcome and introduction Case Review: a risk-based approach Dr Furio Pacini (Italy) Dr R. Michael Tuttle (US) Audience Q&ADr Young-Kee Shong (Korea) Concluding remarksDr Young-Kee Shong (Korea) Luncheon served

4 Questions A voting card is in your pack – this can be used to answer questions from the presenters Q & A session – use the standing microphones

5 Case Review: a risk- based approach Dr Furio Pacini Professor of Endocrinology University of Siena, Italy

6 Clinical case A 45 year-old medical sonographer does a neck US on herself and finds abnormal looking paratracheal nodes. They are hypoechoic with multiple echogenic foci. The thyroid gland is normal. FNAC of one of the paratracheal nodes shows highly atypical cells and serum Tg in the aspirate is 480 ng/ml. A 45 year-old medical sonographer does a neck US on herself and finds abnormal looking paratracheal nodes. They are hypoechoic with multiple echogenic foci. The thyroid gland is normal. FNAC of one of the paratracheal nodes shows highly atypical cells and serum Tg in the aspirate is 480 ng/ml.

7 Clinical case The patient undergoes a total thyroidectomy plus bilateral central and right lateral neck dissection. Pathology: classical papillary thyroid cancer in the right lower pole (3 mm); four of six central nodes are + for classical papillary cancer; lymph nodes in the right lateral nodes normal. AJCC/UICC Stage I ATA risk: intermediate. ETA risk: high The patient undergoes a total thyroidectomy plus bilateral central and right lateral neck dissection. Pathology: classical papillary thyroid cancer in the right lower pole (3 mm); four of six central nodes are + for classical papillary cancer; lymph nodes in the right lateral nodes normal. AJCC/UICC Stage I ATA risk: intermediate. ETA risk: high

8 Risk stratification ATA Guidelines ATA Guidelines 2008. Thyroid 2009:19:1167-1214

9 Indication for RAI ablation (ATA) ATA Guidelines 2008. Thyroid 2009:19:1167-1214

10 Low riskHigh risk Intrathyroidal tumor (T1 >1 cm-T2), uni- or multifocal Aggressive histology No local or distant metastases Possible indication T3 Intrathyroidal or wiht minimal extrathyroidal invasion T4 Locoregional metastases Distant metastases Strong indication Very Low risk Unifocal intrathyroidal tumor (1 cm) No aggressive histology No metastases No indication ETA Consensus 2006. Eur J Endocrinology 2006; 154: 787–803 ETA Consensus

11 Case 1 The patient received 50 mCi of 131I after administration of rhTSH (0.9 mg i.m. for two consecutive days) Basal TSH: 0.2 mU/l, TSH after rhTSH: 156 mU/l Basal Tg <1.0 ng/ml, Tg after rhTSH: 2.1 ng/ml Urinary excretion: 120 mg/l, AbTg negative Post-therapeutic whole body scan: uptake in the thyroid bed and two lateral nodes. The patient received 50 mCi of 131I after administration of rhTSH (0.9 mg i.m. for two consecutive days) Basal TSH: 0.2 mU/l, TSH after rhTSH: 156 mU/l Basal Tg <1.0 ng/ml, Tg after rhTSH: 2.1 ng/ml Urinary excretion: 120 mg/l, AbTg negative Post-therapeutic whole body scan: uptake in the thyroid bed and two lateral nodes.

12 Case Post-therapeutic WBS: uptake in the thyroid bed and in the right cervical region

13 Case 12 months after ablation: rhTSH control diagnostic WBS: no uptake Neck ultrasound: negative Basal and stimulated Tg undetectable (<1 ng/ml) The patient is considered in remission. 12 months after ablation: rhTSH control diagnostic WBS: no uptake Neck ultrasound: negative Basal and stimulated Tg undetectable (<1 ng/ml) The patient is considered in remission.

14 Question for the audience: Is this patient still high risk? A. Yes B. No Is this patient still high risk? A. Yes B. No

15 Tuttle RM, et al. Thyroid 2010;20: 1341-9

16 PPV 95% CI NPV PVEETA0.384*°0.355-0.4070.913*°0.878-0.94119.1% ATA0.392*°0.360-0.4170.906*°0.871-0.93425.4% DRS0.728°0.685-0.759 0.963° 0.963°0.944-0.97762.1% 512 patients * p>0.05; ° p<0.05 Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

17 Question for the audience: What follow-up in this patient? A. Basal serum Tg and neck US once a year B. TSH-stimulated Tg What follow-up in this patient? A. Basal serum Tg and neck US once a year B. TSH-stimulated Tg

18 OUTCOME OF PATIENTS WITH TSH STIMULATED Tg 1ng/mL (Negative neck US) 219 patients Mean follow-up: 15 years Neck lymph node recurrence at US: 1 (< 0.5%). TSH in the normal range (0.5-2.5 mU/L) in > 90%. Cailleux, JCEM, 2000. 219 patients Mean follow-up: 15 years Neck lymph node recurrence at US: 1 (< 0.5%). TSH in the normal range (0.5-2.5 mU/L) in > 90%. Cailleux, JCEM, 2000. Excellent NPV of Tg/TSH No clinical significance of low uptake in thyroid bed 315 patients Mean follow-up: 12 years Mean follow-up: 12 years Neck lymph node recurrences at US: 2 (0.6%). Neck lymph node recurrences at US: 2 (0.6%). Pacini, JCEM, 2002. Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

19 In patients with no evidence of disease: Risk of recurrence at 20 years < 0.5% The daily dose of LT4 may be decreased to achieve a serum TSH in the low-normal range Subsequent follow-up: clinical examination, serum Tg and TSH determination, neck US once a year Is there a need for further rhTSH-stimulated Tg? Risk of recurrence at 20 years < 0.5% The daily dose of LT4 may be decreased to achieve a serum TSH in the low-normal range Subsequent follow-up: clinical examination, serum Tg and TSH determination, neck US once a year Is there a need for further rhTSH-stimulated Tg?

20 NO NEED TO REPEAT rhTSH IN PATIENTS WITH UNDETECTABLE rhTSH STIMULATED Tg CASTAGNA, JCEM, 2008 77 patients with no evidence of disease at 9-12 months. Repeated rhTSH + neck US at 2-3 years. – 67 with undetectable rhTSH stimulated Tg: at 2-3 years, 67 had undetectable rhTSH stimulated Tg neck US demonstrated neck recurrence in 1 – 10 with detectable rhTSH stimulated Tg: at 2-3 years, 6 had undetectable rhTSH stimulated Tg 4 had detectable stimulated Tg 77 patients with no evidence of disease at 9-12 months. Repeated rhTSH + neck US at 2-3 years. – 67 with undetectable rhTSH stimulated Tg: at 2-3 years, 67 had undetectable rhTSH stimulated Tg neck US demonstrated neck recurrence in 1 – 10 with detectable rhTSH stimulated Tg: at 2-3 years, 6 had undetectable rhTSH stimulated Tg 4 had detectable stimulated Tg Castagna MG, et al. JCEM 2008; 93:76–81

21 203 DTC patients fulfilling the criterion of remission after initial therapy TSH-stimulated Tg repeated 5 years later 94.6% stimulated Tg <1-2 ng/ml: no recurrence 5.4% (11 pts) stimulated Tg >2 ng/ml (4.5-43 ng/ml): – 3: Lymph node mets detected by US – 5: mets detected by other imaging (2 in cervical nodes, 1 in the mediastinum, 2 in the lungs) – 3: disease not found Rosario, PW, et al. Thyroid 2012;22:482-6

22 Application of the Risk Based Management Approach – decision-making with regard to RAI ablation Dr R Michael Tuttle, MD Professor of Medicine Memorial Sloan Kettering Cancer Center New York

23 Changing Paradigms in the Management of Thyroid Cancer Increased Emphasis Risk of death Risk of recurrence Risk of persistent disease Risk of failing initial therapy Traditional Paradigm One Size Fits All Total thyroidectomy RAI remnant ablation All with same follow up Risk Adapted Paradigm Management recommendations based individualized risk assessment

24 It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so. Words of wisdom attributed to Mark Twain Changing management paradigms

25 What we know for sure 30% risk of recurrence (Over estimate the risk of recurrence?) RAI ablation decreases recurrence by 50% (Over estimate the impact of RAI on recurrence?) Side Effects of RAI are mild and temporary (Under estimate the side effects of RAI?) RAI ablation decreases the risk of death (Over estimate the impact of RAI on survival?) RAI ablation is required for follow-up (Under estimate neck US and Tg without ablation?)

26 Low Risk Intrathyroidal DTC Intermediate Risk N1 disease, minor extrathyroidal extension vascular invasion, or aggressive histology High Risk Gross extrathyroidal extension incomplete tumor resection, or distant metastases Unifocal PMC (1-2%) Multifocal PMC (4-6%) Intrathyroidal 2-4 cm PTC (5-6%) pN1, < 5 LN involved (4%) pN1, > 5 LN involved (19%) Clinical N1 (22%) pN1, all LN < 0.2 cm (5%) pN1, any LN > 3 cm (27%) pT3 minor ETE (3-8%) pT4a gross ETE (23-40%) Risk stratification by categoryRisk stratification within categories* Risk of Structural Disease Recurrence *Manuscript in preparation, Randolph Thyroid 2012 FTC, extensive vascular invasion (30-55%) Minimally invasive FTC (0-7%) PTC, vascular invasion (16-30%)

27 32 yr old male Total thyroidectomy 1.9 cm unifocal Intrathyroidal PTC No lymph nodes were sampled 2-3 months post-op: Tg 1 ng/mL TSH was 1 mIU/mL Tg Ab negative Neck US is normal First Example Patient RAI Ablation A.Yes B.No

28 32 yr old male Total thyroidectomy, 1.9 cm intrathyroidal PTC Risk Without RRA Recurrence 2-4% Disease Specific Mortality < 1% Distant Metastases about 1% Risks of RAI Permanent dry mouth 1-2% Blocked tear duct 1% Second cancer < 1% Potential Benefits of RAI Facilitate Staging/Follow-up +/- Recurrence No impact on mortality Tilting the Balance Toward Benefit Selective Use Lower administered activities (30 mCi) rhTSH preparation Using RAI as salvage therapy

29 Second Example Patient 22 year old female Total thyroidectomy & left MRN dissection 2.5 cm, multifocal, well differentiated PTC 20/32 lymph nodes positive No extrathyroidal extension No vascular invasion 22 year old female Total thyroidectomy & left MRN dissection 2.5 cm, multifocal, well differentiated PTC 20/32 lymph nodes positive No extrathyroidal extension No vascular invasion RAI Ablation A.Yes B.No

30 22yr old female Total thyroidectomy, 2.5 cm intrathyroidal PTC, N1b Risk Without RRA Recurrence 25-30% Disease Specific Mortality < 1% Distant Metastases about 5-10% Risks of RAI Permanent dry mouth 1-2% Blocked tear duct 1% Second cancer < 1% Potential Benefits of RAI Facilitate Staging/Follow-up +/- Recurrence No impact on mortality Tilting the Balance Toward Benefit Selective Use 100 mCi rhTSH? What if her post-operative Tg was <0.2 ng/mL (TSH of 56 mU/L, no Tg antibodies)?

31 Unifocal PMC (1-2%) Multifocal PMC (4-6%) Intrathyroidal 2-4 cm PTC (5-6%) pN1, < 5 LN involved (4%) pN1, > 5 LN involved (19%) Clinical N1 (22%) pN1, all LN < 0.2 cm (5%) pN1, any LN > 3 cm (27%) pT3 minor ETE (3-8%) pT4a gross ETE (23-40%) Risk stratification by categoryRisk stratification within categories* Risk of Structural Disease Recurrence My personal practice as of Nov 2012 FTC, extensive vascular invasion (30-55%) Minimally invasive FTC (0-7%) PTC, vascular invasion (16-30%) Low Risk Usually no RAI If given, 30 mCi rhTSH High Risk RAI given Probably withdrawal 150 mCi Intermediate Risk Selective use rhTSH or withdrawal 0 to 30 to 150 mCi depending on risk *Manuscript in preparation, Randolph Thyroid 2012

32 New York City

33 Some points on Tg level Dr June-Key Chung Professor of Nuclear Medicine Seoul National University Hospital, Korea

34 Assumption of the ideal tumor marker All cancer cells express the tumor marker homogenously. All cancer cells secrete the tumor marker into the blood relatively equally. There is no change in the expression of tumor marker according to the patients and lesions. There is no change in the expression of tumor marker according to differentiation or progression of cancer.

35 Facts of serum thyroglobulin 660 kDa dimeric protein, > 20 epitopes different antibodies -> different concentrations in commercial kits Different nature CEA, AFP: increase associated with carcinogenesis Tg: normal component Immunostaining results showed that Tg expression was heterogenous and variable in PTC, and related to cellular differentiation in FTC. The expression of Tg might decrease in metastatic tissue of lymph node. Almost all cancers in Korea are PTCs, which often are de-differentiated and negative in Tg expression. In thyroid cancer cells, Tg molecule can be modified inhibiting secretion to the blood, or cannot be measured by some kits.

36 ItemQCConc. CV in 2012 (%) JanFebMarAprMayJunAvr Tg C-12.4515.812.811.617.29.414.6 13.6 C-227.87.712.210.611.99.011.3 10.5 C-370.17.18.79.010.48.39.5 8.8 T3 C-11017.56.33.03.73.22.6 4.4 C-21576.52.42.01.71.81.5 2.7 C-32556.93.42.92.21.22.1 3.1 T4 C-15.8613.88.73.02.93.64.5 6.1 C-29.9810.45.32.53.42.82.2 4.4 C-315.87.94.72.0 1.72.7 3.5 CA 125 C-130.66.71.53.54.05.55.2 4.4 C-298.34.93.63.12.84.0 3.7 C-32602.42.53.74.35.64.5 3.8 AFP C-19.75.55.46.55.04.94.7 5.3 C-270.94.24.0 5.74.54.0 4.4 C-31774.55.85.16.35.64.6 5.3 External QC data in Korea

37 Metastatic lymph nodes 15.93±8.42 mg/g Hurthle adenoma 1969.54±1601.11 mg/g Papillary thyroid carcinoma 206.02±476.56 mg/g Follicular thyroid carcinoma 83.76±24.33 mg/g Anaplastic thyroid carcinoma 1.63±0.48 mg/g Normal 50-100 mg/g A. Czarnywojtek. Archivum Immunologiae et Therapiae Experimentalis, 2002, 50, 143-148 Thyroglobulin Content in Thyroid Tissue

38 Staining intensitiesValue (%) Thyroglobulin (n=47) 00 (0%) 17 (15%) 230 (64%) 310 (21%) Immunohistochemistry results of Thyroglobulin in Papillary cancer J-K Chung and H Min. KTA 2012.

39 Cytoplasm Membrane Location of Thyroglobulin in Cancer tissue

40 Poorly differentiated carcinoma Heterogenous Expression of Tg

41 A C B A: Primary papillary microcarcinoma (x200) B: Tg immunostaining of primary tumor, strong positive (x400) C: Tg immunostaining of lymph node, focal positive (x200)

42 Subject - Differentiated thyroid carcinoma - 01.1~04.12 post-Therapy I-131 WBS ( 30 mCi) - Consecutive 824 patients Tg negative/I-131 WBS positive group (TgFN) - Tg 2 ng/mL (Tg-plus, BRAHMS, Germany) - Tg Ab 100 U/mL (HENNINGtest ® anti-Tg, BRAHMS, Germany) TSH-stimulation state (TSH 30 μ IU/ml) - I-131 WBS: remnant and/or functioning metastasis Tg positive/I-131 WBS positive group (TgP) - Tg > 2 ng/mL - I-131 WBS: remnant and/or functioning metastasis Recurrent/metastatic thyroid carcinoma: false negative Tg, positive I-131 scan Park EK, Chung JK et al, Eur J Nucl Med Mol Imaging, 2009;36:172-9

43 F/55 Tg negative/I-131 positive case TSH 89.4Tg <1.0TgAb <25

44 Tg negative/I-131 positive case M/17 TSH 195Tg <1.0TgAb <25

45 *59 excluded TgAb(-) : 255 (31%) Metastasis: 128 Metastasis: 128 Remnant: 203 Remnant: 203 Metastasis: 52 (6.3%) Metastasis: 52 (6.3%) I-131 WBS: 824 WBS(-): 72WBS(+): 752 Tg(+): 328Tg(-): 365 TgAb(+): 110

46 TgP vs TgFN *p<0.001 Metastatic siteTgPTgFN Cervical/Mediastinal LN91 (71.1%)45 (86.5%) Lung25 (19.5%) 6 (11.5%) Bone11 (8.6%) 1 (2.0%) Brain 1 (0.8%) 0 (0%) Total12852

47 TSH 219 Tg <1.0, Tg Ab<25 2006-12-19 I-131 200 mCi 2006-6-22 I-131 200 mCi 2005-12-17 I-131 200 mCi TSH 158 Tg <1.0, Tg Ab<25 TSH 212 Tg <1.0, Tg Ab<25 2005-8-27 I-131 30 mCi TSH 88 Tg 3.3, Tg Ab<60

48 Audience Q&A Panel discussion Dr Young-Kee Shong Professor, Department of Internal Medicine, Endocrinology and Metabolism Asan Medical Center, Seoul

49 Concluding remarks Dr Young-Kee Shong Professor, Department of Internal Medicine, Endocrinology and Metabolism Asan Medical Center, Seoul

50 Summary An individualised risk stratification approach is an emerging concept to guide initial therapy and follow up Risk should be re-assessed at every follow up to guide further intervention and follow up Importance of measuring Tg and TgAb with the same assay over time Please join us for luncheon in the Restaurant (where breakfast is served)


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