Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
•Als PPT, PDF herunterladen•
7 gefällt mir•2,962 views
En el marco del Simposio de Cáncer de Cabeza y Cuello y Pulmón de la Asociación Colombiana de Hematología Oncología, ACHO, Bogotá, 28.07.2016
Empfohlen
Weitere ähnliche Inhalte
Was ist angesagt?
Was ist angesagt? (20)
Andere mochten auch
Andere mochten auch (18)
Ähnlich wie Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Ähnlich wie Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma (20)
Mehr von Mauricio Lema
Mehr von Mauricio Lema (20)
Kürzlich hochgeladen
Kürzlich hochgeladen (20)
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
- 1. Treatment of radioactive iodine- refractory differentiated thyroid carcinoma Mauricio Lema Medina MD – Clínica de oncología Astorga, Clínica SOMA, Medellín ACHO, Bogotá, 29.07.2016
- 3. Mauricio Lema Medina Conflicts of interest Consulting and honoraria as a speaker: Pfizer, MSD, Novartis, ROCHE, Aztra-Zeneca, Boehringer-Ingelheim. Harrisons’s, 19th Ed.
- 4. >5.0cm 2.1-5.0cm Thyroid cancer in the United States 0-1.0cm 1.1-2.0cm Davies, JAMA 2006 295:2164
- 5. Medullary Anaplastic Papillary Follicular Differentiated Thyroid Cancer (DTC)
- 8. Thyroid Cancer: Treatment Strategy • High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm) – Total Thyroidectomy – RAI (131 I) Ablation – TSH Suppression Therapy with Thyroid Hormone – Follow Serial Thyroglobulin Levels (Tg) – XRT for recurrent local disease/positive margins – Surveillance: NeckUS, Tg, Neck MRI, Chest CT, RAI Whole body scan, FDG-PET
- 9. NCCN: Thyroid cancer – Papillary and Follicular Page 9 NCCN, 1.2016
- 10. RAI-Refractory Disease • 25-50% of Metastatic Thyroid Cancers loose ability to take up Iodine • This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism In other words, the cancer cells “forget” how to take up iodine and so they are immune to the treatment.
- 12. Fig. 1. Survival after the discovery of metastases according to the presence or absence of 131I uptake in the metastases. Published in: C. Durante; N. et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006
- 13. Fig. 2. Survival after the discovery of distant metastases according to the age at discovery and to the extent of disease. 131I uptake was not taken into account, but was closely linked to the two other prognostic factors, and was invariably present in young patients with small metastases (group 1) and rarely present in older patients with large metastases (group 2). Group 1, Patients younger than 40 yr of age with metastases that were not visible on radiographs or that were micronodular (<1 cm in diameter). Group 2, Patients older than 40 yr with macronodular lung metastases or multiple bone metastases. Group 3, Patients older than 40 yr with normal x-rays or micronodular metastases and patients younger than 40 yr with macronodular lung metastases. Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006 Less than 40 yo with small metastases Older than 40 yo with macronodular lung metastases or bone metastases RAI-Sensitive RAI-Refractory
- 14. Fig. 3. Survival after the discovery of distant metastases. Group 1, Patients with 131I uptake who attained negative imaging studies. Group 2, Patients with 131I uptake who did not attain negative imaging studies. Group 3, Patients with no 131I uptake. Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006 Attained negative imaging studies Did not attain negative imaging studies
- 16. Schlumberger M et al. N Engl J Med 2015;372:621-630. Iodine-Refractory mDTC: diagnostic criteria Evidence of radiologic progression within 13 months and at least one of the following criteria: At least one measurable lesion without iodine uptake on any iodine-131 scan, At least one measurable lesion that had progressed according to the Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1, criteria within 12 months after iodine-131 therapy despite iodine-131 avidity at the time of treatment, Or cumulative activity of iodine-131 that was >600 mCi
- 18. RAI-refractory disease • Standard Chemotherapy has minimal efficacy. 1974 Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer. •No longer used because recent data shows response is 5% •High toxicity in patient with otherwise good QOL Cooper DS, et al. Thyroid. 2009;9:1176-214. Hodak SP, Carty SE. Oncology. 2009;23:775-6. Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.
- 19. Overcoming iodine resistance in DTC Page 19
- 20. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer RET NTRK1 RAS BRAF 70% of PTC have one of these mutually exclusive mutations MAP Kinase pathway DECREASE of the Na-I Symporter Thyroid biosynthesis genes Thyroid peroxidaseHo AL et al. N Engl J Med 2013;368:623-632.
- 21. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer Inhibition of BRAF Restores Na-I Symporter Ho AL et al. N Engl J Med 2013;368:623-632.
- 22. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer
- 23. Ho AL et al. N Engl J Med 2013;368:623-632. Protocol Design and Changes in Iodine Uptake.
- 24. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer Ho AL et al. N Engl J Med 2013;368:623-632. Patients screened 24 Patients that could be evaluated 20 BRAF mutations 9 NRAS mutations 5 Increased Iodine-24 uptake 12 Increased Iodine-24 uptake enough for RAI therapy 8 Increased Iodine-24 uptake in BRAF mutated patients 4/9 Increased Ioding-24 uptake in NRAS mutated patients 5/5 Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.
- 25. Ho AL et al. N Engl J Med 2013;368:623-632. Response to Iodine-131 Therapy with Selumetinib Treatment.
- 26. Ho AL et al. N Engl J Med 2013;368:623-632. Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses.
- 27. Ho AL et al. N Engl J Med 2013;368:623-632. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine.
- 28. Targeted therapy in mDTC Page 28
- 29. Page 29
- 30. Thyroid Cancer is associated with aberrant cell signaling Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35% Total >70% >65% MAPKinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
- 31. Thyroid Cancer is associated with aberrant cell signaling Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35% Total >70% >65% MAPKinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
- 32. Cell signalling in differentiated thyroid cancer Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation
- 33. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib Targeting cell signaling in thyroid cancer RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation Everolimus Sirolimus Everolimus Sirolimus
- 34. Targets of Kinase Inhibitors Compound Name VEGFR BRAF PDGFR KIT RET Other Sorafenib + + + + + FLT-3 Sunitinib + + + FLT-3 Axitinib (AG-013736) + + + Motesanib (AMG-706) + + + + Pazopanib (GW786034) + + + Vandetanib + + EGFR Cabozantinib (XL184) + + C-MET Lenvatinib (E7080) + + + + FGFR
- 36. UPCC 03305: Sorafenib in Advanced Thyroid Cancer February 2006-February 2011 Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9 n=55 Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • Evidence of PD within 6 months of study entry • ECOG 0–2 • Good organ and bone marrow function Sorafenib 400mg b.i.d. Primary endpoints • RECIST • PFS • Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
- 37. UPCC 03305: Best Response in 46 Evaluable Patients Papillary Follicular/Hürthle Cell Medullary Poorly Differentiated/Anaplastic 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –10 ChangeinsumoftargetlesionbyRECIST comparedtobaseline(%) PD SD PR Best response of advanced thyroid cancer patients to sorafenib Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)
- 38. Eligibility criteria • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory • No prior targeted therapy, chemotherapy or thalidomide Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial • An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC www.clinicaltrials.gov. NCT00984282 Off study Disease progression Crossover or continue sorafenib 400mg orally b.i.d. Randomisation(1:1) (n=380) Progression Sorafenib 400mg orally b.i.d. Placebo Investigator’s decision n=190 n=190 Primary Endpoint: PFS (RECIST) Independent review Met primary endpoint January 2013 Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory Biomarkers
- 39. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
- 40. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
- 41. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
- 42. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
- 43. LENVATINIB Schlumberger M, et al. NEJM, 2015
- 44. Schlumberger M et al. N Engl J Med 2015;372:621-630.
- 45. Schlumberger M et al. N Engl J Med 2015;372:621-630. Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population.
- 46. Schlumberger M et al. N Engl J Med 2015;372:621-630.
- 47. Schlumberger M et al. N Engl J Med 2015;372:621-630.
- 48. Copyright © 2016 Elsevier Ltd Terms and Conditions BRAFm - RAI-Refractory PTC 51 No prior multikinase therapy (Cohort 1) 26 Prior multikinase therapy (Cohort 2) 25 Vemurafenib 960 mg PO twice a day Endpoint: investigator-assessed ORR Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial Brose MS, Lancet Oncol, 2016
- 49. The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) Copyright © 2016 Elsevier Ltd Terms and Conditions Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial
- 50. The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) Copyright © 2016 Elsevier Ltd Terms and Conditions No prior multikinase therapy Prior multikinase therapy
- 51. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial Copyright © 2016 Elsevier Ltd Terms and Conditions BRAFm - RAI-Refractory PTC 51 No prior multikinase therapy (Cohort 1) 25 Prior multikinase therapy (Cohort 2) 26 PR in Cohort 1 10/26 DCR in Cohort 1 9/26 Median DOR Cohort 1 16 months PR in Cohort 2 6/22 6-mo DCR in Cohort 2 6/22 Median DOR in Cohort 2 27 weeks “Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients”. Brose MS, Lancet Oncol, 2016
- 53. De Souza JA, ASCO, 2016, Abstract 6013
- 54. Proc ASCO, 2013, Abstract 6024 Overcoming Sorafenib Resistance
- 55. De Souza JA, ASCO, 2016, Abstract 6013
- 56. Ann Wild Gramza, ASCO, 2016
- 57. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib Targeting cell signaling in thyroid cancer RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation Everolimus Sirolimus Everolimus Sirolimus
- 58. UPCC 19309: Everolimus + Sorafenib for DTC patients who progress on Sorafenib alone n=35 Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • PD on sorafenib • ECOG 0–2 • Good organ and bone marrow function Sorafenib + Everolimus Intra-patient Dose escalation Primary endpoints • RECIST • PFS • Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal 22 patients accrued so far
- 59. Min Lim S, Oncotarget, 2016 Somatic mutations that confer exceptional response to everolimus (NGS)
- 60. Min Lim S, Oncotarget, 2016
- 61. Min Lim S, Oncotarget, 2016 Somatic mutations that confer exceptional response to everolimus (NGS)
- 62. NCCN: Thyroid cancer – Papillary and Follicular Page 62 NCCN, 1.2016
- 63. Conclusions RAI-Refractory mDTC Sorafenib Lenvatinib Selumetinib + RAI in NRAS mutated Vemurafenib in BRAF mutatedPreferred, unavailable Not ready for prime-time Needs more data
Hinweis der Redaktion
- 25%-50% will loose their ability to take up RAI Loss of Iodine uptake correlates inversly with survival Due to loss of expression of the NIS, and data shows that this is mostly due to increasing methylation of the NIS promotoer. …Once TSH, RAI is ineffective, and XRT has already been maxed, or pt has distant disease, what do we have to offer….?
- Figure 1. Protocol Design and Changes in Iodine Uptake. Panel A shows the protocol design. Baseline iodine avidity in the lesion was first assessed with thyrotropin alfa–stimulated iodine-124 positron-emission tomographic–computed tomographic (PET-CT) scanning. Patients were then treated with selumetinib at a dose of 75 mg given orally twice a day for 4 weeks. In the final week of treatment, a second thyrotropin alfa–stimulated 124I PET-CT study was performed. The double arrows indicate the two thyrotropin alfa injections. Patients with 124I dosimetry that predicted tumor uptake of less than 2000 cGy discontinued the study. If the absorbed dose of radioiodine in the lesion was predicted to be 2000 cGy or greater, full dosimetry with iodine-131 was performed to calculate the maximum tolerable activity that could be administered safely. Patients then received a therapeutic dose of radioiodine the next week after preparation with thyrotropin alfa. Selumetinib was continued until 2 days after the administration of therapeutic radioiodine. Thyroglobulin levels and the radiographic response were assessed at 2 and 6 months after radioiodine administration. Panel B shows a summary of the changes in iodine uptake quantified by 124I PET-CT and the number of patients who met the criteria for treatment with iodine-131.
- Figure 4. Response to Iodine-131 Therapy with Selumetinib Treatment. Panel A shows a waterfall plot of the maximum change in target lesions (relative to a prestudy scan) in the eight patients who received therapeutic radioiodine. The best overall response in each patient according to the Response Evaluation Criteria in Solid Tumors, version 1.1, is also shown. The dashed line indicates a 30% reduction in tumor dimensions. WT denotes wild-type. Panel B shows serum thyroglobulin values in the eight patients treated with radioiodine. NA denotes not available.
- Figure 2. Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses. Panel A shows whole-body maximum-intensity projection images of a patient with a BRAF-mutant papillary thyroid cancer. New iodine uptake is shown in nearly all previously negative lung and neck metastases. Panel B shows fused axial PET-CT images of a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Both new and significantly increased iodine uptake in lung metastases is shown. Panels C and D show PET-CT images from another patient with an NRAS-mutant, poorly differentiated thyroid cancer. In Panel C, fused axial PET-CT images show significantly increased iodine uptake in a sacroiliac bone metastasis after administration of selumetinib (right). In Panel D, fused axial images (top and bottom left) show new iodine uptake in a previously negative site as well as increased avidity in a large left parietal skull metastasis. Three-dimensional rendering highlights changes in the left parietal skull metastasis before and after selumetinib (top and bottom right).
- Figure 3. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine. Panel A shows the maximal standardized uptake value (SUVmax) for iodine in all tumors in a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Each bar represents one malignant lesion identified on the iodine-124 PET-CT scan. The bars to the left indicate the increases in iodine-124 avidity achieved after selumetinib administration in lesions that absorbed some iodine at baseline. The bars on the right indicate selumetinib-induced changes in lesions that were negative for iodine at baseline. Panel B shows the SUVmax in every metastatic lesion identified in the same patient before and after the administration of selumetinib. The dashed lines mark points on the graph corresponding to different degrees of change in the SUVmax in the lesion after the administration of selumetinib. The red dashed line demarcates no change in iodine uptake after the administration of selumetinib (0%). Dashed lines to the left of the red dashed line represent graded percentage increases in iodine-124 uptake (+25%, +50%, and +100%), whereas the lines to the right represent graded percentage decreases (−25%, −50%, and −75%). Nearly all the metastatic lesions in this patient (circles) had more than a 100% increase in iodine uptake after administration of selumetinib. The SUVmax for a sternal metastasis was off the scale (it increased from 220 to 599 with selumetinib) and thus could not be included in these graphs without obscuring the data for the other 54 lesions analyzed.
- So it makes sense that kinase inhibitors are active in this disease however…
- So it makes sense that kinase inhibitors are active in this disease however…
- Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.
- Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.
- When you look at the inhibitors that are active they are all angiogenesis inhibitors Most are VEGFR inhibitors and are angiogenesis inhibitors. This is important because Thyroid cancer which is a highly vascular agent. I will present more intriguing data about this later.
- Minute 05, Second 15
- Figure 2. Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population. Tumor responses were assessed with the use of Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and were confirmed by independent centralized radiologic review. Tumor responses were calculated as the maximum percentage change from baseline in the sum of the diameters of target lesions. CI denotes confidence interval, and NE not estimable.
- Waterfall plots showing mean change from baseline in tumour size in the per-protocol population Change in tumour size recorded as smallest sum of diameters. Objective response was either a complete or partial response. Dotted line represents the threshold for partial response. *Patients who are still on treatment as of data cutoff (April 18, 2014). (A) Patients who have never received a multikinase inhibitor (cohort 1). (B) Patients previously treated with a multikinase inhibitor (cohort 2). One patient in cohort 2 did not have a post-baseline tumour assessment because they died within the first two cycles of treatment.
- Kaplan-Meier curves of progression-free survival and overall survival Progression-free survival in (A) patients who have never received a multikinase inhibitor (cohort 1) and (B) patients previously treated with a multikinase inhibitor (cohort 2). Overall survival in (C) cohort 1 and (D) cohort 2.
- Intracellular signaling pathway aberrancy is critical to the molecular pathophysiology of thyroid cancer tumorigenesis. In tumor cells (left panel), altered expression and mutation involving B-Raf, Ras, and Akt have been implicated in a wide variety of thyroid cancer cell types. In the tumor microenvironment, angiogenesis is also a critical step in tumor progression and metastasis. Angiogenesis is mediated primarily through VEGFR-2, which also signals through Raf and Akt. Inhibition of VEGFR-2 has proven to be a successful therapeutic strategy in thyroid cancer in which drugs such as bevacizumab (BEV), sorafenib (SO), sunitinib (SU), axitinib (AXIT), and motesanib (MOT) have activity as single agents. VEGFR-2 has been found to be expressed on tumor cells in thyroid cancer, raising the question of whether multikinase inhibitor therapy might also be exerting an effect on the tumor cells themselves.