Key Topics in Thyroid Cancer Worldwide epidemic What Should the Endocrinologist and Surgeon do?

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1 Key Topics in Thyroid Cancer Worldwide epidemic What Should the Endocrinologist and Surgeon do? Martin Schlumberger Gustave Presenter Roussy Name and Université Paris Saclay, Villejuif, France 1

2 Disclosure Relevant financial relationships Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Eisai, Exelixis Sobi IPSEN, Roche, Sanofi Genzyme. Agenda 1. Low risk thyroid cancer: definition and incidence 2. Micro tumors: avoid overdiagnosis 3. Clinical DTC: risk based initial treatment and FU Haugen BR (Chair), Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff K, Sherman SI, Sosa JA, Steward DL, Tuttle M, Wartofsky L American Thyroid Association Management Guidelines for adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26:

3 Prevalence of incidental DTC over time in autopsy series: a large reservoir 4.1% 11.2% Same prevalence in males and females Furuya Kanamori L, JCO 2016; 34

4 Thyroid cancer: incidence/mortality in the USA Overdiagnosis Increased incidence due to the discovery of small PTC No decreased mortality from DTC. Davies L & Welch G, JAMA Otolaryngol Head Neck Surg. 2014;140:

5 The main cause of increasing incidence: Screening Ahn HS & Wesch HG. N Engl J Med 2015; 373: 2389

6 Avoid overdiagnosis Definition of Overdiagnosis: diagnosis of tumors that would not, if left alone, result in symptoms or death. For each individual, it is not possible to confirm overdiagnosis (except if the individual is never treated and dies from another cause), and this may lead to treat all individuals with the disease Consequence: Overtreatment induces cost, inconvenience and morbidity, and may transform a healthy individual in a cancer patient

7 Overdiagnosis In 2007, overdiagnosis accounts for 90% of thyroid cancer cases in South Korea, for 70 80% in the USA, Italy and France and for 50% in Japan, Nordic Countries and UK. Vaccarella S et al., NEJM; 2016

8 Avoid overdiagnosis! Avoid overdiagnosis!! The 2015 ATA recommendations: 1. do not perform neck US in asymptomatic subjects 2. do not perform thyroid FNA on solid nodules < 10 mm unless there is evidence of extrathyroidal extension or of lymph node or distant metastases; 3. restrict surgery to lobectomy and avoid RAI in those with low risk features; 4. conduct further research to define the role of active surveillance instead of immediate surgery for patients with low risk tumors.

9 An alternative to immediate surgery: active surveillance An observational trial for papillary thyroid microcarcinoma in Japanese patients (Ito Y et al.) 340 patients Risk of progression decreases with older age and is rare (3%) in pts > 65 years

10 Thyroid cancer Decrease the number of useless treatments: Avoid overdiagnosis Improve treatment of thyroid nodules >10 mm: 1. Increase the rate of thyroid cancer from 5% of all thyroid nodules to >30% of operated nodules. Neck ultrasonography and EU TIRADS classification Fine needle aspiration biopsy in selected nodules 2. Extent of treatment based on prognostic factors

11 Thyroidectomies, incidence Incidence of thyroid cancers: / / year > 70% are microcarcinomas Incidence of thyroidectomies / / year Germany: 109 (2012) France: 80 (2012) according to the region UK: 27 (2012) The Netherlands: 16 (2008) USA: 42 (2011) Need to improve the ratio thyroid cancers/surgeries

12 Thyroid cancer Decrease the number of useless treatments: Avoid overdiagnosis Improve treatment of thyroid nodules >10mm: 1. Increase the rate of thyroid cancer from 5% of all thyroid nodules to >30% of operated nodules. Neck ultrasonography and EU TIRADS classification Fine needle aspiration biopsy in selected nodules 2. Extent of treatment based on prognostic factors

13 ATA Nodule Sonographic Pattern Risk of Malignancy (S. Mandel) High Suspicion 70 90% Intermediate Suspicion 10 20% Low Suspicion 5 10% Very low Suspicion <3% Benign <1%

14 Clinico pathological algorithms Category Risk of Malignancy (%) Usual Management 1. Insufficient for Diagnosis 1-4 Repeat FNA under US 2. Benign (65%) <1 Follow up with US 3. AUS or FLUS ~5-15 Repeat FNA, then surgery? 4. Susp for a Follicular Neo Lobectomy 4. Susp for a Hürthle Cell Neo 25% Lobectomy 5. Susp for Malignancy (usually papillary CA) Lobectomy or total thyroidectomy 6. Malignant (4-5%) Total thyroidectomy Corrolate cytology and US findings Use mutation screening or other genetic tests in category 4

15 Thyroid cancer Decrease the number of useless treatments: Avoid overdiagnosis Improve treatment of thyroid nodules >10 mm: 1. Increase the rate of thyroid cancer from 5% of all thyroid nodules to >30% of operated nodules. 2. Extent of treatment based on prognostic factors

16 Risk Assessment: A Dynamic, Active Process Initial Assessment of Risk of Recurrence/Death AJCC/MACIS & ATA Risk Estimates Guide initial treatment Ongoing Risk Re-assessment: guide subsequent follow-up (Re-assessed at each follow-up visit) Excellent Biochemical Incomplete Structural Incomplete Indeterminate MR Tuttle 2009/2015 ATA Guidelines

17 TNM classification 8 th edition 2017: risk of thyroid cancer related death Age < 55 years 55 years 90-95% 5-10% Stage I M0 pt1 T2, N0/x Stage II M1 pt1 T2, N1, M0 pt3a b, any N, M0 Stage III pt4a, any N, M0 Stage IVA pt4b, any N, M0 Stage IVB M1 Higher risk of cancer related death

18 Differentiated Thyroid Cancer (E.Mazzaferri. JCEM 2001) % 50 Recurrence AJCC/TNM Predict risk of death, not recurrence Death > 70 Age (yrs) at time of initial therapy

19 Risk of Structural Disease Recurrence (In patients without structurally identifiable disease after initial therapy) FTC, extensive vascular invasion ( 30 55%) pt4a gross ETE ( 30 40%) pt4 M1 R1, R2 Inappropriate post op Tg High Risk (>20%) Intermediate Risk (5% 20%) pt3 N0 Nx pt1 3, N1a N1b Aggressive histology or vascular invasion RAI uptake outside the thyroid bed Low Risk (<5%) pt1 T2 N0/Nx No aggressive histology, no vascular invasion pn1 with extranodal extension, >3 LN involved (38%) pn1, any LN > 3 cm ( 30%) BRAF mutated, not intrathyroidal ( 10 40%) PTC, vascular invasion ( 15 30%) Clinical N1 ( 20%) pn1, > 5 LN involved ( 20%) BRAF mutated, intrathyroidal, < 4 cm ( 10%) pt3 minor ETE ( 3 8%) pn1, all LN < 0.2 cm ( 5%) pn1, < 5 LN involved ( 5%) Intrathyroidal 2 4 cm PTC ( 5%) Multifocal PMC ( 4 6%) pn1 with extranodal extension, 3 LN involved (2%) Minimally invasive FTC ( 2 3%) BRAF wild type, intrathyroidal, < 4 cm ( 1 2%) Intrathyroidal, encapsulated, FV PTC; Unifocal PMC ( 1 2%)

20 Changes in WHO classification 2017 vs Papillary carcinoma Tall cells ( > 30%) Solid ~ 100% Follicular variant. NIFTP 2. Follicular carcinoma Minimally invasive (capsular invasion only) Encapsulated with angio invasion (prognostic significance of angioinvasion > size of the tumor) Widely invasive 3. Hürthle cell carcinoma 4. Poorly differentiated carcinoma

21 FVPTC Encapsulated without invasion: Non invasive follicular thyroid neoplasm with papillary like nuclear features NIFTP (WHO 2017)

22 The past: recurrence rate after initial treatment (E. Mazzaferri, 1976)

23 The past: the old dogma Total thyroidectomy + RAI ablation + TSHsuppression in all patients with extended disease. Surgery Thyroid cancer RAI ablation Hormonal therapy The spectrum of disease has changed: extent of most thyroid tumors is limited and the quality of care (surgery) improved: need for a risk based approach.

24 US National Cancer Data Base: PTC < 4 cm, no aggressive histology Bilimoria, 2007 N=52,173 pts operated between Adam, 2014 N=61,775 pts operated between Survival at 10 years: HR = 1.21 [ ], p=0.027 ATA guidelines 2009: TT for all TC >1 cm Survival at 10 years: HR = 0.96 [ ], p=0.54 ATA guidelines 2015: lobectomy may be enough in low risk patients (extrathyroid extension, multifocality and completeness of resection were taken into account)

25 Extent of surgery: avoid morbidity in lowrisk thyroid cancer patients Optimal surgery may be a total thyroidectomy, when performed with a minimal risk of morbidity However, total thyroidectomy does not improve OS in low risk thyroid cancer patients when the risk of morbidity is high, a lobectomy is an alternative for many patients (T1 T2) many low risk patients do not need post op RAI Same debate for prophylactic lymph node dissection: not needed in T1 T2 patients? randomized trial (ESTIMABL3) in T2cN0 patients

26 Objectives of post op RAI administration After Total Thyroidectomy Definition Benefits Limitations Post RAI TBS Sensitive and specific with SPECT/CT To assess absence of persistent RAIavid disease. Previous Dg-TBS not needed Low risk of persistent disease in most patients Treatment Destruction of neoplastic foci, known (treatment) or remote (adjuvant) To improve disease free survival and overall survival Applies only to patients with persistent disease Remnant ablation Destruction of normal residual thyroid tissue To achieve an undetectable serum thyroglobulin (Tg) level Tg can be measured on T4 in the presence of thyroid remnants

27 Mayo Clinic: survival according to TNM stage < 5% of DTC patients received post op RAI

28 Post operative RAI: patient selection (2015 ATA guidelines) RECOMMENDATION 50: After total thyroidectomy, RAI remnant ablation: is not routinely recommended for ATA low risk. should be considered for ATA intermediate risk. is routinely recommended for ATA high risk patients. Low and intermediate risk patients can be selected for RAI based on serum Tg determination

29 ESTIMABL1: 641 low risk patients without anti Tg antibodies 11 N1/ % Tg/TSH ng/ml Persistent disease at ablation 1 5 / 305 (1.6%) >1 5 6 / 216 (2.4%) / 62 (3.3%) >10 6 /55 (10.7%) Outcome at 5 years Persistent disease Only 19/641 (2.5%) patients had evidence of persistent disease. They should be selected to avoid RAI ablation in the other 97.5%. Schlumberger M et al. NEJM 2012

30 Sensitive Tg Functional sensitivity of : 0.1 ng/ml : Correlation stg/lt4 and Tg/rhTSH Tgus/LT4 <0.1 ng/ml % de Tg/rhTSH > patients 2 (0,3%) No need for routine rhtsh stimulation test when stg/lt4 < 0.3 ng/ml Spencer C. et al. JCEM, 2010

31 Persistent disease according to Tg/l T4 at 3 4 months after total thyroidectomy Tg levels <0.1 ng/ml ng/ml > 1 ng/ml Patients (low/intermediate risk) Patients with disease 1 (0.7%) 15 (5.2%) 11 (16.2%) Detected with Neck US only Detected with ptwbs only N1: 3 / bone: 1/ lung 3 Detected with neck US and ptwbs 0 0 N1: 3 Matrone A, JCEM 2016

32 Tg/T4 level may be used for follow up in the absence of RAI ablation Retrospective study on low risk patients (T1-T2, N0, M0) after TT Study population (n=290) No 131 I Median follow-up: 6 yrs Range: Serum Tg/LT4 (Functional sensitivity: 1 ng/ml) 1 ng/ml: 274 >1 ng/ml: 16 (5%) 1 recurrence Control (n=495) Durante C, JCEM I Median follow-up: 5 yrs Range: ng/ml: 492 (99%) >1 ng/ml: 3 (1%) 0 recurrence

33 Selection of low risk patients for post op RAI When stim Tg is < 1 5 ng/ml or Tg/T4 is < 0.3 ng/ml, the risk of persistent disease is to 1 2%: RAI and imaging techniques are not costeffective. Follow up on T4 treatment (neck US Tg) In the few patients with a stim Tg >10ng/mL or Tg/T4>1 ng/ml: RAI administration Ongoing prospective trials: 30mCi/rhTSH vs no RAI; ESTIMABL2 (T1b, N0, NX with normal neck US), IoN

34 Optimal protocol for RAI administration in low risk patients TSH stimulation 131I activity rhtsh administration LT4 withdrawal Low 1100 MBq T1aN1,Nx T1bN0,N1,Nx pt2n0) High 3700 MBq M Schlumberger, NEJM 2012: ESTIMABL1 U Mallick, NEJM 2012: HiLo

35 Follow up strategy Surgery ± 131 Iablation Check for TSH target Check for disease status: serum Tg+neck US Subsequent follow-up months Is the patient disease free? What is the risk for recurrence? Serum Tg is obtained either following rhtsh or on l-t4 treatment (stg with a reliable method). No role for diagnostic RAI-WBS

36 Estimabl1: Ablation success with rhtsh vs THW and 30 mci vs 100 mci 100% Success Rates, 6 10 Months After Ablation (684 evaluable patients) 90% 93% 92% 94% Complete Thyroid Ablation (%, both Tg and neck US) 80% 60% 40% 20% 0% Thyrogen 30 mci (n=160/177) THW 30 mci (n=159/171) Thyrogen 100 mci (n=156/170) THW 100 mci (n=156/166) Ablation success in 631 (92%) patients: serum Tg/rhTSH < 1ng/mL + normal neck US 5 years FU: 1 N1 recurrence among 631 patients with complete ablation Schlumberger M, et al. N Engl J Med. 2012;366:

37 ESTIMABL1: mean change in EQ 5D utility score during post op RAI treatment ABLATION Recombinant human thyroid stimulating hormone Thyroid hormone withdrawal Months Schlumberger M et al. N Engl J Med 2012; 366:1663; Borget I et al. JCO 2015; 33: 2885.

38 Estimabl1: outcome of the 711 patients mean FU: 62 months (> 3 years for 91%) 700/711 patients (98.5%) had no evidence of disease 11 patients had persistent disease: 5 had persistent structural disease: 4 had initial persistent disease Only 1/631 patients with complete ablation had a N1 recurrence 6 had serum Tg > 0.3 ng/ml on l T4 without any structural abnormality Initially, among these 11 patients: 6 patients received 1.1 GBq (4 after rhtsh and 2 after THW) 5 patients received 3.7 GBq (3 after rhtsh and 2 after THW). No thyroid cancer related death was observed. Schlumberger M. Lancet Diabetes Endocrinol. 2018

39 Indications: Post op RAI administration NO RAI 1100 MBq/rhTSH 3700 MBq/rhTSH 3700 MBq/withdrawal pt1a N0/Nx pt1b T2, pt3>4cm N0/Nx/Min N1 pt3 ETE N0/Nx/min N1 pt1 3 N1a N1b : according to location, number, size, ECE of N1 pt4 or M1 Undetectable or low Tg and normal neck US Elevated Tg and/or Abnormal neck US No need for routine Dx WBS before RAI administration

40 Conclusion: take home messages