Case-Based Discussion of Thyroid Cancer Therapy

Case-Based Discussion of Thyroid Cancer Therapy Matthew D. Ringel, MD Ralph W. Kurtz Chair and Professor of Medicine Director, Division of Endocrinology The Ohio State University Co-Leader, Molecular Biology and Cancer Genetics Program Arthur G. James Comprehensive Cancer Center The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Disclosures Funding from NIH Member NCCN Thyroid Cancer Guidelines Panel Not member of ATA Guidelines Panel 2

Clinical Case: Primary Evaluation 23 year old woman who noted a lump in the neck in 5/2015. She saw her physician who thought it was likely a node. She had no other symptoms. TSH was normal in 1/2015 at an annual physical. It did not resolve and in 9/2015 she had a neck CT with contrast. CT with right lobe nodules and nodes in the neck felt to be normal size but perhaps more on right than left. Ultrasound revealed two right lobe nodules; 2.4x2.5x2.1 cm, palpable, spongiform 1.4x1.8x0.7 cm with calcifications, irregular border, posterior invasion, hypervascularity Nodes not reported or visualized Referred for Evaluation 3

2016 ATA Guidelines approach to this patient Laboratory Evaluation? TSH is recommended. Calcitonin can be considered. Adequate Ultrasound? Guidelines recommend lymph node evaluation as part of a thyroid ultrasound Fine Needle Aspiration? Yes. Based on report, choice of nodule based on pattern recognition. Haugen, et al Thyroid 2016 4

2016 Guidelines Nodule FNA Selection Table 8: Ultrasound features of lymph nodes predictive of malignant involvement. (adapted with permission from the European Thyroid Association guidelines for cervical ultrasound Sign Reported sensitivity % Reported specificity % Microcalcifications 5-69 93-100 Cystic aspect 10-34 91-100 Peripheral vascularity 40-86 57-93 Hyperechogenicity 30-87 43-95 Round shape 37 70 5 Haugen, et al Thyroid 2016

Case: Neck Ultrasound Confirms the presence of the two nodules but also Neck Nodes Right jugular nodes; level 3 and 2A with malignant characteristics; largest is posterior to the jugular vein measuring 0.8x0.9x1.5 cm Right posterior triangle node that is solid with hypervascularity measuring 2.3x2.1x2.2 cm. Left Lobe normal No concerning nodes in the left central or lateral neck TSH is 0.68 mu/l Review of CT images also demonstrated concerning nodes in the right lateral neck; none in mediastinum; no clear tracheal invasion

Case: Ultrasound-guided FNA of the right posterior node Three Passes: Smears from all three; hub washout from two passes for Tg measurement; one hub washout for liquid preparation FNA Tg: 11,740 ng/ml; serum Tg is 75 ng/ml Cytology: Consistent with Papillary Thyroid Cancer The Nodule was not aspirated in this circumstance

Next Steps per the ATA 2016 Guidelines Surgery Recommendation: For intrathyroidal nodules without nodes hemithyroidectomy or total thyroidectomy are acceptable options. For more extensive disease, total thyroidectomy and compartmental node dissection in selected cases with involved nodes is recommended. Surgery Performed: Total thyroidectomy, central neck dissection, lateral neck dissection to include the involved compartments of the neck Haugen, et al Thyroid 2016

Surgical Pathology 2.1x.1.7 PTC with local invasion into muscle and 5 sites of vascular invasion 3/14 nodes positive in the central neck, all < 5 mm 4/14 nodes in the jugular chain positive: largest 1.2 cm with extranodal invasion 2/46 nodes in the lateral neck; the largest is 2.4 cm with no local invasion Radiology: CT of the chest without contrast with no evidence of lung metastases

AJCC 8 th Edition/ TNM System Identify High-Risk Patients in whom mortality may be increased Allow Accurate Communication Maintain Common Cancer Registries Does not Predict Residual/Recurrent Disease Firm Age Cut-off that may not match clinical severity of disease Does not account well for extent of surgery AJCC Cancer Staging Manual, 8 th Edition (2016), Springer Publishing

Revised ATA Initial Risk Stratification Low Risk for Recurrence Intrathyroidal differentiated 1-4 cm No Local or Vascular Invasion 5 LN micromets ( 2mm) Minimally Invasive FTC (Capsular Invasion or minor Vascular Invasion) Intermediate Risk for Recurrence Everything not in Low or High Risk ~40% High Risk Variants of DTC Intrathyroidal 1-4 cm or multifocal micro PTC with local invasion if BRAF V600E ; Nodes 2 mm up to 3 cm High Risk for Recurrence Gross Extrathyroidal Extension Incomplete Resection; Large Nodes (>3 cm) Distant Metastases; Extensive Vascular Inv. FTC Modified from Erik Alexander ~15% ~80%

What is the Staging and Risk Category for This Patient? TNM: Stage 1 or Stage 2 T4a N1b Mx (M0 based on the CT scan) Excellent Anticipated Long Term Survival ATA Risk Category High Risk for Residual disease or Recurrence Molecular Testing of Tumor Not Performed, No Impact on Therapeutic Decisions at This Time

Should I-131 be Administered? Recommendations Based on Risk Stratification of High Risk: YES Preparation and Dosing RhTSH vs Thyroxine Withdrawal Pt and Physician Preference Dosing based on goals of therapy Adjuvant Therapy for Probably Residual Disease 13

Continued Postoperative Restaging Pt on L-T4. TSH 0.35; Tg 3.2 six weeks after surgery TSH: 0.12; Tg: 0.4 three months after surgery Neck Ultrasound with postoperative change and no identifiable residual thyroid cancer. Should I-131 be administered? If so, what preparation and dose?

Guidelines 2016 Recommendation Recommendation 56: When RAI is intended for initial adjuvant therapy to treat suspected microscopic residual disease, administered activities above those used for remnant ablation up to 150 mci are generally recommended (in absence of known distant metastases). Weak recommendation, Low-quality evidence Haugen, et al Thyroid 2016

Treatment Decision Based on pathology and clinical features, I-131 was recommended Dose was determined based on: Post-operative Staging Pre-therapy scan Patient wishes Pre therapy scan: Thyroid bed uptake only Dosed with 100 mci I-131 Stimulated Tg: 28 ng/ml Post-therapy scan with thyroid bed and lung metastases 16

Post-treatment Course 6 months later: Tg <0.1 ng/ml with TSH 0.06 mu/l and normal Free T4 Two episodes of significant sialoadenitis Otherwise doing well 17

RESPONSE TO THERAPY STAGING Response to Therapy Excellent Response: Suppressed Tg <0.2 or Stim Tg <1.0 Negative Ultrasound Incomplete Biochemical Response Suppressed Tg >1.0 or Stim Tg <10 Negative Ultrasound Incomplete Structural Response Structural Evidence of Disease Indeterminate Response TgAb+ Stable or declining Suppressed Tg 0.2-1.0 or Stim Tg 1.0-10 Indeterminate Imaging Recommendations: Decrease Intensity and Frequency of Follow-up and TSH Suppression Stable/Lower Tg - Observe Rising Tg Additional Investigations Consider Additional Investigations & Therapies Continued Observation and Testing

Response Status of the Patient Excellent Response Based on Tg With Distant Mets Plan for the following TSH-stimulated Tg Chest CT without Contrast Neck Ultrasound Once completed will have a more complete assessment of response to therapy. 19

Persistent/Recurrent Local Thyroid Cancer: Case 2

Case 2 43 year old white woman diagnosed with a 2.0 cm leftsided intrathyroidal papillary thyroid cancer with 0/1 nodes with evidence of nodal spread at age 27 in 1993. Stage 1 T2N0Mx PTC She was treated with 100 mci of I-131 for remnant ablation following thyroxine withdrawal. She had uptake in the thyroid bed on pre and posttherapy scans.

Case 2 1994: She had a negative 5 mci I-131 whole body scan following thyroxine withdrawal Serum Tg was 3.5 ng/ml with negative anti-tg antibodies and she was treated with 150 mci I-131. Post-therapy scan had minimal uptake in the thyroid bed. She had negative diagnostic I-131 scans in 1994 and also 2004. 2004 was after rhtsh and her Tg level stimulated to 5.5 ng/ml She had a negative CT of the neck with contrast and a negative thyroid ultrasound in 2004. Basal Tg levels are between 0.6 and 1.2 ng/ml with TSH levels between 0.02 and 0.4 mu/l.

Case 2 After delivery of a healthy child she is referred for evaluation of thyroglobulin positive, scan negative persistent papillary thyroid cancer.

Case 2 She has no personal history of radiation exposure She denies hoarse voice or dysphagia. The remainder of her medical history and her physical examination are unremarkable. She has no palpable neck adenopathy or tissue in the thyroid bed.

Case 2 Laboratories:TSH: 0.05 mu/l; Tg: 0.5 ng/ml; anti-tg antibodies are negative. What would you recommend at this point? A. PET/CT B. Neck Ultrasound C. Chest CT without IV contrast D. No additional imaging E. B and C

PET/CT in Tg positive, Scan Negative Thyroid Cancer Shammas, et al. retrospectively reported PET/CT data on 61 patients with suspected recurrent thyroid cancer 51 with Tg positive, I-131 scan negative disease True Positive results were noted in 26/61 23 patients had resectable tumor recurrence mostly in the neck and/or mediastinum. Neck ultrasound was not routinely performed New distant metastases were identified in the lungs (n=5) and bones (n=3). Shammas, et al J Nucl Med 2007:48;221-226

PET/CT Tg positive, Scan Negative Thyroid Cancer: Tg level correlation True positive PET/CT based on Tg levels: Stimulated Tg: <5 ng/ml: 22% 5-10 ng/ml: 28.5% >10 ng/ml: 60.8% Basal Tg: <5 ng/ml: 8.3% 5-10 ng/ml: 75% >10 ng/ml: 66.7% No obvious difference when performed with a suppressed or elevated TSH level in this study. Shammas, et al J Nucl Med 2007:48;221-226

Does rhtsh stimulation improve FDG PET accuracy? Leboullex, et al. (J Clin Endocrinol Metab. 2009: 94:1310-1316) PET/CT performed before and 24-48 hours after rhtsh in 63 patients with DTC rhtsh enhanced the number of lesions detected overall rhtsh PET/CT did not increase the number of patients with any detected lesions. 8 lesions were found only by rhtsh PET/CT 4 of these 8 were thyroid cancer on pathology and 4 were not. rhtsh administration led to treatment changes for proven thyroid cancer in 6% of cases, this was not statistically significant.

Neck Ultrasound to Detect Residual/Recurrent Thyroid Cancer Castagna, et al reported on a cohort of patients with undetectable stimulated Tg one year after I-131 therapy (n=68) 67 patients underwent neck ultrasound 2.5 yrs later 1 patient (1.5%) developed a recurrence at follow up detected by neck ultrasound, but not basal Tg. Authors Conclusion: Neck Ultrasound is the most sensitive method for detecting recurrent PTC in lowrisk patients. Castagna MG. J Clin Endocrinol Metab 2008: 93; 76-81.

Case 2 Neck ultrasound was performed.

ATA Guidelines on Node Evaluation Recommendation 65: If a positive result would change management, ultrasonographically suspicious lymph nodes greater than 8-10 mm in the smallest diameter should be biopsied for cytology and thyroglobulin measurement in the needle washout fluid. Weak rec, low quality of evidence Suspicious lymph nodes less than 8-10 mm in largest diameter may be followed without biopsy with consideration for intervention if there is growth or in the node threatens vital structures. Weak rec, low quality of evidence Haugen, et al. Thyroid 2016

Tg on FNA of Nodes: Clinical Practice Points Wash out hub in total 1.0 ml volume of saline Typically perform 3 passes in a node. All have smears for cytology; for 2 passes the hub is washed in the 1 cc of saline and for the third pass, the hub wash is put into liquid medium for pathology. Tg sample is put on ice. Positive result if Tg>10 ng/ml in the node and > circulating level. Often times in the thousands. True positive value uncertain as is the role of different sample dilutions between studies but has varied between 1 and 10. Not affected by circulating anti-tg antibodies (Snozek et al J Clin Endocrinol Metab 2007; 92:4278-4281)

Efficacy of Reoperation: OSU Experience 107 surgeries were undertaken in 70 patients. Biochemical CR (Stim Tg< 0.2) was initially achieved in 12 (17%) patients. 28 of 58 people with detectable postoperative Tg went on to re-exploration with biochemical CR in 5 (18%). 2 other patients had a delayed CR after one reoperation In total, CR was achieved in 19 patients (27%) with 60 months follow-up (range 4-116). 46% achieved a stimulated Tg < 2.0 ng/ml. 3% new hypoparathyroidism; no new RLN damage Al-Saif O, Farrar WM, Bloomston M, Porter K, Ringel MD, Kloos RT J Clin Endocrinol. Metab. 2010; 95(5):2187-94

ATA Guidelines Management of Residual/Recurrent Thyroid Cancer in the Neck Rec 71: Therapeutic comprehensive compartmental lateral and/or central neck dissection, sparing uninvolved vital structures, should be performed for patients with biopsyproven perisistent or recurrent disease for central neck nodes >8 mm and lateral neck nodes >10 mm in smallest dimension that can be localized on anatomic imaging. Recommendation: Strong; Evidence: Moderate Rec 73 (C24): For regional nodal metastases discovered on Dx WBS, RAI may be employed in patients with lowvolume disease or in combination with surgery, although surgery is typically used in the presence of bulky disease or disease amenable to surgery. Haugen, et al Thyroid 2016

Case 2 FNA of the node was consistent with papillary thyroid cancer on cytology; Tg level in the node was 1830 ng/ml. Chest CT had no evidence of distant metastases What would you recommend now? A. Surgery B. I-131 Therapy C. Monitor with no surgery

Case 2 The neck was marked at the site of the nodes and a limited right lateral neck dissection was performed. 1 of 4 nodes removed had PTC The malignant node measured 1.7x0.9.0.6 cm What would you do next?

Case 2 3 months after surgery: TSH 0.112 with a Tg 0.3 ng/ml with negative antibodies 6 months after surgery: TSH: <0.04 with Tg <0.2 with negative antibodies 8 months after surgery: rhtsh Tg is 0.4 ng/ml 12 months after surgery: TSH 0.13 mu/l; Tg <0.2 ng/ml with negative anti-tg antibodies. 24 months after surgery: rhtsh Tg is <0.2 ng/ml and neck US is negative

38 Metastatic Thyroid Cancer: Case 3

Case 3 51 year old gentleman with right-sided thyroid nodule diagnosed in 2003 Right hemithyroidectomy was performed Pathology read as a 2.5 cm encapsulated non-invasive follicular carcinoma without evidence of either capsular or lymphovascular invasion. Reviewed by two pathologists at that time. Subsequent pathology review: Well-differentiated tumor of undetermined malignant potential. What would you recommend?

Case 3 Options for this patient Completion thyroidectomy Monitor by Tg and ultrasound Remnant lobe ablation

Case 3 After discussion with the patient he was monitored without a second surgery. Thyroid Ultrasound with residual tissue in the right lobe and a normal size left lobe with no nodules. From 2004 2006 Tg levels between 7 and 13 ng/ml with positive anti-tg antibodies at 28 mu/l and TSH levels in the 0.1-0.4 mu/l range.

Case 3 2007: Tg levels increase to the 15-20 ng/ml with the same degree of TSH suppression with continued anti-tg antibodies at 56 mu/l. PET/CT imaging was performed and was negative for FDG-avid lesions. Neck ultrasound is unchanged He is referred to OSU for evaluation.

Case 3 The patient is managed on 137 mcg of L-thyroxine daily and metoprolol for heart palpitations. Exam is unremarkable TSH: 1.57 mu/l; Tg 34.2 ng/ml with positive anti- Tg antibodies at 72 mu/l. What diagnostic tests would you perform? Are the Tg or anti-tg antibodies reliable markers?

Effects of Anti-Tg antibodies on Tg Immunometric Assays Tg antibodies generally reduce measured Tg levels in the immunometric assays used by most laboratories. Measurable Tg levels in the setting of positive antibodies might reflect a non-interfering antibody, or an underestimate of the actual Tg levels Ringel MD and Nabhan F. J Clin Endocrinol Metab. 2014

Case 3 Neck ultrasound confirmed residual tissue in the thyroid bed, a normal left lobe and no concerning neck nodes. CT of the chest without contrast revealed multiple pulmonary nodules in a lower lobe distribution bilaterally.

Case 3 What would you do now? Completion Thyroidectomy I-131 therapy Neither Both

Case 3 The patient was referred for a completion thyroidectomy. The residual tissue in the right bed and a left lobectomy were performed Normal thyroid tissue was removed. Post-op labs: TSH: 2.18 mu/l; Tg: 34.8 ng/ml with Tg Antibody level of 30 mu/l

Case 3 The patient was withdrawn from L-thyroxine. TSH: 35.5 mu/l; Tg 160 ng/ml; anti-tg antibodies <20 mu/l Pre-therapy scan with minimal uptake in the thyroid bed. 217 mci of I-131 administered Post-therapy scan with uptake in the thyroid bed and faint uptake in the lower lung fields consistent with pulmonary metastases

Case 3: Questions to Consider Why was the PET/CT negative? Lack of avidity Small size of nodules What is the patient s prognosis with small PET negative pulmonary metastases?

Case 3 4 months after I-131 therapy: TSH: 0.24 mu/l; Tg: 17.7 ng/ml with anti-tg antibodies <20 mu/l. ~12 months after therapy; Tg 44 ng/ml with negative anti-tg antibodies. Chest CT with mild progression, largest lesion 0.9x1.0 cm. Most recent labs: TSH: 0.036; Tg: 84 ng/ml (- antibodies) CT scan: Slow progression with the largest nodule 13x10 mm. Neck ultrasound was negative. Lung lesions not FDG Avid on Repeat PET/CT. No other mets noted What are the options now?

Case 3 Options for consideration Repeat I-131 Therapy Treatment off label with a FDA-approved kinase inhibitor previously studied in differentiated thryoid cancer Sorafenib, Sunitinib, Pazopanib Clinical Trial but rate of progression is currently too slow to qualify (good news!!) Continue to Monitor with no therapy

Case 3 Issues to Consider Prognosis based on Imaging and Tg Levels Likelihood of Remission or Stabilization with Treatment Side effects of treatment vs current quality of life (which is excellent) Now has developed T11 bone met requiring surgery and stereotactic radiotherapy Toxicities and Quality of Life Expected Response

Tg Doubling Time Predicts Outcome Tg Doubling Time (DT): Miyauchi A, et al. 2011 Thyroid 707-716. 426 patients with at least 4 serial Tg levels with TSH <0.1 and no anti-tg antibodies for calculation of doubling time. 137 had detectable Tg levels DT<1 Yr: 87.5% 5 yr survival; 50% 10 Yr survival DT 1-3 Yrs: 95% 5Yr survival; 95% 10 Yr survival DT >3 Yrs: 100% 5 Yr survival; 100% 10 Yr survival

Thyroid Cancer Kinase Inhibitors: Primary Active Targets Drug VEGFR2/3 RET BRAFV600E BRAF WT MEK 1/2 cmet PDGF Axitinib X Cabozantinib X X X Dabrafenib X Lenvatinib X X X, FGFR1 Motesanib X X X Pazopanib X X X, C-KIT Selumetinib X Sorafenib X X X Sunitinib X X Vandetinib X X EGFR Vemurafanib X

Tyrosine Kinase Inhibitors in Differentiated Thyroid Cancer: Clinical Trials Efficacy 1 2 5 6 3 4 1 Pennell NA, et al Thyroid, 2008: 18:317-23; 2 Sherman SI, et al. N Engl J Med. 2008:359:31-42 3 Cohen EE, et al J Clin Oncol 2008: 26:4708-13 4 Gupta-Abramson V, et al.j Clin Oncol. 2008: 26:4714-19 5 Kloos RT and Ringel MD, et al J Clin Oncol. 2009: 27:1675-84 6 Bible, et al Lancet Oncol. 2010:11:962-72 7 Schlumberger, et al N Engl J Med. 2015

Tyrosine Kinase Inibitors: Caveats Side Effects Fatigue, Rash, and others GI: including fistulae and perforations including some fatalities Hypertension and Cardiac Side Effects Most studies show best response. Duration can be variable and side effects may worsen over time Limit use to patients with high expected mortality from thyroid cancer

Sorafenib Improves Progression Free Survival in Patients with Progressive DTC Progression-Free Survival Best Tumor Response Brose, et al. Lancet 4/2014 epub 62

Lenvatinib Phase III Study: of Progression-free Survival in the Intention-to-Treat Population. Schlumberger M et al. N Engl J Med 2015;372:621-630.

Kinase Inhibitors Thyroid Cancer: Patient Selection for Treatment Patients that are appropriate for kinase inhibitor therapies for thyroid cancer have surgical and iodine non-responsive, typically life-threatening, and radiographic progressive or anaplastic thyroid cancer Lenvatinib is often the first line Side Effects May Determine Choice of Drug 1-2 % Drug Related death rate in all studies Ongoing studies to start low and increase

Summary Individualize Thyroid Cancer Treatment Initial Therapy with I-131 and Degree of TSH suppression Local Residual/Recurrent Disease Distant Metastases