The use of Radioactive Iodine (RAI) for Differentiated Thyroid Cancer

Transcription

1 The use of Radioactive Iodine (RAI) for Differentiated Thyroid Cancer Wendy Sacks, M.D. Cedars Sinai Medical Center California Chapter Annual Meeting, AACE Nov 5, 2016

2 Increasing Incidence of Thyroid Cancer in the United States, Davies L, Welch HG, JAMA.2006;295:2164

3 From: Current Thyroid Cancer Trends in the United States JAMA Otolaryngol Head Neck Surg. 2014;140(4): doi: /jamaoto Data are from Surveillance, Epidemiology, and End Results (SEER), 1975 to 2009 Copyright 2016 American Medical Association. All rights reserved. 56% <1.5cm

4 Lecture Outline Rise in prevalence of thyroid cancer Risks and benefits of I-131 treatment for well differentiated thyroid cancer (WDTC) Postoperative risk for thyroid cancer recurrence Using risk stratification to decide whether to treat with RAI The recommendations for RAI treatment from the 2015 ATA Guidelines

5 Disease-free survival after I-131 remnant ablation Tumors >1.5cm Age > 40 Mazzaferri, E. L. et al. J Clin Endocrinol Metab 2001;86:

6 Rationales for Radioactive Iodine Ablation Ablate remnant thyroid tissue Facilitate patient staging and follow up Adjuvant therapy microscopic or gross residual disease

7 Side effects of 131 I therapy Transient : Neck pain and swelling (10-26%) Sialoadenitis (2-34%) Nausea, vomiting, gastritis (5-50%) Change in taste and smell Myelosuppression: thrombopenia, leukopenia Germ cell damage: hypospermia, azoospermia, oligomenorrhea, amenorrhea (usually transient, low risk for permanent damage) Chronic: Xerostomia, caries, sicca syndrome (5-20%) Bone-marrow suppression **Second primary malignancies 100mCi will cause an excess of 53 solid malignancies and three leukemias in 10,000 patients over 10 yr f/u. Pulmonary fibrosis (rare) Hyer, S et al. Clin Oncology. 2007;19(1):83-6 Sawka AM, et al. Thyroid. 2009;19:451 Lin, W et al. Clin Nucl Medicine. 1996;21(10):780 Rubino, C et al. British Journal of Cancer. 2003;89(9):1638

8 Initial stage predicts cause-specific survival but not disease-free survival Disease-specific survival after diagnosis Disease-free survival after diagnosis Jonklaas et al. Thyroid. 2006;16(12):

9 Prospective results from National Thyroid Cancer Treatment Cooperative Group for low risk patients Prospective, nonrandomized study Low risk = stage I & II (using NTCTCS classification system) Results: Postsurgical Stage 1 disease No significant treatment benefit of RRA was observed using propensity analysis for the outcomes of overall survival, disease-specific survival and disease-free survival Jonklaas et al. Thyroid. 2006:16 (12);

10 Staging of differentiated thyroid carcinoma papillary Tumor size Invasion <1 cm 1-2 cm 2-4 cm >4 cm Micro Gross Age < 45 yrs Age > 45 yrs AJCC-TNM NTCTCS AJCC-TNM NTCTCS I I I I I I I II I I II II I II III III I I III II I II IV III Node mets I I III/IV III Distant mets II III IV IV

11 Improved survival after radioiodine: Stage III-IV National Thyroid Cancer Treatment Cooperative Group high risk patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Overall Survival RR 1.43 P = Multivariate P = <NT/TT vs. NT/TT 1.26 ( ) No RAI vs. RAI 1.35 ( ) RAI No RAI Jonklaas et al. Thyroid. 2006:16 (12);

12 Improved survival after radioiodine: 100% Stage II 90% < 45 yo Gross invasion 80% 10% Overall Survival RR 1.71 P = RAI No RAI >45 yo T 1-4cm +/- microinvasion 0% Multivariate P = <NT/TT vs. NT/TT 1.56 ( ) No RAI vs. RAI 1.54 ( ) Jonklaas et al. Thyroid. 2006:16 (12);

13 Survival after radioiodine: Stage I National Thyroid Cancer Treatment Cooperative Group for low risk patients 100% 100% 90% 95% 10% 5% 0% Overall Survival RR P = RAI No RAI % 10% Disease-Free Survival RR 0.64 P = RAI No RAI 0% Jonklaas et al. Thyroid. 2006:16 (12);

14 Tumor Size (T) All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Intrathyroidal tumor 2cm T1a Intrathyroidal tumor 1cm T1b Intrathyroidal tumor >1cm but not more than 2cm T2 Intrathyroidal tumor >2cm but not more than 4cm T3 Intrathyroidal tumor >4cm or tumor of any size with minimal extrathyroidal extension (i.e. sternothyroid muscle or perithyroid soft tissues) T4a Moderately advanced disease Any size tumor with extension or invasion to subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Very advanced disease Tumor invading prevertebral fascia, encasing mediastinal vessels or carotid artery All anaplastic thyroid cancers are considered T4 T4a Intrathyroidal anaplastic carcinoma T4b Extrathyroidal anaplastic carcinoma Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/delphian lymph nodes) N1b Metastasis to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV or V) or superior mediastinal lymph nodes (Level VII) Distant Metastasis (M) M0 No distant metastasis M1 Any distant metastasis AJCC/TNM 7 th edition PTC/ FTC <45 years of age Stage I Any T, any N, M0 Stage II Any T, any N, M1 PTC/FTC 45 years T1, N0, M0 T2, N0, M0 Stage III N/A T3, N0, M0 T1-T3, N1A, M0 Stage IVA N/A T1-T3, N1B, M0 T4a, N0-N1, M0 Stage IVB N/A T4b, any N, M0 Stage IVC N/A Any T, any N, M1 American joint Committee on Cancer, 2010

15 MACIS Scoring System +3 if distant metastasis present +3.1 if patient 39 years of age or 0.08 x age if tumor incompletely resected +1 if local invasion present +0.3 x tumor size (cm) = MACIS Score Total Score Stage 20 Year Survival Rate <6 I 99% II 89% III 56% >8 IV 24% Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through Surgery. 1993;114(6):

16 20 year experience from Mayo Clinic: No improvement in disease-free survival in low risk patients (MACIS < 6) treated with I-131 Disease-free survival Hay, I. J Surgical Oncology. 2006;94:

17 Recurrence similar if node positive at presentation with or without I-131 remnant ablation Hay, I. J Surgical Oncology. 2006;94:

18 What is the evidence for radioiodine ablation for low risk patients with differentiated thyroid cancer?

19 Cedars-Sinai literature review Primary inclusion criteria* met? y n RAI compared to no RAI Only one risk population included OR analysis adjusted for or stratified by stage OR analysis adjusted for the combination: age, size, and metastases y n y n Adjusted for non-risk or non-stage variables (esp. surgery type) Adjusted for some demographic, tumor, or treatment variables y n y n Group A: Most helpful Group A1 : Adjusted only Group A2 : Stratified & adjusted Group B: Helpful but flawed Group C: Marginal Group D: Not helpful Group E: Rejected Total of 79 articles from included in groups A-D Sacks et al. Thyroid 2010

20 Low risk patients: I-131 RRA did not improve survival Majority of studies found that RRA is not associated with improved survival Low risk patients: I-131 RRA and recurrence, mixed results Mixed results: half of the studies found decreased recurrence with RRA and half did not Sacks et al. Thyroid 2010

21 Cedars-Sinai guideline for RRA for low risk patients Age < 45 years Very Low risk: (MACIS <6; TNM stage I: T0-T2, N0, M0) Microcarcinoma: unifocal or multicentric Tumor <4cm confined to the thyroid (no LN involvement) Low risk: (MACIS <6; TNM stage I: T0-T2, N0-N1a, M0) Tumor <4cm with central compartment lymph node metastases (no lateral node involvement) Age > 45 years Very Low risk: (MACIS <6; TNM stage I: T1, N0, M0) Microcarcinoma: unifocal or multicentric Low risk: (MACIS <6; TNM stage II: T2, N0, M0) Tumor < 4cm confined to the thyroid (no LN involvement)

22 p= p<0.0001

23 Systematic review examining the effectiveness of RRA on thyroid cancer-related mortality and disease recurrence in early stage WDTC Sawka, A.M. et al. Endocrinol Metab Clin N Am 2008;37: Inclusion criteria: Surgery: total or near-total resection RAI given within one year of operation Median follow-up period of 5 years Reporting of outcomes of any cancer-related death, cancer recurrence (loco-regional or distant recurrence) 28 studies included, all observational data

24 Risk of thyroid cancer-related mortality after RAI treatment After adjusting for important prognostic factors, majority of studies showed no mortality benefit using RRA The authors could not confirm a significant, consistent, benefit of RRA in decreasing causespecific mortality or recurrence in early stage WDTC. RRA use was associated with a significantly decreased risk of distant metastases; 10 year incidence however, this of thyroid event was cancerrelated rare death in is papillary 1.7% (45/2,627) cancer. relatively Not to be generalized to higher risk patients Sawka, A.M. et al. Endocrinol Metab Clin N Am 2008;37:

25 2009 ATA guidelines for postoperative radioiodine ablation

26 No difference in recurrence for patients with PTMC with or without remnant ablation (N=344) Low risk with no intermediate risk features Median follow up: 5 years No FH DTC No past h/o radiation exposure No vascular invasion No capsular invasion Non aggressive histology *Remnant Ablation No Remnant ablation (N=175) (N=137) Structural incomplete Structural incomplete Response = 0 Response = 0 Detectable Tg in 7 pts *median dose 73mCi I-131 Durante, et al. JCEM. 2010; 95:4882

27 Overall and disease-free survival in ATA low-risk differentiated thyroid cancer patients with tumors 1-4cm low risk DTC patients treated between (pt1,pt2, N0 or NX, M0): Median follow up 10.3 years 398 no RAI 1.0% 911 +RAI 1.6% p=ns Schvartz et al. JCEM 2012.

28 Limitations of the Literature Lack of prospective, randomized controlled trials Multiple staging systems in thyroid cancer literature Lack of agreed upon definitions for low risk vs high risk results in difficulty comparing outcomes Pooling of histological types in analyses Recent recognition that many follicular cell carcinomas are follicular variant of PTC Study duration variability Improved methods for detection of recurrent disease

29 RAI adjuvant treatment for intermediate risk patients Lamartina, Cooper et al. JAMA. May 2015 Low risk confirmed prior systematic reviews that there is no benefit to RRA for decreasing recurrence. Intermediate risk: minimal ETE, aggressive histology, vascular invasion, N1, uptake outside the thyroid bed on DxWBS. Other potential higher risk features multifocality or V600E BRAF mutation. 10 studies observed benefit in DFS 14 studies failed to show benefit in DFS

30 Lamartina, et al. JAMA. May 2015 RAI adjuvant treatment for intermediate risk patients

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34 2015 Update: Postoperative staging and risk stratification TNM/MACIS New prognostic factors contribute to risk categories for recurrence 1. Tumor size recurrence risk is variable. Unifocal PTMC 1-2% Multifocal PTMC 4-6% 2-4cm intrathyroidal PTC 5-6% Intrathyroidal PTC >4cm 8-10% 2. Node positive disease recurrence risk for N1a & N1b is highly variable depending on location, number & size 3. Vascular invasion (FTC) 4. BRAF status

35 Risk of recurrence based on the characteristics of the cervical LN metastases cn1 (clinically apparent LNs) identified by physical exam, imaging, or intraoperative inspection. Randolph GW et al. Thyroid. 2012:22(11).

36 Risk of PTC persistence/recurrence in 305 patients treated with surgery + RAI assessed by lymph node metastases Macro: 7-70mm Micro: mm Figure 1. Cumulative probability of structural persistent/recurrent disease (locoregional and/or distant disease) according to the pathological pn status. Bardet JCEM 2015

37 Schematic illustration of the MAPK pathway. Xing M Endocrine Reviews 2007;28: by Endocrine Society

38 Clinical significance of BRAF+ thyroid carcinoma Prevalence: 44-60% in Classic PTC 80-85% in recurrent PTC BRAF mutation linked to features of high risk PTC: Extrathyroidal invasion Multicentricity Increased tumor size Advanced disease stages III & IV +/- Lymph node metastases Conflicting results Variations in study population size, age distribution, histological variants, genetic factors, environmental factors, disease stage at initial diagnosis Xing M. Endocrine Reviews. 2007, 28(7):742; Kim, et al. Clin Endocrin 65;364

39 Correlation of BRAF with clinicopathologic features of PTC Odds ratio:

40 BRAF V600E: a prognostic molecular marker? N=54 N=149 Increased recurrence with univariate analysis (P=0.037) No difference in recurrence with multivariate analysis (P=0.29) Kim, et al. Clin Endocrin ;364

41 BRAF V600E mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid PTC: Single institution T1aN0M0 T1b-T2N0M0 Groups B&C Treated w RAI Eleisi, R. JCEM 2015

42 2009 and 2015 ATA Recurrence Risk Stratification System Low Risk Intermediate Risk High Risk No local or distant metastases All macroscopic tumor has been resected and no tumor invasion of locoregional tissues or structures Microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery. I131 uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation Macroscopic tumor invasion Incomplete tumor resection No aggressive histology (ie tall cell, insular..) RAI generally not If I131 is given, there are no RAI recommended avid metastatic foci outside the thyroid bed on the first posttreatement whole body RAI scan No vascular invasion Clinical N0 or 5 pathologic N1 micrometastatses (<0.2cm in largest dimension) Intrathyroidal, well differentiated FTC with capsular invasion but no or minimal (<4 foci) vascular invasion Intrathyroidal microptc, unifocal or multifocal, including BRAFV600E mutated Tumor with aggressive histology or vascular Consider invasion. RAI PTC with vascular invasion treatment Clinical N1 or >5 pathologic N1 with all involved lymphg nodes <3cm in largest dimension. Intrathyroidal PTC with primary tumor 1 4cm, BRAF mutated if known Multifocal microptc with extrathyroidal extension and BRAF+ Distant metastastases RAI Thyroglobulinemia out of proportion recommended to what is seen on the post treatment scan Pathologic N1 with any metastatic lymph node 3cm FTC with extensive vascular invasion (>4 foci)

43 Use of low dose RAI for low risk PTC patients

44 Comparison of 2 studies: patients, methods France U.K. Type randomized randomized Age Pathology pt1,t2 N0, N1, NX M0 pt1,t2,t3 N0,N1,NX M0 Inclusion Same other than ECOG 0 1 Total TX; +/ LND, low risk DTC; ECOG 0 2 Exclusion Same High risk subtypes; recent Iodine Iodine preparation Same rhtsh or THW (same w/drawal protocols) I 131 treatment dose Same 1.1GBq & 3.7GBq Pretreatment tests Tg>30; no scan Technesium scan; Tg>30 Post treatment tests 3 5d WBS; 8+/ 2 rhtsh diagnostic WBS + Tg + US 3 7d WBS; 6 9 month rhtsh diagnostic WBS + Tg + US Primary endpoint Ablation success same Secondary endpoint Sx s hypothyroidism; Aes; QOL same

45 Efficacy equivalent with 30 mci as with 100mci for lowintermediate risk DTC and fewer side effects. Preparation with rhtsh compared with TH withdrawal: Efficacy equivalent Increased convenience Higher cost More patients treated with 30mCi needed retreatment. Longer follow-up needed to determine recurrence rates. Prospective, randomized trial, Mallick, et al. Iodine or Not (IoN) for Low-risk Differentiated Thyroid Cancer: The Next UK National Cancer Research Network Randomised Trial following HiLo

46 MSK, n = 471 Median follow up 7 years 96% NED 4% recurrence 68% NED 20% persistent biochemica 19% persistent structural 15% NED 10% persistent biochemica 37% persistent structural 38% death Clinical implications of

47 87% NED 15% persistent biochemical

48 Risk-adapted individualized approach versus one size fits all approach Limitations to AJCC TNM and MACIS staging systems Must account for recurrence risk in addition to cause-specific mortality to better tailor follow-up Initial management recommendations should be based on specific clinicopathologic risk factors rather than a uniform recommendation for all thyroid cancer patients regardless of risk analysis.

49 Conclusions Thyroid cancer incidence is increasing. Individualized approach using risk factor analysis versus one size fits all approach for the use of I-131radioactive iodine. Ration use of RAI in patients with low risk differentiated thyroid cancer and consider low dose treatment if remnant ablation is recommended. Patient preference must be considered

50 Thank you!

51 Risk stratification ATA Guidelines for management of thyroid carcinoma

52 Results: recurrence Subgroup analysis of early stage PTC patients: 10 year absolute recurrence rates: 9.3% (154 out of 1,652) any recurrence 7.3% (50/684) locoregional recurrence 1.3% (9/684) distant metastatic recurrence Sawka, A.M. et al. Endocrinol Metab Clin N Am 2008;37:

53 BRAF: a prognostic molecular marker? Multivariate analysis significant Limitations: all subtypes included P=0.04 Xing M. Endocrine Reviews Xing M. Molec & Cellular Endocr 2010