Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Selecting Optimal Therapeutic Strategies for Patients With Differentiated and Medullary Thyroid Cancer

1,187 views

Published on

i3 Health is pleased to make the speaker slides from this activity available for use as a nonaccredited self-study or teaching resource.

Published in: Education
  • Be the first to comment

Selecting Optimal Therapeutic Strategies for Patients With Differentiated and Medullary Thyroid Cancer

  1. 1. Selecting Optimal Therapeutic Strategies for Patients With Differentiated and Medullary Thyroid Cancer Jochen Lorch, MD, MS Assistant Professor of Medicine Harvard Medical School
  2. 2. Disclosures Dr. Lorch discloses the following commercial relationships: ◼ Consultant: Eisai ◼ Research Support: Bayer, Bristol-Myers Squibb, Millennium
  3. 3. Learning Objectives ▶ Assess risk-adapted approaches to the management of thyroid cancer ▶ Evaluate efficacy and safety data on novel therapies for differentiated and medullary thyroid cancer ▶ Apply posttreatment monitoring strategies to ensure optimal outcomes for patients with thyroid cancer
  4. 4. Thyroid Cancer Scope of Problem ▶ Most common endocrine cancer ◼ An estimated 56,870 cases per year in US ◼ Incidence rising: 5% increase between 2004-2013 ◼ Relatively stable mortality rate at 0.5 deaths per 100,000 people but may be rising as well ▶ Subtypes ◼ Papillary ~80% ◼ Follicular ~10% ◼ Poorly differentiated 5-10% ◼ Medullary 4% ◼ Anaplastic 2% ACS, 2017; ACS, 2016.
  5. 5. Traditional Approach to Thyroid Nodules >1-1.5 cm TSH = thyroid-stimulating hormone. Haugen et al, 2016. Initial Assessment Ultrasound Check TSH Normal or Elevated (~95%) Suppressed (<5%) Fine Needle AspirationThyroid Scan (Noncancerous)
  6. 6. Thyroid Nodule FNA: High Rate of Indeterminate Cytology Courtesy of Erik K. Alexander, MD. Cooper et al, 2006. ~5% Malignant (Papillary Carcinoma) ~65-70% No Malignant Cells ~20-25% Indeterminate “Suspicious for malignancy” “Suspicious for a follicular neoplasm” “Atypical (follicular) lesion of uncertain significance” ~5% Nondiagnostic
  7. 7. The Problem: Low Specificity of Indeterminate Cytology US = ultrasound; UG-FNA =ultrasound-guided fine-needle aspiration. Yassa et al, 2007. ~4,595 consecutive thyroid nodules evaluated with US and UG-FNA Despite recommendations for surgery, >50% of patients with “abnormal” cytology are proven to have benign disease. FNA Cytology Proportion Cancer on Histopathology Suspicious for papillary carcinoma 60% Suggestive of a follicular neoplasm 28% Atypical of an undetermined significance 24%
  8. 8. Gene Expression FNA = fine-need aspiration; AUS/FLUS = atypia (or follicular lesion) of undetermined significance; FN/SNF = follicular neoplasm/suspicious for follicular neoplasm; NPV = negative predictive value. Alexander et al, 2012. Afirma Gene Expression Classifier – 164 Genes  Prospective, blinded, study with nodules >1 cm  1-2 additional samples after FNA (“standard of care approach”)  Comparison with 2-expert, blinded, gold-standard histopathology n=129 Performance on All Indeterminate Cytology AUS/FLUS Cytology FN/SNF NPV: 95% NPV: 94%NPV: 93% n=265 n=81  False-negative rate similar to benign cytology  High NPV prevents unnecessary surgery 95% 94%
  9. 9. Pre-Operative Imaging ▶ Helps avoid incomplete surgery ▶ Recurrence rates up to 35% ◼ Most within 5 years ◼ Some due to inadequate surgery ▶ Ultrasound to evaluate primary tumor and nodes recommended in all patients ▶ Cross-sectional imaging used in a minority of patients ◼ Indistinct margins between tumor and major vessels, esophagus, airway ◼ Bulky nodal disease incompletely imaged with US ◼ Nodal disease in deep structures of the neck or mediastinum Yeh et al, 2015.
  10. 10. Surgery: Mainstay of Therapy ▶ Total thyroidectomy for tumors >1 cm ◼ ATA guidelines now recommend lobectomy for low-risk cancers – <4 cm – No clinical evidence of nodes – No extrathyroidal extension ▶ Lobectomy for unifocal cancer <1 cm ◼ No clinical evidence of nodes ◼ No history of radiation therapy or familial thyroid cancer ATA = American Thyroid Association. Haugen et al, 2016.
  11. 11. Postoperative Risk Stratification ▶ AJCC staging: Predicts mortality not recurrence ▶ Operative report ◼ Gross extrathyroidal extension ◼ Completeness of resection ▶ Specific histology ▶ Mutational status (BRAF?, BRAF + TERT promoter, PIK3CA, TP53, AKT1) ▶ Postoperative serum thyroglobulin testing AJCC = American Joint Committee on Cancer. Omry-Orbach, 2016.
  12. 12. Postoperative Risk Stratification (cont.) ▶ Post-op I123 or I131 scans ◼ May be useful in select cases ◼ Avram and colleagues (2015): – I131 scan detected nodal or distant metastatic disease in 29.4% of cases, which lead to management changes – Many of these also had elevated post-op Tg ▶ Post-op PET/CT ◼ FDG+ predicts poorer outcome and radioiodine resistance ◼ Recommended in patients with aggressive histology and Tg >10 ng/mL ◼ Can have false-positive rate of 0-39% PET/CT = positron emission tomography/computed tomography; FDG = fluorodeoxyglucose; Tg = thyroglobulin. Nascimento et al, 2015; Avram et al, 2015.
  13. 13. Differentiated Thyroid Cancer: AJCC Staging Primary tumor (T) TX Primary tumor cannot be assessed TO No evidence of primary tumor is found T1 Tumor size ≤ 2 cm in greatest dimension and is limited to the thyroid T1 a Tumor ≤ 1 cm, limited to the thyroid T1 b Tumor > 1 cm but ≤ 2 cm in greatest dimension, limited to the thyroid T2 Tumor size > 2 cm but ≤ 4 cm, limited to the thyroid. T3 Tumor size >4 cm, limited to the thyroid or any tumor with minimal extrathyroidal extension (eg, extension to sternothyroid muscle or perithyroid soft tissues) T4 a Moderately advanced disease; tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4 b Very advanced disease; tumor invades prevertebral fascia or encases carotid artery or mediastinal vessel Edge et al, 2010. Regional lymph nodes (N) Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes: NX Regional nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) N1b Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (level VII) Distant metastasis (M) M0 Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (level VII) M1 Distant metastasis is present
  14. 14. Edge et al, 2010. Papillary and follicular thyroid cancer (age <45y): Stage T N M I Any T Any N M0 II Any T Any N M1 Papillary and follicular; differentiated (age > 45y): Stage T N M I T1 N0 M0 II T2 N0 MO III T3 N0 M0 IVA T1-3 N1b M0 T4a N0-1b M0 IVB T4b Any N M0 IVC Any T Any N M! Differentiated Thyroid Cancer: AJCC Staging (cont.)
  15. 15. ATA 2009 Risk Stratification Haugen et al, 2016.
  16. 16. Risk of Recurrence as a Continuum Haugen et al, 2016.
  17. 17. DTC: Mutational Landscape ▶ 402 cases, whole exome sequencing performed ▶ Low frequency of somatic alterations ▶ Mutation density correlates with age, risk of recurrence, MACIS score ▶ BRAF V600E in 61.7%, RAS (N-, H- and KRAS) 12.9% ▶ Along PI3K axis: 20/402 (5%) DTC = differentiated thyroid cancer. Agrawal et al, 2014.
  18. 18. DTC: BRAF vs RAS Agrawal et al, 2014.
  19. 19. DTC: Metastatic Disease ▶ Metastatic disease frequently affects: ◼ Lungs (49%) ◼ Bones (25%) ◼ Both (15%) ▶ RAI if significant iodine uptake is detected on scans ➔ remission ~30% ▶ May follow indolent course with slow disease progression on TSH suppression ▶ Disease considered RAI refractory if: ◼ At least one lesion with no uptake ◼ Progression within 1 year following RAI ◼ Persistent disease following dose of 600 mCi RAI = radioactive-iodine refractory. NCCN, 2017; Haugen et al, 2016.
  20. 20. RAI-Refractory DTC: Characteristics ▶ Inverse relationship between ◼ BRAF and RET mutations/rearrangements ◼ FDG and RAI avidity Ricarte-Filho et al, 2009; Cantwell-Doris et al, 2011; Xing et al, 2013.
  21. 21. Modulating RAI Uptake in Refractory Disease Through MEK Inhibition ▶ Selective MAPK pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine in animal models ▶ Selumetinib MAPK kinase inhibitor (MEK1 and MEK2) ◼ 20 patients with RAI-refractory thyroid cancer evaluated: – 9 BRAF+ – 5 NRAS+ ◼ 12/20 patients demonstrated increased uptake of I124 – 4/9 patients with BRAF mutations – 5/5 patients with NRAS mutations ◼ 8 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations ◼ 5 had confirmed PR and 3 had SD; all patients had decreases in serum thyroglobulin levels (mean reduction 89%) ◼ No toxicities grade ≥3 attributable to selumetinib observed PR = partial response; SD = stable disease; MAPK = mitogen-activated protein kinase. Ho et al, 2013.
  22. 22. Modulating RAI Uptake in Refractory Disease: Selumetinib Ho et al, 2013. RAI RAI + Selumetinib RAI RAI + Selumetinib
  23. 23. RAI-Refractory Metastatic Disease ▶ Doxorubicin ◼ Response rate 10-30% ◼ No known impact on survival ▶ Carboplatin, paclitaxel and docetaxel, bleomycin ◼ Response rates approximately 10-30%, usually short lived Until recently, RAI-refractory disease was NOT considered treatable. NCCN, 2017.
  24. 24. DECISION Phase III: Sorafenib vs Placebo in RAI-Refractory DTC ▶ Double-blind, randomized, multicenter phase III ▶ Patients with locally advanced/metastatic RAI-refractory DTC ▶ Progression within 14 months ▶ Randomly assigned 1:1 to sorafenib 400 mg BID PO or placebo, crossover allowed ▶ Primary end point: PFS ▶ 417 patients randomly assigned (207 to sorafenib and 210 to placebo) BID = twice daily; PO = by mouth; PFS = progression-free survival. Brose et al, 2014. Treatment until progression or unacceptable toxicity Locally advanced or metastatic RAI refractory DTC Sorafenib 800 mg Placebo 1:1 Randomization PROGRESSION Survival follow-up
  25. 25. DECISION: PFS ▶ Median PFS 10.8 mo for sorafenib vs 5.8 mo for placebo ◼ HR=0.59; 95% CI: 0.45-0.76; P<0.0001 ▶ No difference in OS (crossover allowed) Brose et al, 2014. All Cohorts
  26. 26. DECISION: PFS in BRAF Mutants WT = wild type. Brose et al, 2014. BRAF WT BRAF V600E (27% sorafenib, 31.4% placebo) BRAF V600: 20.5 vs 9.4 mo; HR=0.46; P=0.02 BRAF WT: 8.9 vs 3.8 mo; HR=0.55; P<0.001
  27. 27. SELECT Phase III: Lenvatinib in DTC ▶ Design similar to DECISION study ▶ 392 patients randomly assigned (2:1), double-blind, placebo-controlled ▶ Documented disease progression within 13 months ▶ Crossover to open-label lenvatinib allowed upon progression ▶ Primary end point: PFS Schlumberger et al, 2015; Stjepanovic & Capdevila, 2013.
  28. 28. SELECT: PFS ▶ PFS 18.3 mo (15.1-NR) vs 3.6 mo (2.2-3.7) ▶ 4 CRs (1.5%) ▶ Benefit similar for BRAF-positive and BRAF-WT cases ▶ No difference in OS except for older (>65 years) patients OS = overall survival; NR = not reached. Schlumberger et al, 2015.
  29. 29. Schlumberger et al, 2015. SELECT: Subgroup Analysis
  30. 30. Nonapproved Therapies
  31. 31. Targeting BRAF: Vemurafenib in BRAF-Positive PTC ▶ 51 patients with RAI-refractory progressive PTC positive for BRAF V600E mutation ◼ Cohort 1 (n= 26) if TKI treatment naive ◼ Cohort 2 (n= 25) if previously treated with TKIs ▶ Cohort 1 vs Cohort 2 results: ◼ PRs in 38.5% and 27.3%, no complete response ◼ Clinical benefit rate (CR + PR + SD = 6 months) was 58% and 36% ◼ Median PFS at the time of data cut-off for the analysis was 18.2 mo (95% CI: 15.5-29.3) and 8.9 mo (95% CI: 5.5-NE) ◼ Cutaneous squamous cell cancer in 27% and 20% ▶ Other grade 3/4 toxicity: Liver 4% ▶ 2 deaths reported on study, not felt to be treatment related PTC = papillary thyroid cancer; TKI = tyrosine kinase inhibitor; CR = complete response. NE = not estimable. Brose et al, 2016.
  32. 32. Everolimus in DTC: Key Eligibility Criteria ▶ Main cohort: ◼ RAI-refractory DTC (n=33) ▶ Disease progression within 6 months prior to enrollment ▶ PS 0-2 PS = performance status. Lorch et al, 2013.
  33. 33. Everolimus in DTC: PFS ▶ PFS 12.3 mo (95% CI: 10-NR) ▶ Disease stability for 6 mo achieved in 19/33 patients ▶ Disease stability for 12 mo or more in 11/33 patients Lorch et al, 2016. Progression-Free Survival Months Survival 0 5 10 15 20 25 25 50 75 100
  34. 34. Future Directions in RAI-Refractory DTC ▶ Lenvatinib plus PD-1 inhibition ◼ ITOG study opening 2017/18 ▶ Second-generation mTOR inhibitors ◼ MLN0128 ▶ Immunotherapy with PD-1/CTLA-5 inhibitors ◼ Pembrolizumab in 22 patients with RAI-refractory thyroid cancer – 2 patients had a PR for an ORR (confirmed) of 9.1% (95% CI:1.1-29.2) ITOG = International Thyroid Oncology Group; ORR = overall response rate. Mehnert et al, 2016.
  35. 35. Medullary Thyroid Cancer ▶ Derived from parafollicular C cells ▶ Usually presents with solid mass ▶ Frequently secretes: ◼ CEA, calcitonin ◼ VIP ➔ diarrhea ◼ ACTH ➔ Cushing’s disease ▶ Metastatic disease frequently affects mediastinum, lung, bone, and liver ▶ Growth rate ranging from indolent to extremely aggressive Courtesy of Justine Barletta, MD and Cheryl Adackapara, MD. NCCN, 2017; Haugen et al, 2016.
  36. 36. Medullary Thyroid Cancer (cont.) ▶ Sporadic MTC accounts for 75% of cases, familial MTC 25% ▶ Familial MTC occurs in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but non-MEN familial MTC can also occur ▶ Sporadic and familial cases usually involve mutation of RET proto-oncogene MTC = medullary thyroid cancer. Zbuk & Eng, 2007. Sporadic MEN2A/B RET mutation Somatic Germline Age (Average years) 40-45 15-25 Associated tumors – MEN2A: MTC, pheochromocytoma, parathyroid hyperplasiaMEN2B: MTC, pheochromocytoma, intestinal/mucosal ganglioneuromatosis, marfanoid habitus
  37. 37. MTC Therapy ▶ Aggressive surgery: Complete thyroidectomy with bilateral central compartment node dissection and unilateral neck dissection ▶ Adjuvant radiotherapy considered largely ineffective with no impact on survival ▶ Local recurrence treated surgically ▶ Systemic disease: ◼ Often indolent with no significant progression over long period of time ◼ Increase in calcitonin without radiographic evidence for disease progression does not indicate need for systemic therapy NCCN, 2017; Haugen et al, 2016.
  38. 38. Phase III: Vandetanib in MTC ▶ Double-blind, placebo-controlled trial ◼ 331 patients with advanced MTC ◼ Measurable disease (no progression required), calcitonin level >500 pg/mL ◼ Vandetanib 300 mg (n=231) or placebo (n=100) ◼ Crossover allowed ◼ Primary end point: PFS Wells et al, 2012. Treatment until progression or unacceptable toxicity Locally advanced or metastatic RAI refractory MTC Vandetanib 300 mg Placebo 1:1 Randomization PROGRESSION Survival follow-up
  39. 39. Vandetanib in MTC: PFS ▶ 54% reduction in the rate of progression (HR=0.46; P=0.001) ▶ PFS NR in vandetanib arm, 19.3 mo for placebo ▶ Objective response rate (ORR) 45% vs 13% (P<0.001) Wells et al, 2012. P=0.001
  40. 40. Vandetanib in MTC: OS ▶ No difference in OS ▶ Subgroup analysis showed no association with patient characteristics (but small n in some categories) Wells et al, 2012. Overall Male Female White Other PS 1-2 PS 0 Hereditary Sporadic or unknown Locally advanced Metastatic ≥1 prior Rx No prior therapy Response to prior Rx No response to prior Rx Unknown
  41. 41. Phase III: Cabozantinib in MTC ▶ Randomized, placebo-controlled study ▶ 330 patients with locally advanced or metastatic MTC ▶ Documented RECIST progressive disease within 14 mo of screening ▶ No limit on prior therapy ▶ Primary end point: PFS Schöffski et al, 2012. Treatment until progression or unacceptable toxicity Locally advanced or metastatic MTC with documented RECIST progression Cabozantinib 140 mg Placebo 1:1 Randomization PROGRESSION Survival follow-up No Cross-over No Unblinding
  42. 42. Cabozantinib in MTC: PFS Elisei et al, 2013. PFS: 11.2 vs 4.0 mo (HR=0.28 95%; CI: 0.19-0.40; P<0.001)
  43. 43. Cabozantinib in MTC: Subgroup Analysis ▶ RET M918T subgroup greatest PFS benefit from cabozantinib vs placebo (HR=0.15; 95% CI: 0.08- 0.28; P<0.0001) Elisei et al, 2013; Sherman et al, 2016.
  44. 44. Vandetanib vs Cabozantinib in MTC: Adverse Events GI = gastrointestinal. Wells et al, 2012; Schöffski et al, 2012. Vandetanib N=231 Cabozantinib N=214 Adverse Event All n (%) Grade ≥3 n (%) All n (%) Grade ≥3 n (%) Hypertension 73 (32) 20 (9) 70 (33) 18 (8) Fatigue 55 (24) 13 (6) 87 (41) 20 (9) Diarrhea 130 (56) 25 (11) 135 (63) 34 (16) Hemorrhage NR NR 54 (25) 7 (3) Venous thrombosis NR NR 12 (6) 8 (4) GI perforation NR NR 7 (3) 7(3) Non-GI fistula NR NR 8 (4) 4 (2) QT prolongation 33(14) 18 (8) NR NR
  45. 45. MTC Trials ▶ RET inhibitors: Ponatinib ▶ Regorafenib open since spring 2016 ▶ Immunotherapy? Clinicaltrials.gov, 2016; Clinicaltrials.gov, 2017a.
  46. 46. Anaplastic Thyroid Cancer ▶ Typically a tumor of older adults ▶ Presence of pre-existing or co-existing well-differentiated carcinoma in 23-78% of cases, usually papillary thyroid cancer ▶ History of long-standing goiter is common ▶ Clinical presentation: Rapidly growing neck mass, hoarseness, vocal cord paralysis, dysphagia ▶ Early hematogenous metastasis, cure rate 0-10%, median survival 4-6 mo Images courtesy of Justine Barletta, MD & Cheryl Adackapara, MD. NCCN, 2017; Haugen et al, 2016. Spindle Cell Pattern Pleomorphic Giant Cell PatternSquamoid Pattern
  47. 47. Mutational Landscape in ATC ATC = anaplastic thyroid cancer. Kunstman et al, 2015.
  48. 48. ATC Therapy ▶ Thyroidectomy or debulking thyroid surgery with neck dissection if possible ▶ Adjuvant radiotherapy or chemoradiotherapy ▶ Metastatic disease frequent, affecting mediastinum, lung, bone, and liver ▶ Prognosis poor with 5-yr survival 0-14% Kebebew et al, 2005; Edge et al, 2010. All anaplastic carcinomas are considered stage IV: T4a Intrathyroidal anaplastic carcinoma T4b Anaplastic carcinoma with gross extrathyroid extension Anaplastic carcinoma (all anaplastic carcinomas are considered stage IV): Stage T N M IVA T4a Any N M0 IVB T4b Any N M0 IVC Any T Any N M1
  49. 49. Metastatic ATC Therapy ▶ Doxorubicin + cisplatin: ◼ 7/30 (23%) response rate ◼ PFS 10 months ▶ Sorafenib: ◼ 2/15 (13%) PR ◼ 4/15 (27%) SD ▶ Axitinib: ◼ 1/2 PR No generally accepted standard for treatment of metastatic ATC. De Crevoisier et al, 2004; Nagaiah et al, 2009; Cohen et al, 2008.
  50. 50. FACT Phase II/III: Fosbretabulin in ATC OS = overall survival. Sosa et al, 2011; Sosa et al, 2014. Design ◼ Multicenter, open-label, 2:1 randomized trial ◼ 80/180 planned patients randomly assigned. Trial stopped early because of slow accrual ◼ Up to 6 cycles of carboplatin and paclitaxel ± CA4P ◼ Primary end point: OS Results ◼ 75/80 randomly assigned patients received treatment ◼ Median follow up of 4.7 (0.1-32.6) mo ◼ Median survival time for the CA4P arm was 5.2 mo vs. 4.0 mo control (HR=0.65; 95% CI: 0.38-1.10) ◼ 1-year survival was 27% on the CA4P arm vs 9% (P=0.065) Adverse Events ◼ Grade 1/2 hypertension and grade 3-4 neutropenia were more common on the CA4P arm
  51. 51. ATC Trials ▶ Clinical Trials: MLN0128 ▶ Everolimus: Among 7 patients, 1 had near complete response, 1 case with PFS of 26 mo ▶ Lenvatinib: 3/9 responses ▶ Immunotherapy? Clinicaltrials.gov, 2017b. Takahashi et al, 2014; Wagle et al, 2014.
  52. 52. Exceptional Response With Everolimus H & E = hematoxylin and eosin. Wagle et al, 2014. H & E at Diagnosis ▶ 57-year-old patient with ATC ▶ Response to everolimus x 18 mo Prior 6 months Progression
  53. 53. Response and Resistance ▶ Sequencing shows TSC2 mutation Q1178* in all samples ▶ Resistant sample with a new mutation in mTOR conveying resistance Wagle et al, 2014; Takei et al, 2014.
  54. 54. Case Study 1 A 35-year-old man presented with a right-sided neck mass to his primary care physician and was administered an antibiotic. The neck mass persisted, however, and a thyroid ultrasound showed a 3-cm nodule in the right lobe of the thyroid. FNA revealed malignant cells consistent with PTC. A complete thyroidectomy with central neck dissection was performed, which revealed a 3.3-cm well differentiated PTC with extracapsular extension and lymphovascular invasion. Three out of 25 lymph nodes tested positive for metastatic thyroid cancer. A chest x-ray was negative for metastatic disease. Which of the following treatment options would you now recommend? a. No further treatment b. RAI to ablate thyroid remnants and eliminate possible micrometastatic disease c. External beam radiotherapy d. Start sorafenib 400 mg PO twice daily e. Bilateral neck dissection levels II-IV followed by concurrent chemoradiotherapy
  55. 55. Case Study 1 A 35-year-old man presented with a right-sided neck mass to his primary care physician and was administered an antibiotic. The neck mass persisted, however, and a thyroid ultrasound showed a 3-cm nodule in the right lobe of the thyroid. FNA revealed malignant cells consistent with PTC. A complete thyroidectomy with central neck dissection was performed, which revealed a 3.3-cm well differentiated PTC with extracapsular extension and lymphovascular invasion. Three out of 25 lymph nodes tested positive for metastatic thyroid cancer. A chest x-ray was negative for metastatic disease. Which of the following treatment options would you now recommend? a. No further treatment b. RAI to ablate thyroid remnants and eliminate possible micrometastatic disease c. External beam radiotherapy d. Start sorafenib 400 mg PO twice daily e. Bilateral neck dissection levels II-IV followed by concurrent chemoradiotherapy
  56. 56. Case Study 1: Correct Answer Rationale ▶ Patient has locally advanced PTC. Because of the size of the lesion and presence of involved lymph nodes, treatment with RAI is indicated. Prognosis is excellent based on favorable histology and young age (<45 years) ▶ External beam radiotherapy delivers less radiation to cancer cells than RAI and carries more acute and chronic side effects. Furthermore, it does not address potential micrometastatic distant disease ▶ Sorafenib is an option in RAI-refractory disease, which is an unlikely scenario in this case ▶ Further surgery is not indicated in the absence of clinically suspicious areas of disease
  57. 57. Case Study 2 A 52-year-old woman noticed a lump on the left side of her thyroid area and presented to her primary care physician. She was referred for a ultrasound and FNA, which revealed a 4.2-cm MTC in the left lobe of the thyroid. Her calcitonin was 2,342 pg/mL. A CT scan showed 2 left level III enlarged lymph nodes but no distant metastatic disease. She underwent a complete thyroidectomy, central neck dissection, and left neck dissection. There was no extracapsular extension but 4/34 lymph nodes were positive for metastatic carcinoma. Follow-up CT scans 6 months after surgery showed new lung nodules bilaterally, up to 2.4 cm in diameter and several enlarged mediastinal lymph nodes. Calcitonin, which dropped to 135 pg/L following surgery, rose to 547pg/L. She was asymptomatic. Which of the following treatment options would you now recommend? a. No further treatment b. Radioactive iodine c. Start vandetanib 300 mg daily d. Start doxorubicin e. Surgical removal of lung metastases
  58. 58. Case Study 2 A 52-year-old woman noticed a lump on the left side of her thyroid area and presented to her primary care physician. She was referred for a ultrasound and FNA, which revealed a 4.2-cm MTC in the left lobe of the thyroid. Her calcitonin was 2,342 pg/mL. A CT scan showed 2 left level III enlarged lymph nodes but no distant metastatic disease. She underwent a complete thyroidectomy, central neck dissection, and left neck dissection. There was no extracapsular extension but 4/34 lymph nodes were positive for metastatic carcinoma. Follow-up CT scans 6 months after surgery showed new lung nodules bilaterally, up to 2.4 cm in diameter and several enlarged mediastinal lymph nodes. Calcitonin, which dropped to 135 pg/L following surgery, rose to 547pg/L. She was asymptomatic. Which of the following treatment options would you now recommend? a. No further treatment b. Radioactive iodine c. Start vandetanib 300 mg daily d. Start doxorubicin e. Surgical removal of lung metastases
  59. 59. Case Study 2: Correct Answer Rationale ▶ Patient has widely metastatic MTC with evidence of rapid disease progression ▶ While metastatic MTC can follow an indolent course and watchful waiting is often appropriate, therapy should be initiated in this case ▶ Vandetanib is approved for MTC ▶ MTC is derived from parafollicular C-cells and is not RAI avid ▶ Doxorubicin has some activity and is no longer considered appropriate first-line therapy ▶ Surgical removal of metastatic disease is a consideration for symptom control or debulking of mass that is encroaching on vital structures
  60. 60. Case Study 3 A 56-year-old woman noticed a rapidly enlarging lump at the base of her neck approximately 2 weeks ago. She presented with hoarseness and 10-lb weight loss. Laryngoscopy revealed a paralyzed right vocal cord. A CT scan of the neck showed a 7-cm neck mass originating from the thyroid causing displacement and compression of the trachea. A CT scan of the chest revealed numerous pulmonary nodules. Needle biopsy of the neck mass was consistent with anaplastic thyroid cancer. Which of the following treatment options would you now recommend? a. Surgical debulking followed by chemoradiotherapy b. Radioactive iodine c. Start sorafenib 400 mg twice daily d. No therapy e. Radiofrequency ablation of thyroid tumor and lung metastases
  61. 61. Case Study 3 A 56-year-old woman noticed a rapidly enlarging lump at the base of her neck approximately 2 weeks ago. She presented with hoarseness and 10-lb weight loss. Laryngoscopy revealed a paralyzed right vocal cord. A CT scan of the neck showed a 7-cm neck mass originating from the thyroid causing displacement and compression of the trachea. A CT scan of the chest revealed numerous pulmonary nodules. Needle biopsy of the neck mass was consistent with anaplastic thyroid cancer. Which of the following treatment options would you now recommend? a. Surgical debulking followed by chemoradiotherapy b. Radioactive iodine c. Start sorafenib 400 mg twice daily d. No therapy e. Radiofrequency ablation of thyroid tumor and lung metastases
  62. 62. Case Study 3: Correct Answer Rationale ▶ ATC is very aggressive with early distant metastasis and poor prognosis. Fortunately, it is also quite rare ▶ Surgical debulking to prevent airway compromise is standard of care, irrespective of the presence of metastatic disease. To reduce or—if possible—eradicate regional disease and prevent or delay recurrence, radiotherapy or concurrent chemoradiotherapy is used ▶ Sorafenib appears to have minimal activity in this disease and may be tried in an attempt to control systemic disease but should not be used as initial treatment ▶ ATC is not RAI avid, thus patients are not candidates for RAI treatment ▶ Radiofrequency ablation of primary or metastatic lesions is considered experimental and should not be used if more established frontline therapy is possible
  63. 63. Key Takeaways ▶ Targeted therapy has transformed the treatment of metastatic thyroid cancer ▶ Sorafenib and lenvatinib approved for RAI-refractory DTC ▶ Vandetanib and cabozantinib approved for MTC ▶ Thyroid cancer is an active area of investigation and treatment options should multiply in coming years
  64. 64. Audience Q&As
  65. 65. References Agrawal N, Akbani R, Askoy BA, et al (2014). Integrated genomic characterization of papillary thyroid carcinoma. Cell, 159(3);676-690. DOI:10.1016/j.cell.2015.09.050 Alexander EK, Kennedy GV, Baloch ZW, et al (2012). Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. New Engl J Med, 367:705-715. DOI:10.1056/NEJMoa1203208 Avram AM, Esfandiari NH & Wong KK (2015). Preablation 131-I scands with SPECT/CT contribute to thyroid cancer risk stratification and 131-I therapy planning. J Clin Endocrinol Metab, 100(5):1895-1902. DOI:10.1210/jc.2014-4043 Brose MS, Cabanillas ME, Cohen EE, et al (2016). Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol, (9):1272-1282. DOI:10.1016/S1470-2045(16)30166-8 Brose MS, Nutting CM, Jarzab B, et al (2014). Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet, 384(9940):319-328. DOI:10.1016/S0140-6736(14)60421-9 Cantwell-Dorris ER, O’Leary JJ & Sheils OM (2011). BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther, 10(3):385-394. DOI:10.1158/1535-7163.MCT-10-0799 Clinicaltrials.gov (2016). Ponatinib for medullary thyroid cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT01838642. NLM Identifier: NCT01838642. Clinicaltrials.gov (2017a). A study using regorafenib as second or third line therapy in metastatic medullary thyroid cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02657551. NLM Identifier: NCT02657551. Clinicaltrials.gov (2017b). A phase II study of MLN0128 in metastatic anaplastic thyroid cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02244463. NLM Identifier: NCT02244463. Cohen SJ, Punt CJ, Iannotti N, et al (2008). Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol, 26(19):3213-3221. DOI:10.1200/JCO.2007.15.8923 Cohen EE, Rosen LS, Vokes EE, et al (2008). Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008;26:4708-4713. Cooper DS, Doherty GM, Haugen BR, et al (2006). Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 16(2):109-142. De Crevoisier R, Baudin E, Bachelot A, et al (2004). Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys, 60(4):1137-1143. Edge S, Byrd DR, Compton CC, et al (2010). AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer.
  66. 66. References Elisei R, Schlumberger MJ, Müller SP, et al (2013). Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol, 31(29):3639-3646. DOI:10.1200/JCO.2012.48.4659 Haugen BR, Alexander EK, Bible KC, et al (2016). 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26(1):1-133. DOI:10.1089/thy.2015.0020 Ho AL, Grewal RK, Leboeuf R, et al (2013). Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 368(7):623- 632. DOI:10.1056/NEJMoa1209288 Hundahl SA, Fleming ID, Fremgen AM, et al (1998). A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer, 83(12):2638-48 Kebebew E, Greenspan FS, Clark OH, et al (2005). Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer, 103(7):1330-1335. DOI: 10.1002/cncr.20936 Kunstman JW, Juhlin CC, Goh G, et al (2015). Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet, 24(8):2318-2329. DOI:10.1093/hmg/ddu749 Lim H, Devesa SS, Sosa JA, et al (2017). Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA, 317(13):1338-1348. DOI:10.1001/jama.2017.2719 Lloyd RV, Beuhler D & Khanafshar E (2011). Papillary thyroid carcinoma variants. Head Neck Pathol, 5(1):51-56. DOI:10.1007/s12105-010- 0236-9 Lorch JN, Busaidy N, Ruan DT, et al (2013). A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC). J Clin Oncol, 31(15_suppl):6023. DOI:10.1200/jco.2013.31.15_suppl.6023 Lorch JH, Chau N, Hanna G, et al (2016). A multi-center phase II study of everolimus in patients with aggressive thyroid cancer and genetic analysis. 86th Annual Meeting of the American Thyroid Association. Poster 33. Mehnert JM, Varga A. Brose M, et al (2016). Pembrolizumab for advanced papillary or follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 study. J Clin Oncol, 34(15_suppl):6091. DOI:10.1200/JCO.2016.34.15_suppl.6091 Nagaiah G, Fu P, Wasman JK, et al (2009). Phase II trial of sorafenib (bay 43-9006) in patients with advanced anaplastic carcinoma of the thyroid (ATC). J Clin Oncol, 27(suppl_15):A6058. DOI:10.1200/jco.2009.27.15s.6058 Nascimento C, Borget I, Al Ghuzian A, et al (2015). Postoperative fluourine-18-fluorodeoxyglucose positron emission tomography/computed tomography: an important imaging modality in patients with aggressive histology of differentiated thyroid cancer. Thyroid, 25(4):437- 444. DOI:10.1089/thy.2014.0320
  67. 67. References Omry-Orbach G (2016). Risk stratification in differentiated thyroid cancer: an ongoing process. Rambam Maimonides Med, 7(1):e0003. DOI:10.5041/RMMJ.10230 Ricarte-Filho JC, Ryder M, Chitale DA, et al (2009). Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res, 69(11):4885-4893. DOI:10.1158/0008- 5472.CAN-09-0727 Schlumberger M, Tahara M, Wirth LJ, et al (2015). Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med, 372(7):621-630. DOI:10.1056/NEJMoa1406470 Schöffski P, Elisei R, Müller S, et al (2012). An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol, 30(15_suppl):5508. DOI:10.1200/jco.2012.30.15_suppl.5508 Sherman SI, Clary DO, Elisei R, et al (2016). Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Cancer, 122(24):3856-3864. DOI:10.1002/cncr.30252 Sosa JA, Elisei R, Jarzab B, et al (2011). A randomized phase II/III trial of a tumor vascular disrupting agent fosbretabulin tromethamine (CA4P) with carboplatin (C) and paclitaxel (P) in anaplastic thyroid cancer (ATC): final survival analysis for the FACT trial. J Clin Oncol, 29(suppl). Abstract 5502. Sosa JA, Elisei R, Jarzab B, et al (2014). Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma. Thyroid, 24(2):232-240. DOI:10.1089/thy.2013.0078. Stjlepovic N & Capdevila J (2014). Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib. Biologics, 8:129-139. DOI:10.2147/BBT.S39381 Takahashi S, Tahara M, Kiyota N, et al (2014). Phase II study of lenvatinib (len), a multi-targeted tyrosine kinase inhibitor, in patients (pts) with all histologic subtypes of advanced thyroid cancer (differentiated, medullary and anaplastic). Ann Oncol, 25(suppl 4):iv340-iv356. DOI:10.1093/annonc.mdu240.10 Takei N, Furukawa K, Hanyu O, et al (2014). A possible link between BDNF and mTOR in control of food intake. Front Psychol, 5:1093. DOI:10.3389/fpsyg.2014.01093 Wagle N, Grabiner BC, Van Allen EM, et al (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med, 371(15):1426-1433. DOI:10.1056/NEJMoa1403352 Wells SA Jr, Robinson BG, Gagel RF, et al (2012). Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol, 30(2):134-141. DOI:10.1200/JCO.2011.35.5040
  68. 68. References Xing M, Alzahrani AS, Carson KA, et al (2013). Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA, 309(14):1493-1501. DOI:10.1001/jama.2013.3190 Yassa L, Cibas ES, Benson CB, et al (2007). Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer, 111(6):508-516. DOI: 10.1002/cnr.23116 Yeh MW, Bauer AJ, Bernet VA, et al (2015). American Thyroid Association statement on preoperative imaging for thyroid cancer surgery. Thyroid, 25(1):3-14. DOI:10.1089/thy.2014.0096 Zbuk KM & Eng C (2007). Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer, 7(1):35-45. DOI: 10.1038/nrc2037

×