Towards a selective use of postoperative radioiodine in thyroid cancer patients

Transcription

1 Towards a selective use of postoperative radioiodine in thyroid cancer patients 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. Clinical DTC: risk based initial treatment 3. Selective use of post operative RAI and protocols 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 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

10 Mayo Clinic: survival according to TNM stage

11 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

12 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

13 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%)

14 N1 and risk of recurrence (Randolph et al. Thyroid 2012) Characteristics Median Range References Clinically N0 2% 0-9% Wada 2008 Bardet 2008 Yamashita 2009 Cranshaw 2008 < 5 N1 Size<2mm 4% 3-8% Leboulleux 2005 Bardet 2008 Sugitani 2004 > 5 N1 19% 7-21% Leboulleux 2005 Sugitani 2004 cn1, risk increases with size cn1 & extracapsular extension 22% 10-42% Ito2004,05,06,09 Cranshaw 2008 Wada 2003,08 Bardet 2008, Moreno % 15-32% Leboulleux 2005 Yamashita 2009

15 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

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

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

18 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.

19 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)

20 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; indicated if post op RAI may be necessary Same debate for prophylactic lymph node dissection: not needed in T1 T2 patients? randomized trial (ESTIMABL3) in T2cN0 patients

21 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

22 Objectives of post op RAI administration Definition Benefits Limitations Post RAI TBS Sensitive and specific with SPECT/CT To assess absence of persistent RAIavid disease. Low risk of persistent disease in most patients Previous Dg-TBS not needed 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

23 TBS at 2 7 days after 131 I administration TBS is more informative when thyroid bed uptake is < 2% (need for a total thyroidectomy). It may detect and localize persistent neoplastic foci SPECT-CT is a major advance In >97% of low-risk patients, the TBS shows only foci of uptake in the thyroid bed.

24 SPECT/CT: a major advance Single Photon Emission Tomography / Computerized Tomography 131 I TBS-2D 131 I-3D In the neck: normal thyroid remnants-n1 In the chest: ribs-lungs In the pelvis: urinary/digestive-bone

25 Abnormal post operative TBS n N1 M1 Avram 2013 Avram 2013 Schlumberger 2012 Pre ablation TBS with SPECT/CT Pre ablation TBS with SPECT/CT Post ablation TBS Prospective study pt1a % 4 % pt1b 67 52% 4.5% pt1bnxn0 pt2n0 pt1an % (13) 0.5% (3) When patients are correctly classified as low risk: TNM: the risk of thyroid cancer death is not increased ATA: the risk of persistent disease is 2 3% (multiple series!!). Question: how can we avoid useless post op RAI in the 97 98% of low risk patients with no residual disease?

26 Objectives of post op RAI administration 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 Low risk patients: post op RAI does not improve the excellent DFS or overall survival 1298 low risk patients Bicentric retrospective Median follow-up: 10 years Schvartz C., JCEM 2012

29 Risk of recurrence in the absence of post op RAI Retrospective study on low risk patients (T1-T2, N0, M0) after TT Serum Tg/LT4 (Functional sensitivity: 1 ng/ml) Study population (n=290) No 131 I Median follow-up: 6 yrs Range: ng/ml: 274 >1 ng/ml: 16 (5%) 1 recurrence Control (n=495) 131 I Median follow-up: 5 yrs Range: ng/ml: 492 (99%) >1 ng/ml: 3 (1%) 0 recurrence Durante C, JCEM 2012

30 Objectives of post op RAI administration 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

31 Potential interest of ablation Tg may be produced in the serum by normal thyroid remnants and by neoplastic foci. Eradication of normal thyroid remnants improves its sensitivity/specificity (Van Herle, 1973). Currently, the volume of «normal» thyroid remnants is small after total thyroidectomy and Tg production in the serum is minimal during l-t4 treatment.

32 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

33 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

34 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

35 Tg/T4 level may be used for follow up in the absence of post op RAI 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

36 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

37 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

38 Conclusion «In patients with low-risk thyroid cancer, it is unclear whether the administration of radioiodine provides any benefit after a complete surgical resection. Therefore, radioiodine should be used with great care, administer the minimal amount of radioactivity, and involve the best-tolerated methods.» NEJM, 2012; 366: 1663.

39 E S T I M A B L H I L O

40 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

41 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

42 Current definition of a successful ablation In patients without persistent disease on the postablation TBS, a successful ablation (the eradication of normal thyroid tissue) and an excellent response are defined at 6-12 months by: 1. A normal neck ultrasonography 2. And a rhtsh stimulated Tg level <1 (or 2) ng/ml (or a serum Tg level <0.2ng/mL on l- T4 treatment with a sensitive assay)

43 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 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:

44 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.

45 Total body effective half life of 131 I (GR) TSH stimulation before 131 I administration: THW (hypothyroidism) or rhtsh (euthyroidism) Teff (235 patients) THW: /- 4.9 h rhtsh: /- 0.9 h Remy H, J Nucl Med, 2008; 49:

46 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

47 rhtsh vs withdrawal in low risk patients Similar efficacy for ablation with 100 mci or 30mCi No hypothyroidism; better quality of life Lower body exposure; lower exposure of medical staff and relatives; shorter stay in the hospital No toxicity. No complication Long term outcome is not related to the ablation protocol. Schlumberger M, et al. N Engl J Med. 2012;366:

48 High risk thyroid cancer patients Total thyroidectomy + RAI ablation + TSHsuppression in all patients with extended disease. Surgery Thyroid cancer RAI ablation Hormonal therapy High risk patients represent 5 10% of all DTC patients

49 High risk thyroid cancer patients Patients with a high risk of recurrence and/or thyroid cancer related death are routinely treated with a high activity (100 mci) following prolonged withdrawal (R50) Uptake in neoplastic foci may be lower after rhtsh than after withdrawal No evidence that activities >100 mci may produce better results (no need for pre-therapy TBS; benefits of dosimetry not demonstrated)

50 Activity to be used in high risk patients Deandreis D, Rubino C, Tala H, Leboulleux S, Terroir M, Baudin E, Larson S, Fagin JA, Schlumberger M, Tuttle RM Comparison of empiric versus whole body/ blood clearance dosimetrybased approach to radioactive iodine treatment in patients with metastases from differentiated thyroid cancer. J Nucl Med. 2017;58: Gustave Roussy, Villejuif, France and Memorial Sloan Kettering Cancer Center, New York, USA Distant mets with 131 Iuptake 231 pts from GR: 3.7 GBq 121 pts from MSKCC: GBq

51 Empiric (3.7 GBq) vs dosimetric approach: survival according to age and size of lesions Higher activities do not result in better OS: standard activity is 3.7 GBq. Question: can lesion dosimetry improve RAI efficacy for DM?

52 Single vertebral metastasis from a follicular thyroid cancer: rhtsh vs withdrawal TSH (µu/ml) Tg (ng/ml) 131 I uptake retention On LT4 <0, rhtsh (48h) ,2 3,2 (72h) withdrawal (48h) ,6 10,3 treatment (96h) - - 0,6 - A: 4mCi/rhTSH B: 4mCi/wd C: 100mCi/wd

53 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

54 RAI ablation and tumor size: be consistent! Haymart, JAMA 2011

55 Conclusion: take home messages