3/8/2018. Head and Neck Oncology Tumor Board Focus on Thyroid Cancer. Panel Members. Case 1: 65 year old woman with papillary thyroid cancer

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1 18 th Multidisciplinary Management of of Cancers: A A Case based Approach Head and Neck Oncology Tumor Board Focus on Thyroid Cancer Session Chair A. Dimitrios Colevas MD Professor of Medicine (Oncology) and, by courtesy, of Otolaryngology Head and Neck Surgery, Stanford Panel Members Tanaya Shree MD. medical oncology fellow, Stanford Chrysoula Dosiou MD, MS. Clinical Associate Professor of Medicine, Stanford Lisa Orloff MD. Professor of Otolaryngology Head and Neck Surgery, Stanford Michael Campbell MD. Assistant Professor of Surgery, UC Davis Shyam Rao MD PhD. Assistant Professor of Radiation Oncology, UC Davis Quan Yang Duh MD. Professor of Surgery, UCSF Alain Algazi MD. Associate Professor of Medicine, UCSF Jed Katzel MD. Medical Oncologist, The Permanente Medical Group Case 1: 65 year old woman with papillary thyroid cancer Presented in Taiwan with large right thyroid mass (cancer suspected) Clinically staged T3N0M0 June 2011: total thyroidectomy, right neck dissection Solitary tumor in right lobe, tracheal deviation, tight fixation to trachea, infiltration of strap muscles Residual tumor on trachea (R2 resection) Pathology: 8.5cm papillary thyroid cancer in right lobe, extensive capsule invasion, margins extensively positive, 0/5 LN positive. AJCC T3N0M0 Stage III Case 1 / Question 1: How important is the completeness of resection for differentiated thyroid cancers? A. Not important if radioactive iodine (RAI) ablation is planned anyway B. Not important if radiation is planned anyway C. An important factor, significantly influencing risk of recurrence D. Important for papillary but not follicular thyroid cancers 1

2 Incomplete tumor resection portends high risk for recurrence in DTCs Case 1: 65 year old woman with papillary thyroid cancer Incomplete resection is considered high risk for recurrence by both ATA and ETA 5 year DSS R0 94.4% R1 87.6% R2 67.9% p = n = 153 R0 R1 R2 Patient received postoperative RAI therapy with 200 mci Adjuvant radiotherapy recommended, but patient declined Started on levothyroxine 100 mcg daily Lost to follow up Moved to the United States MSKCC Operative Series Wang et al., Surgery (2016) ATA Guidelines 2015 Case 1: 65 year old woman with papillary thyroid cancer Question for the radiotherapists: What do medical oncologists need to know about 131 I dosing? (Our patient received 200 mci) Case 1 / Question 2: What is the appropriate follow up of patients with locally advanced differentiated thyroid cancers after initial therapy? A. Periodic thyroglobulin (Tg), anti Tg antibody, thyroid stimulating hormone (TSH) and radioiodine scan B. Periodic Tg, anti Tg antibody, TSH and neck ultrasound C. Periodic Tg, anti Tg antibody, TSH and PET/CT D. Clinical follow up only; no benefit to Tg measurements or surveillance scans 2

3 Follow up depends on estimation of recurrence risk High risk patients: Serum Tg, anti Tg antibody, TSH every 3 6 months Periodic neck ultrasound Consider TSH stimulated 131 I imaging Additional imaging (CT, MRI, PET, extended ultrasounds) as clinically indicated Case 1: 65 year old woman with papillary thyroid cancer April 2017: Patient presents with recurrent large right neck mass, difficulty swallowing, inspiratory and expiratory sounds, and diffuse neck pain Referred to a surgeon, who performs a fine needle aspiration (FNA) of the neck mass and orders a neck MRI Low risk patients: Serum Tg, anti Tg antibody, TSH at 6 and 12 months then annually Periodic neck ultrasound (could be omitted in very low risk patients) ATA Guidelines 2015 FNA results: papillary thyroid carcinoma Case 1: 65 year old woman with recurrent papillary thyroid cancer Case 1: 65 year old woman with papillary thyroid cancer 10 cm mass Traversing midline Completely encasing right common carotid artery Extending along C2 through C7 vertebrae Infiltrating bilateral cricoarytenoid complex Narrowing airway to a 3 mm slit Question for the surgeons: What defines a resectable vs. an unresectable tumor? 3

4 Case 1 / Question 3: What is the appropriate next step in management? Case 1: 65 year old woman with recurrent papillary thyroid cancer A. Evaluate for resection or debulking to facilitate retreatment with radioactive iodine B. 68 Ga DOTATATE PET/CT to complete staging C. 18 FDG PET/CT to complete staging D. Blood thyroglobulin level, anti Tg antibodies, TSH E. Tracheostomy PET/CT June 2017 Large right neck mass Extensive right neck adenopathy Many pulmonary nodules, largest 1.7cm Tg = 9432 ng/ml TSH = μiu/ml Case 1 / Question 4: 18 FDG PET avid differentiated thyroid cancer FDG PET avid DTCs are generally resistant to radioiodine treatment A. is typically resistant to radioactive iodine therapy B. carries a better prognosis than PET negative DTC C. is likely to be negative for BRAF mutation D. is all of the above Retrospective study of 25 PET(+) and 22 PET( ) patients with metastatic DTC given 131 I therapy Retrospective study of 32 PET(+) and 13 PET( ) patients with treated DTC but now rising Tg, who were then given 131 I therapy Wang et al., Thyroid (2001) Salvatore et al., Q J Nucl Med Mol Imaging (2008) 4

5 BRAF V600E mutant DTCs are more likely to be FDG PET avid and have higher SUVs FDG PET avidity is associated with worse prognosis in DTC Likelihood of PET positivity 7 studies 1144 patients 843 BRAF V600E (+) 301 BRAF V600E ( ) Pooled odds ratio of having a positive FDG PET = 2.12 Mean SUV difference 4 studies 338 patients 268 BRAF V600E (+) 70 BRAF V600E ( ) Pooled mean difference in SUV MAX on FDG PET = patients with thyroid cancer Volume of PET avid disease was single strongest predictor 10 patients with PET( ) distant metastatic disease remained alive and well 76 patients with positive Tg and negative 131 I scan 5 year survival: 100% in PET negative group 63% in PET positive group Santhanam et al., Endoc Pract (2017) A review and metanalysis of PET avidity and BRAF mutation status in PTCs Wang et al., J Endocrinol Metab (2000) Case 1: 65 year old woman with recurrent papillary thyroid cancer RAI re challenge deferred given large tumor that could not be debulked (and given PET avidity, less likely to respond to RAI therapy) Molecular testing and trial of targeted therapy recommended If no response, recommended to consider radiation therapy Started on lenvatinib 20mg daily (unclear if molecular testing ultimately performed) Lenvatinib improves PFS in RAI refractory thyroid cancer Lenvatinib inhibits VEGF receptors, FGF receptors, PDGFRα, RET, and KIT Lenvatinib significantly improved PFS over placebo (18 months vs 4 months) No overall survival difference, but many patients crossed over Schlumberger et al., NEJM (2015) 5

6 Possible other issues to flesh out for case 1 / DTCs: Case 2: 64 year old woman with thyroid cancer When if ever to reconsider surgery? When to re challenge with RAI? Strategies for increasing RAI uptake by malignant tissue? What is adequate TSH suppression in RAI refractory patients? Choices of systemic therapy? Importance of molecular testing for BRAF, NKTR, VEGFR? Discussion of early results with new kinase inhibitors? Situations where we may use a kinase inhibitor before RAI? Early May 2017: New onset hoarseness, dysphagia, right otalgia, right mandibular pain, 8 pound weight loss in 1 month. ECOG 3. Large right anterior neck mass noted on physical exam. May Neck US: Multiple bilateral thyroid nodules are present. A large complex heterogeneous nodule occupies the entire right lobe, with irregular margins and intranodular vascularity. June FNA: malignant, significant degree of atypia, worrisome for anaplastic thyroid cancer Case 2: 64 year old woman with thyroid cancer Right thyroid mass has possible direct involvement with trachea, possible invasion at the right posterior contour. There is also concern for possible involvement with the right internal jugular vein and right common carotid artery as well. Lung with innumerable nodules, ranging from 1 8 mm, suspicious for metastases Case 2 / Question 1: What additional information is needed prior to starting treatment? A. Larger biopsy to confirm pathological diagnosis B. Genomic profiling C. Microsatellite instability status evaluation D. PD L1 expression level E. None Noncontrast CT Neck & Chest 6

7 Case 2: 64 year old woman with thyroid cancer Re biopsy of neck mass showed: Anaplastic thyroid carcinoma Intact expression of MLH1, MSH2, MSH6 PMS2 (mismatch repair proteins) PD L1 expressed in 90% of tumor cells STAMP (Solid tumor associated mutation panel) sent Tracheotomy performed FDG PET CT ordered to verify extent of disease Thyroglobulin 4050 ng/ml Case 2: 64 year old woman with anaplastic thyroid cancer Staging PET/CT shows large anterior neck/upper mediastinal mass, pulmonary nodules, suspicious left iliac lesion Case 2 / Question 2: What would be your initial choice of therapy? Case 2: 64 year old woman with metastatic anaplastic thyroid cancer A. Surgical resection B. Immune checkpoint inhibitor C. Chemotherapy D. Radiation therapy E. Chemoradiation Recommended chemoradiation vs. supportive care alone given incurable disease with poor prognosis Received paclitaxel 80 mg/m2 weekly with radiation Response at 2 months excellent Progressed at 4 months, but performance status significantly improved Mutation panel resulted: TP53 loss of function 6% VAF TERT enhanced telomerase 7% VAF NRAS activation 16% VAF 2 months 4 months 7

8 Weekly paclitaxel for anaplastic thyroid cancer Retrospective study by Higashiyama et al., showed 31% response rate at a single institution Prospective multicenter study by Onoda et al., confirmed efficacy of weekly paclitaxel in anaplastic TC: 0 CR 21% PR 52% SD Median TTP still poor at 1.6 months Onoda et al., Thyroid (2016) Case 2 / Question 3: What would be your next choice of therapy? A. Doxorubicin B. Immune checkpoint inhibitor C. TKI targeting NRAS pathway D. Everolimus E. Supportive care alone Immunotherapy for thyroid cancer : Current evidence Thyroid cancers can contain many PD 1+ T cells Thyroid cancer cells frequently express PD L1, especially if BRAF mutant and especially when aggressive One patient with an impressive response to nivolumab (Kollipara et al., Oncologist 2017) 64yo male with metastatic anaplastic thyroid cancer, BRAF mutant, PD L1 positive Had progressed on Doxorubicin/Cisplatin and on Paclitaxel; mixed response to vemurafenib Started on nivolumab; achieved CR; received 12 cycles (~6 months); still in remission 20 months after starting nivolumab Pre treatment Post treatment Immunotherapy for thyroid cancer : Ongoing/planned studies Nivolumab + Ipilimumab (NCT , NCT ) Pembrolizumab (NCT , NCT ) Pembrolizumab + Docetaxel (NCT ) Pembrolizumab + Lenvatinib (NCT ) Pembrolizumab +/ Surgery + Chemoradiation (NCT ) Durvalumab + RAI (NCT ) Tremelimumab + SBRT (NCT ) Taxane induction + Atezolizumab + Vemurafenib OR Cometinib (NCT ) Many other immunotherapy strategies being tested 8

9 Case 2: 64 year old woman with metastatic anaplastic thyroid cancer Started on nivolumab 240 mg every two weeks After two doses, complained of shadow over right visual field Ophthalmologist: mass in right eye MRI: Sub centimeter nodule in the superior nasal aspect of the right eye globe posteriorly without evidence of extraocular extension suspicious for metastatic disease. Received radiation to eye metastasis with improvement Awaiting trametinib approval (given NRAS mutation) Has met with hospice Case 3: 28yo woman with palpable left neck mass Presented with palpable neck mass; biopsy recommended but patient lost to follow up 2 years later: Mass slowly growing, 20 lb weight loss in last year, increasing diarrhea, anxiety, flushing Recently diagnosed with diabetes and hypertension and started on medications for both Has a 9 year old son, but 3 pregnancies in past two years ended prematurely On evaluation: very thin, multiple anterior and lateral left neck masses palpable Excisional left neck lymph node biopsy: metastatic medullary thyroid cancer, strongly positive for TTF 1, CEA, synaptophysin, chromogranin A, and CK 7 Case 3: CT Neck, labs Case 3 / Question 1: What additional work up is needed? A. PET/CT to evaluate for metastases given Calcitonin > 500 and extensive disease in neck B. Chest and abdominal imaging given extensive disease; RET mutation testing, then screen for pheochromocytoma and hyperparathyroidism only if positive; C. Plasma and urine metanephrines, then CT abdomen only if metanephrines positive in order to localize pheochromoctytoma TSH 89, ft4 1.0, ft3 2.6 Calcitonin 148,568 CEA 2589 D. Plasma and urine metanephrines, PTH, RET mutation testing, chest and abdominal imaging 9

10 Case 3 / Question 1: What additional work up is needed? A. PET/CT to evaluate for metastases given Calcitonin > 500 and extensive disease in neck B. Chest and abdominal imaging given extensive disease; RET mutation testing, then screen for pheochromocytoma and hyperparathyroidism only if positive; C. Plasma and urine metanephrines, then CT abdomen only if metanephrines positive in order to localize pheochromoctytoma D. Plasma and urine metanephrines, PTH, RET mutation testing, chest and abdominal imaging ATA, UpToDate NCCN Case 3: 28yo woman with metastatic medullary thyroid cancer 24h urine metanephrines 9208 [<222] 24h urine normetanephrines 7311 [<412] Plasma metanephrine 2343 Plasma normetanephrine 3057 Plasma total metanephrine 5400 PTH 41 [10 80], Ca 9.9, Alb 4.3 MRI Abdomen: Bilateral adrenal masses (left 5.9 x 5.3 x 5.9; right 3.3 x 2.8 x 2.2), innumerable liver lesions, bony lesions Heterozygous for RET Cys634Arg mutation (germline) Case 3: 28yo woman with MEN2A with metastatic MTC and bilateral PHEOs MEN2A Started on phenoxybenzamine for alpha blockade Must start at least two weeks prior to surgery Underwent open bilateral adrenalectomy & liver biopsy Findings: 6cm left adrenal mass, 2.5cm right adrenal mass, liver mets Pathology: adrenal masses both pheochromocytomas; liver metastasis consistent with metastatic medullary thyroid cancer RET protein Mulligan LM. Nat Rev Cancer (2014) Underwent total thyroidectomy for debulking 10

11 Case 3 / Question 2: What next? Tyrosine Kinase Inhibitors for Medullary Thyroid Cancer A. Observation B. Dabrafenib and trametinib C. Vandetanib D. Cabozantinib E. Immune checkpoint inhibitor Vandetanib approved for metastatic MTC in April 2011 Cabozantinib approved for metastatic MTC in Nov 2012 Pappa & Alevizaki. Endocrine (2016) Tyrosine Kinase Inhibitors for Medullary Thyroid Cancer Vandetanib vs. Placebo, PFS Cabozantinib vs. Placebo, PFS Case 3: 28yo woman with MEN2A with metastatic MTC and bilateral PHEOs Started on Cabozantinib Great response Progression after 1.5 years Started on Vandetanib Responded but discontinued due to toxicity Wells et al., J. Clin. Oncol. (2012) Elisei et al., J. Clin. Oncol. (2013) 11

12 180, , , , ,000 80,000 60,000 40,000 20,000 Felt good Felt bad Felt good Felt OK Thyroidectomy Cabozantinib 140mg/d Cabozantinib 120mg/d Cabozantinib 100mg/d Discontinued Cabozantinib Vandetanib 300 mg/d Discontinued vandetanib 11/25/14 5/19/15 11/10/15 5/3/16 10/25/16 4/18/17 Case 3: 28yo woman with MEN2A with metastatic MTC and bilateral PHEOs BLU 667 is a potent and selective inhibitor of RET mutations, fusions, and predicted resistant mutants. Phase 1 Study of BLU 667 in Patients With Thyroid Cancer, Non Small Cell Lung Cancer, and Other Advanced Solid Tumors NCT Dr Matthew Taylor, OHSU Feels great. BLU 667 Case 3 / Question 3: What about her family? Case 3: 28yo woman with MEN2A with metastatic MTC and bilateral PHEOs A. If no family history suggestive of MEN2A, recommend RET mutation testing only for son B. Recommend RET mutation testing of all first degree relatives C. Recommend RET mutation testing and neck ultrasound for all first degree relatives D. Recommend RET mutation testing, neck ultrasound, plasma and urine metanephrines, and PTH for all first degree relatives 30 year old brother, 18 year old sister, and 9 year old son all tested for RET mutations Son tested positive for RET Cys634Arg mutation (same as patient) Adapted from ATA Guidelines 2015 Figure from Van der Tuin et al., Cancer Research Frontiers (2015) 12

13 Case 4: 52 yo woman with a right thyroid nodule 52 year old female; physician palpated right thyroid mass Ultrasound shows 1.8 cm hypoechoic solid nodule in right thyroid; left lobe homogenous and free of nodules Fine needle aspirate revealed Follicular Lesion of Undetermined Significance ( FLUS ) Case 4 / Question 1: What is the next step in management? A. Hemithyroidectomy B. Total thyroidectomy C. Repeat US FNA D. Repeat US FNA with molecular testing ATA guidelines, Thyroid (2016) Case 4: 52 yo woman with a right thyroid nodule Bethesda 2017 Case 4: 52 yo woman with a right thyroid nodule Frequency Diagnostic category Risk of malignancy 5-11% 55-74% 2-18% 2-25% 1-6% 2-5% AUS and FLUS FN Overall: About 25% of FNAs are indeterminate % of these are malignant Molecular Testing for Indeterminate FNAs Gene expression classifier test (Afirma) Analyzes mrna expression of 167 genes Results: benign vs suspicious PPV = 37 44% NPV = 93 95% Panel testing for mutations (e.g. Thyroseq) Includes BRAF, RAS, RET/PTC, PAX8/PPAR PPV = 87 95% NPV = 72 94% Our patient undergoes Afirma testing: suspicious FNA Result Suspicious for malignancy Afirma Result Malignancy rate Benign 15 28% AUS/FLUS or FN Benign 6 7% AUS/FLUS or FN Suspicious 37 44% 13

14 Case 4: 52 yo woman with a right thyroid nodule Patient undergoes right hemithyroidectomy Pathology: Papillary thyroid carcinoma, follicular variant Case 4 / Question 2: What is the next step in management? A. Completion thyroidectomy B. Completion thyroidectomy and radioiodine ablation C. Observation with periodic neck ultrasounds D. No further intervention needed E. Need to review pathology in greater detail to decide Follicular Variant Papillary Thyroid Cancer (FVPTC) Classical PTC Non-encapsulated FVPTC (infiltrative/diffuse), very close to classical PTC FVPTC Follicular adenoma/ carcinoma Encapsulated FVPTC (close to follicular adenoma/carcinoma Cancer Volume 107, Issue 6, pages , 9 AUG 2006 DOI: /cncr Characteristic Classic PTC FVPTC Follicular CA Extrathyroidal Extension 25% 15% 9% LN metastases 34% 16% 2% Distant metastases 1% 2% 4% 15 year Disease Specific Survival 97% 98% 92% Yu, X M. et al., Thyroid (2013) Follicular Variant Papillary Thyroid Cancer (FVPTC) Characteristic Encapsulated FVPTC Non encapsulated FVPTC Number Extrathyroidal 5% 65% extension 1 Positive margins 1 2% 50% Lymph node 5% 65% metastases 1 Tumor fibrosis 1 18% 88% BRAF 2 0% 26% RAS 2 36% 10% 1 Liu et al., 2006, Cancer 107: Rivera et al., 2010, Mol Pathol 23: % of cases noninvasive (n=42) At 11 years follow-up: NO recurrences NO metastatic disease NO deaths 8/2016 Noninvasive encapsulated FVPTC renamed Non Invasive Follicular Thyroid Neoplasm with Papillary like Nuclear Features or NIFTP about 19% of PTCs 14

15 Case 4: 52 yo woman with a right thyroid nodule Detailed examined of histology revealed NIFTP Observation recommended 73% of malignancies identified after suspicious Afirma 1,2 and 74% of malignancies identified after positive Thyroseq 3 testing in AUS/FLUS or FN FNAs were FVPTC 1 Lastra et al., Wong et al., Nikiforov et al.,