Anca M. Avram, M.D. Professor of Radiology

Thyroid Cancer Theranostics: the case for pre-treatment diagnostic staging 131-I scans for 131-I therapy planning Anca M. Avram, M.D. Professor of Radiology Department of Nuclear Medicine University of Michigan Ann Arbor, USA

Disclosures Nothing to disclose

Objectives: I. Address WHY Pre-treatment RAI Scans need be performed: Because they are useful 1) Change post-operative staging 2) Change post-operative risk stratification 3) Change patient management Result: Individualized RAI therapy prescription for patients with advanced DTC

Objectives: II. Address WHEN Pre-treatment scans need to be performed: When the patient is referred for 131-I therapy 2015 ATA Guidelines most patients with low, and low-intermediate recurrence risk are no longer referred for Ablation Pre-treatment RAI scans are useful to detect iodine-avid regional and distant metastatic disease in the intermediate- and high risk patients

Objectives: III. Address HOW to perform Pre-treatment scans: Review progress in gamma camera technology that makes possible acquisition of spectacular diagnostic fusion SPECT/CT images with low (1-2 mci) 131-I activity Stunning is not a clinically significant issue when RAI Rx. is administered within 72h of pre-treatment scan, and post- Rx. scans are done early (2-4 days postrx) Stunning may be related to a true cytocidal effect of the high 131-I diagnostic doses (5 10 mci) used in the past McDougall IR, Iagaru A. Thyroid Stunning: fact or fiction? Semin Nucl Med. 2011 Mar;41(2):105-12

Radiation-induced thyroid stunning: cellular effects Lundh C et al. JNM, 2009: Objective: to assess the iodide transport and NIS - mrna expression in thyrocytes after 123-I and 131-I exposure Method: - TSH-stimulated thyroid cell monolayers were exposed to 0.5 Gy of 123-I and 131-I in the culture medium for 6 h. - Exposure to various absorbed doses of 123-I or 131-I for 48 h. - NIS mrna expression was analyzed using quantitative RT-PCR

Lundh C et al. JNM 2009 Results: - At the same absorbed dose, iodide transport was reduced more by 123-I than 131-I; the onset of NIS downregulation was rapid (<1 d after irradiation) in cells exposed to 123-I, and was delayed in cells irradiated with 131-I; - 123-I reduced the iodine transport and the NIS mrna expression more efficiently than did 131-I at an equivalent absorbed dose Conclusion: The stunning effect per unit absorbed dose is more severe for 123-I than for 131-I. Despite the lower absorbed dose per unit activity for 123-I than for 131-I, stunning by 123-I cannot be excluded in patients.

To scan or not to scan prior to 131-I therapy? Cons: Reduced sensitivity of Dx scans vs. post-rx scans: Waxmann AD et al. JNM, 1981: study in 21 pts: 400% increased sensitivity for disease detection for 10 mci vs. 2 mci. 131-I scans due to higher photon flux. When compared to post-rx (30 and 100mCi) scans: positive correlation between focal uptake and increasing administered 131-I dose Schlumberger M et al. JNM, 1988: 2 mci 131-I dose missed lung metastases in 11/23 pts. (48%) whose disease was identified after a subsequent therapeutic 100 mci 131-I Murphy EJ et al. J Invest Med. 2000: 13 pts. with negative diagnostic scans and high THYG. received 131 I therapy: 8/13 pts. (62%) demonstrated focal abnormal uptake on post-rx scan Siddiqi A et al. Clin. Endo. 2001: 18 pts. with neg. 131 I scans and high THYG evaluation received131-i therapy and post-rx scans showed abnormal focal uptake in 16/18 pts (89%)

Concordance: Diagnostic vs. Post-therapy scans McDougall IR et al. Nucl Med Comm, 1997: Findings on Dx. (2 mci) 131-I pre-ablation and post-rx (8d) planar scans were concordant in 274 of 280 patients (98%); in only 6 of 280 pts (2%) a relative decreased uptake in the previously detected foci was seen on the post-rx. Avram AM et al. JCEM, 2013: Findings on Dx. (1 mci) 131-I pre-ablation and post-rx (2d) planar scans were concordant in 280 of 303 patients (92%); in only 4 of 303 pts. (1.3%) a relative decreased uptake in the previously detected foci was seen on the post-rx. in 19/303 pts. (6%) additional foci were detected on post-rx scan however, in only 4 pts. (1.4%) the findings were clinically significant (upstaged the patient)

Post-therapy vs. Pre-ablation Scans Historical perspective: - Post-Rx. scans are more sensitive - Stunning is avoided - Nodal Mets vs. Remnant - difficult star artifact - Unnecessary - Fixed dose therapy for Ablation However, times have changed

Progress: Hybrid SPECT/CT camera Co-registration of functional and anatomic data Superior image quality: Improved spatial resolution Improved contrast resolution Application of scatter rejection algorithms Iterative Reconstruction SPECT CT-based Attenuation Correction High quality images can be achieved with tracer 131-I activity (e.g. 1 mci) Wong KK et al. AJR Am J Roentgenol. 2010 Sep;195(3):730-6.

ATA Guidelines: Selective use of 131-I therapy Low risk, and selected medium-risk patients are no longer recommended ablation after total thyroidectomy. Management decisions are predicated by histopathologybased risk stratification. A post-therapy scan may not exist in all patients Without a Diagnostic Pre-ablation Scan to complete staging after total thyroidectomy, regional and/or distant metastases may not be recognized and addressed at an early stage, for curative intent. The best chance to eliminate iodine-avid metastatic foci is with the 1 st 131-I treatment.

What Dose of 131-I therapy? What Target for 131-I therapy? Individualized 131-I therapy What is the contribution of diagnostic Radio-iodine scans to management?

Accurate Staging is Important knowing the extent of disease makes a difference Staging predicts survival Staging determines the strategy for initial treatment and for long-term surveillance

Patients with stage I-II disease have favorable prognosis (mortality < 1% at 20 years) (low risk group) Prognosis Mortality increases to 25-40% among patients at stages III and IV (high risk group) Jonklaas J et. al. Thyroid. 2006 (12):1229-42 - NTCTCS National Thyroid Cancer Treatment Cooperative Study Group - initiated in 1987 - multicenter Registry at 11 North American Institutions - central data repository at MD Anderson, Texas

National Thyroid Cancer Treatment Cooperative Study Group Registry Staging Classification Stages I and II = Low Risk Stages III and IV = High Risk

Therapeutic factors for Outcome: Overall Survival (OS) and Disease-free Survival (DFS) RAI Rx improved OS in Stage III & Stage IV improved DFS in Stage II TSH Suppression Therapy (TSHT) Moderate TSH suppression improved OS and DFS across ALL Stages (I - IV) * Unexpected for Low-Risk patients (Stages I-II), c/w with residual disease NTCTCS Analysis 1987-2012: 4941 patients Carhill AA, Jonklaas J et. al J Clin Endocrinol Metab, Sept. 2015

2009 ATA Risk Stratification ATA Low Risk: no regional or distant metastases complete tumor resection, no evidence of invasion non-aggressive histology ATA Intermediate Risk: microscopic invasion in peri-thyroidal tissues cervical nodal metastases (or 131-I uptake outside of thyroid bed on PostRx Scan) aggressive histology or vascular invasion ATA High Risk: macroscopic invasion, incomplete resection distant metastases Tg. out of proportion of PostRx. findings

2015 ATA Guidelines There is a broad range of new or modified recommendations in 2015 as compared to 2009 ATA Guidelines: - 8 New Clinical Questions - 21 New Recommendations - 21 significantly changed Recommendations

The Result: a seismic shift in thyroid cancer management Initial treatment: dramatic pendulum swing away from prior standard of care for thyroid cancer treatment (i.e. total thyroidectomy, central neck dissection, post-op RAI Rx) to: Less than total thyroidectomy for PTC < 4 cm Not using RAI in the majority of patients (~ 85%) of thyroid cancer pts. Surveillance strategy: shift away from Dx and/or PostRx Scans to US surveillance and serial Tg testing

The Goal of performing Pre-treatment Scans is to provide individualized RAI Treatment Patient-specific 131-I therapy prescription: 1) Clinical data (patient s age and clinical presentation: with/without palpable lymphadenopathy) 2) Surgical pathology report: defining T and N depending on the extent of surgical dissection 3) Post-operative Tg levels (suppressed/stimulated; Thyrogen vs. hypothyroid stimulation) 4) Diagnostic imaging findings: neck US and DxWBS (123-I vs. 131-I scans, planar SPECT/CT imaging) Avram AM. J Nucl Med. 2012 May;53(5):754-64.

University of Michigan Protocol Diagnostic 131 I scans (37 MBq, 1 mci) are performed for ALL pts referred for RAI treatment 24 h Whole Body (WB) + Static Neck & Chest planar images (Table speed: 5 cm /min; Static images acquired for 20 min, 256x256 matrix Routine SPECT-CT imaging for: characterization of central neck activity: Thyroid Remnant vs. Nodal metastases anatomic localization of distant disease rapid exclusion of suspected physiologic mimics SPECT Technique: 64 projections (20 s/stop); 128x128 matrix Avram AM et al. J Clin Endocrinol Metab. 2013 Mar;98(3):1163-71.

Why is this important? Define instances where initial staging based on clinical & surgical pathology (ptnm) changes after diagnostic 131 I imaging - Complete patients risk-stratification - Define if the patient will / (will not) benefit from therapeutic 131 I administration - Define the target of 131 I therapy

Study Design All patients were initially staged and risk stratified by Endocrinologist based on clinical and surgical pathology (ptnm) All 131 I scans were interpreted to assess for thyroid remnant, nodal or distant metastases (2 independent readers) All patients were re-staged and re-stratified after incorporating the information from diagnostic 131 I SPECT-CT to arrive at final TNM and final Risk Stratification

Study Design Aim: to assess the impact of findings on DxWBS + SPECT/CT on Staging, Risk Stratification & Management: the decision of treat or withhold 131-I therapy based on risk stratification the decision to refer to surgery for resection of bulky residual metastatic disease the prescribed 131-I activity defined as: Low activity (30-50 mci) Medium activity (100-150 mci) High activity ( 200 mci)

Methods 320 consecutive pts. (47 ± 16 yrs, range 10 90) Female 68%; Male 32% Avram AM et al. J Clin Endocrinol Metab 2013; 98(3):1163-71

Methods: Tumor Characteristics Size: 2.4 1.8cm; range: 0.1-12 cm Multifocality: 144 (45%) Vascular invasion, present: 96 (30%) Capsular invasion, present: 202 (63%) Extrathyroidal extension, yes: 116 (36%) Surgical margins: Positive 26%; Negative 72%; Unknown 2% Neck nodal metastases, pn1*** 149 (47%) *** before diagnostic imaging

Pre-treatment Scans Complete Staging Characterization of N status and M status 320 consecutive pts. (47 ± 16 yrs, range 10 90) detected regional mets. in 35% pts. detected distant mets. in 8% pts. Changes TNM staging: 4% of young pts. (age <45 yrs) 25% of older pts. (age 45 yrs) Avram AM et al. J Clin Endocrinol Metab 2013; 98(3):1163-71

Identification of Distant Metastases lead to dosimetrically guided RAI Rx. 32 year old woman 1.8 cm follicular-variant PTC left lobe; + margins - 15+/27 nodes central neck - 6+/46 nodes left neck - TSH 118 mu/l - Tg 862 ng/ml

Dosimetry Calculations - Whole Body Dosimetry: 0.56 cgy/mci adm. activity - Blood Dosimetry: 0.62 cgy/mci adm. activity RAI Rx. 320 mci 131-I therapy

Sub-analysis of T1 Tumors n =116 (36%) T1 a ( 1.0 cm) n=49 (15%) T1b ( 2.0 cm) n=67 (21%) Dx. Scans detected: - Nodal Mets in 22% - Distant Mets in 4% Dx. Scans detected: - Nodal Mets in 42% - Distant Mets in 4.5% Detection of iodine-avid regional and distant metastases altered patient management Avram AM et al. J Clin Endocrinol Metab 2013; 98(3):1163-71

56 year old woman 1.2 cm PTC, no ETE 0/3 central nodes pt1b, N0, M0; Stage I (anti-tg Ab +)

Restaging: T1b, N0, M1; Stage IV C

Diagnostic (1 mci) 131-I scan at 6 Mos. after 200 mci RAI Rx; interval resolution of liver metastasis and of thyroid remnant tissue resolution of anti-tg Ab; stim Tg < 0.5 ng/ml (TSH 112 mu/l) No Evidence of Disease (NED)

Pre-ablation Scans Complete Risk Stratification Univ. of Michigan experience in 320 patients Risk Stratification performed by Endocrinologist before and after information from pre-ablation scans was made available: - 15% pts. (48/320) changed risk stratification after imaging information on nodal and distant metastatic status - Management changed in 31% pts. (99/320 pts) Avram AM et al. J Clin Endocrinol Metab 2015 May;100(5):1895-902

Identification of large residual nodal metastases led to surgical referral 45 year old man with 3.5 cm PTC 30+/58 bilateral metastatic lymph nodes: central neck : N1a 17+/17 right neck (9+/26) left neck (4+/15) N1b 13+/41 Total Nodes resected: 30+/58

3 large residual metastatic lymph nodes (~ 1 x 1.2 cm) at the sternal notch and in the left supraclavicular area. Surgical referral prior to 131-I therapy

Detection of non-iodine avid disease on SPECT/CT

Detection of non-iodine avid disease on SPECT/CT 3 cm cystic lesion with internal calcifications in the right thyroid bed US-guided FNA: Non-diagnostic, acellular Aspirated fluid contained Tg >300 ng/ml

Avram AM et al. J Clin Endocrinol Metab 2015 May;100(5):1895-902

Do we make a difference in Outcomes? 350 pts with Advanced DTC treated at University of Michigan (2007-2013) Pre-treatment 131-I scans with SPECT/CT were performed in all patients: for completion of staging and risk stratification for guiding 131-I therapy Clinical, Biochemical & Imaging Follow-up to assess for Outcomes after initial treatment strategy (surgery and 131-I therapy): Dynamic Risk Restratification Outcomes Follow-up: 1-5 years Mean (±SD) = 39.6 (±23.4) Months Rosculet N et al. Endocrine Reviews, Vol 37, Issue 2 Suppl. OR22-5

Tumor Histology Mean Size± SD (range) 2.48cm± 1.73 (0-12 cm) Multifocal 161 (45%) Vascular invasion 120 (34%) Capsular invasion 226 (64%) Extrathyroidal extension Positive surgical margins 154 (44%) 114 (32%) Nodal mets. (N1a, N1b) 239 (68%) Rosculet N et al. Endocrine Reviews, Vol 37, Issue 2 Suppl. OR22-5

Criteria for Defining Outcome 2015 ATA Haugen et al. Thyroid 2016; 26:1-133 Complete/Excel lent Response Biochemical Incomplete Structural Incomplete Indeterminate Response -Negative imaging & -Suppressed Tg <0.2 ng/ml or -TSH stimulated Tg <1 ng/ml -Negative imaging & -Suppressed Tg 1 ng/ml or -TSH stimulated Tg 10 ng/ml or -Rising Anti-Tg antibodies -Structural or functional evidence of disease with any Tg level -With or without Tg Ab -Non-specific imaging -Faint uptake in thyroid bed on RAI -Non-stim Tg detectable, <1 ng/ml -Stimulated Tg detectable, <10 ng/ml or -Anti-Tg Abs stable/declining w/o structural or functional disease

Treatment Response after Surgery + Single RAI Rx. Response # of patients (n=350) Complete 295 (84.3%) Biochemical incomplete 5 (1.4%) Structural incomplete 42 (12%) Indeterminate 8 (2.3%) Rosculet N et al. Endocrine Reviews, Vol 37, Issue 2 Suppl. OR22-5

47 yo man 1.2 cm PTC 5+/6 N1a 7+/9 N1b T1b, N1b, Mx Stim. Tg 10 (TSH 86 mu/l) Pre-treatment 131-I scan Escalation of 131-I therapy to 225 mci 131-I based on dosimetry calculations

Identification of multiple iodine-avid lymph nodal metastases led to escalation of 131-I therapy to 225 mci 131-I based on dosimetry Follow-up Thyrogen 131-I scan (1 yr post-rx) rhtsh-stim. Tg < 0.5 ng/ml Negative 131-I SPECT/CT & negative neck US Outcome: Complete Response to treatment

Conclusions Complete Response to initial treatment in 84% of regionally advanced DTC: - 42% pts (13/31) with iodine-avid distant metastatic disease responded completely to 1st RAI Rx. - 89% pts (153/172) with iodine-avid lymph nodal metastases responded completely to 1st RAI Rx. Rosculet N et al. Endocrine Reviews, Vol 37, Issue 2 Suppl. OR22-5

Structural Non-Iodine Avid metastatic disease detected by CT and PET/CT Structural incomplete responders (N=42) Positive PET/CT Positive CT No imaging besides RAI scan Negative RAI scan=34 34 23 0 Positive RAI scan=8* 0 3 5 Only 8 pts (2%) had residual iodine-avid disease (distant metastases) and required repeated RAI Rx.

Conclusions Structural Incomplete Response in 42 pts : 34 pts (80%) of pts. with structural ds. had Negative Follow-up RAI Scans and positive PET/CT or CT Majority of patients with persistent structural disease after 1 st targeted RAI Rx. have non-iodine avid metastases. Early diagnosis with PET/CT or CT allows a different approach to treatment.

Dx (1 mci) 131-I Scan

PostRx (150 mci) 131-I Scan Follow-up RAI scan Tg 32 ng/ml; TSH 56 mu/l

18-F FDG PET/CT

18F-FDG PET/CT

The END Department of Nuclear Medicine University of Michigan Ann Arbor, USA

Do Scans and targeted RAI Rx make a difference? Outcomes in Regionally Advanced Thyroid Cancer Best Response to Initial Therapy 61 pts. N1b, M0-68% NED -18% Struct. Ds (11/61) - 5% new distant mets (non-iodine avid -3/61) -1 died of dediff. tumor Median FU: 20 Mos Hughes el al. Ann Surg Oncol 2014 181 pts N1b, M0-39% NED - 30% Structural Ds - 15% Biochem. Ds (stim. Tg > 10 ng/dl) - 16% Indeterminate (unstim. Tg 1-10 ng/dl) FU: 12-18 Mos Sabra MM et al. Thyroid, 2014 May