TARGETED THERAPY IN THYROID CANCER

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Science-Technology

Published on February 23, 2014

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TARGETED THERAPY IN THYROID CANCER: TARGETED THERAPY IN THYROID CANCER DR. R. RAJKUMAR M.D., D.M. MEDICAL ONCOLOGIST GURU HOSPITAL THYROID CANCER CLINICAL PATHOLOGY: THYROID CANCER CLINICAL PATHOLOGY American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7 th edition. Lippincott Williams and Wilkins. 2005. Parafollicular cells Follicular cells Differentiated Anaplastic Medullary Papillary Follicular Hurtle Cell Sporadic Familial PowerPoint Presentation: US EU Japan Estimated Thyroid Cancer Incidence in 2008 0 5000 10000 15000 20000 25000 30000 35000 40000 Annual Incidence LA/C ~37,000 ~33,000 ~18,000 ~6,000 GLOBAL INCIDENCE OF THYROID CANCR LA/C = Latin America and Caribbean. 1. GLOBOCAN 2008, International Agency for Research on Cancer. http://globocan.iarc.fr/. 2. Sherman. Lancet. 2003;361:501-511. 3. Eustatia-Rutten et al. J Clin Endocrinol Metab. 2006;91:313-319. Thyroid cancer is the most common form of endocrine malignancy 1 DTC represents > 90% of all thyroid carcinomas 2 The prognosis of patients with DTC is generally good due to tumor biology and efficacy of the initial surgery and 131 I therapy 3 DIMENSIONS OF THE PROBLEM:  DIMENSIONS OF THE PROBLEM Increasing in incidence 95% sporadic or RT-induced, 5% familial 3.5 to 4:1 female to male gender distribution > 95% of carcinomas arise from thyroid follicular cells and are well-differentiated Surgery +/- I-131 remains the standard of care Vast majority treated in this manner are cured Emergence of Multiple TKIs in Iodine-Refractory TC and MTC that can affect response and likely prolong PFS and OS THYROID CANCER IN THE UNITED STATES: THYROID CANCER IN THE UNITED STATES New Diagnosis Cancer Deaths Pfister, D. Treatment of Radioactive Thyroid Cancer. Presentation. ASCO, 2007. THYROID CANCER IN THE UNITED STATES: >5.0cm 2.1-5.0cm THYROID CANCER IN THE UNITED STATES 0-1.0cm 1.1-2.0cm Davies, JAMA 2006 295:2164 PowerPoint Presentation: 0 10 8 4 6 2 12 14 0% 20% 40% 60% 80% 100% Survival Stage I Stage II Stage III Stage IV DTC: INITIAL DISEASE STAGE PREDICTS OVERALL SURVIVAL Years 75% of all tumors 25% of all tumors p<0.001 Jonklaas J et al. Thyroid. 2006, 16(12): 1229-1242. PowerPoint Presentation: Pr i n c i p l e s of Hi g h Risk Pa ti e n ts Tr e atme n t • • T o t a l T h y r o i dec t o my Ra d i o iod i n e – – – Gross E x trath y roidal > 4 c m primary Distant metastases E x tension • Ne c k Dis s ec t io n – Clinical or U S -det e cted dise a se – Locoregional recurrence TS H S upp r e s s ion – <0.1 for those at high risk or w ith disease • kno w n resid u al A T A Gu i d e l in e s. C o o p e r et a l . T hy r o i d 2 0 0 9 . 1 9( 1 1 ) . N C CN Gu i de l i n e s. T h y ro i d Ca r c i no m a v 2 . 2013 . THYROID CANCER TREATMENT STRATEGY: 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 TSH SUPPRESSION IMPROVES SURVIVAL FOR DTC PATIENTS WITH METASTASES: TSH SUPPRESSION IMPROVES SURVIVAL FOR DTC PATIENTS WITH METASTASES 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 Survival, % Years All > 45 yr TSH suppressed 15 yr 10 yr TSH unsuppressed 11 yr 6 yr p < 0.01 p < 0.005 Median n = 450 Jonklaas et al. Thyroid. 2006;16:1299-1242. SURVIVAL AND RESPONSE TO TREATMENT: Survival (%) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years after the discovery of metastases 0 5 10 15 20 25 30 35 40 1 2 3 127 patients 4 cancer related deaths 168 patients 149 patients SURVIVAL AND RESPONSE TO TREATMENT Group 1 : initial 131 I uptake and CR Age < 40 years Well-differentiated cancer Small size of metastases Group 2 : initial 131 I uptake and persistent disease Group 3 : no initial 131 I uptake Durante et al. J Clin Endocrinol Metab. 2006;91:2892-2899. PowerPoint Presentation: Rad i o i o d i n e R e fr ac to r y Pro g n os is O ut c om e 1 – M edian Sur v i v al 3 -6 y ears – 1 0- y ear s ur v i v al less t han 15% Progno s t i c Factor s 2 ,3 – – – Age B R AF M uta t ion PET posi t i v i t y D u r a n te et a l. J C li n E n d oc r i n o l M e t ab 2 0 0 6 ; 9 1 (8 ) :2 8 9 2 – 2 8 9 9. E li s e i e t. a l , J C li n E ndo c r i no l M e t a b 2008 ; 93(1 0 ) : 3 9 4 3 - 9 Ro bb i n s an d W e i l . B e st P ra ct Res C li n E ndo c r i no l M e t ab . 2008 ; 22( 6 ) : 10 4 7- 59 PowerPoint Presentation: Rad i o i o d i n e R e fr ac to r y C r i te r ia A. O ne or mo r e (measurable) l e si ons that do 131 I not de m on s trate radio i od i ne sc an upta k e on d i agno s t i c B. O ne or mo r e l e si ons that has prog r e ss ed 131 I with i n 12 m onths of therap y . 131 I C. Cumu l at iv e a c t ivi ty of of > 600 m Ci RAI-REFRACTORY DISEASE: RAI-REFRACTORY DISEASE 25–50% of metastatic thyroid cancers lose ability to take up iodine RAI refractory means that there are progressing lesions that do not take up RAI (Note: there may still be some that do) Loss of iodine uptake inversely correlates with survival 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. RAI-REFRACTORY THYROID CANCER: RAI-REFRACTORY THYROID CANCER L-T4 treatment: serum TSH < 0.1 mU/L Local treatments when needed: surgery, radiation, radiofrequency or cryoablation Imaging follow-up every 6 months Stable disease: follow-up Progression: > 20% (RECIST) in 6-15 months Inclusion in a trial Chemotherapy: low efficacy, significant toxicity (eg, doxorubicin: 5% PR, 47% SD, median PFS 7 months) Targeted therapy as first line (ATA, 2009) Cooper et al. Thyroid. 2009;9:1167-1214. NCCN AND ATA GUIDELINES FOR THE TREATMENT OF DIFFERENTIATED THYROID CANCER (DTC): NCCN AND ATA GUIDELINES FOR THE TREATMENT OF DIFFERENTIATED THYROID CANCER (DTC) Initial treatment Total thyroidectomy , except in patients with unifocal microcarcinoma (individualized to patient and extent of disease) 1,2 Postoperative treatment Radioactive iodine ( 131 I) (RAI) therapy 1,2 Follow-up treatment Levothyroxine to suppress TSH levels to < 0.1mU/L 1,2 Recurrent or metastatic disease treatment Local therapy (re-operation, external radiation) Systemic therapy RAI therapy patients with refractory advanced disease chemotherapy (limited efficacy and considerable toxicity) 1,2 participation in clinical trials with small molecule tyrosine kinase inhibitors is recommended 1,2 1. NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V.1.2010. 2. Cooper DS, et al. Thyroid .2009;9:1167-214. NCCN = National Comprehensive Cancer Network. ATA = American Thyroid Association . CYTOTOXIC AGENTS IN DTC: CYTOTOXIC AGENTS IN DTC ADRIAMYCIN IS THE MOST STUDIED AGENT. Others include- Bleomycin , platinums , etoposide , and Pemetrexed . <20% Response Rate. MSB 09/21/09 THYROID CANCER IS ASSOCIATED WITH ABERRANT CELL SIGNALING: 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% MAP Kinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007 RAS/BRAF MUTATIONS ARE MORE PREVALENT IN RAI REFRACTORY THYROID CANCER: RAS/BRAF MUTATIONS ARE MORE PREVALENT IN RAI REFRACTORY THYROID CANCER Ricarte-Filho JC , Cancer Research 2009 Jun 1;69(11):4885-93 CELL SIGNALLING IN DIFFERENTIATED THYROID CANCER: 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 WHO IS APPROPRIATE FOR KINASE INHIBITOR THERAPY?: WHO IS APPROPRIATE FOR KINASE INHIBITOR THERAPY ? Patients whose tumors no longer take up radioactive iodine or who have exceeded their lifetime dose Patients with disease measurable by exam or CT scan Patients with >1 lesion which is >1 cm in size and who are symptomatic Patients with progressive disease KINASE INHIBITORS:  KINASE INHIBITORS KI ATP KI P Y Y ATP Activated pathway Cancer Activated Pathway Cancer VEGFR inhibition Tumor angiogenesis Tumor growth RET, BRAF….. inhibition TARGETING CELL SIGNALLING IN THYROID CANCER: 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 SIGNALLING 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 UPCC 03305: SORAFENIB IN ADVANCED THYROID CANCER : UPCC 03305: SORAFENIB IN ADVANCED THYROID CANCER 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 e ndpoints RECIST PFS Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal Update UPCC O3305: May 2009: Update UPCC O3305: May 2009 Results : Response for all 50 evaluable patients PR 36% (18 patients) SD 46% (23 patients) clinical benefit 82% (41 patients) Exact binomial confidence interval excludes the null hypothesis (p<0.0001) PFS is 63 weeks for all patients, and 84 weeks in patients with DTC Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002) UPCC 03305: BEST RESPONSE IN 46 EVALUABLE PATIENTS: UPCC 03305: BEST RESPONSE IN 46 EVALUABLE PATIENTS Papillary Follicular/H ü rthle Cell Medullary Poorly Differentiated/Anaplastic 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –10 Change in sum of target lesion by RECIST compared to baseline (%) 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) CUTANEOUS ADVERSE EVENTS WITH SORAFENIB IN THYROID CARCINOMA PATIENTS: CUTANEOUS ADVERSE EVENTS WITH SORAFENIB IN THYROID CARCINOMA PATIENTS Cutaneous toxicity peaks in the second cycle Brief dose holidays and dose reductions are reasonable. Rash usually improves with continued sorafenib treatment Rash is more common in patients with extensive sun exposure in the past Skin creams may be used as well as NSAIDs for control of the pain from the rash MSB 09/21/09 PowerPoint Presentation: [ T I TL E ] PHASE III STUDY OF SORAFENIB IN LOCALLY ADVANCED OR METASTATIC PATIENTS WITH RADIOACTIVE IODINE REFRACTORY THYROID CANCER (DECISION) TRIAL – PRIMARY ENDPOINT POSITIVE: Eligibility criteria Locally advanced or metastatic DTC Progression within 14 months RAI refractory No prior targeted therapy, chemotherapy or thalidomide PHASE III STU D Y OF SORAF E NIB IN LO C ALLY ADVANCED OR METASTAT I C PATIENT S WITH RADIOACTIVE I ODINE REFRACTORY THYR O ID CA N CER ( DECISION ) TRIAL – PRIMARY ENDPOINT POSITIVE 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 Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory Biomarkers PHASE III DECISION Trial: PHASE III DECISION Trial Over 400 patients enrolled in the trial world wide January 3, 2013 press release revealed that the primary endpoint of Progression Free Survival significantly favored the Sorafenib arm PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: [ T I TL E ] PowerPoint Presentation: RA I - re f ra c to r y DTC 2 0 13 DECISION e s tab lis hes s orafenib as a s tandard therapy Mul t iple Questions Rai s ed  W ho t o t reat?  W i t h w hat agent?  C an w e identi f y alterna t i v e t arget s ? • W il l s e l e c t iv e B R A F V 6 0 0E i n hi b i tors be e f f e c t iv e ?  Sora f enib re s i st an c e ?  I s t his t he right s t rateg y ? THERAPEUTIC OPTIONS BEYOND FRONTLINE TKI THERAPY: THERAPEUTIC OPTIONS BEYOND FRONTLINE TKI THERAPY Single progressive lesions can be resected or irradiated and the frontline TKI continued Minimally progressive lesions can often be observed on the original TKI as this disease frequently progresses very slowly For patients progressing on a frontline TKI, an m-TOR inhibitor can be added to block the PI3K escape pathway For disease progressing in multiple areas one might switch to another available TKI or a clinical trial with an investigational agent ADVANCED THYROID CANCER’S NEW UNMET NEED: PROGRESSION ON SORAFENIB/VEGFR2 INHIBITOR: ADVANCED THYROID CANCER’S NEW UNMET NEED: PROGRESSION ON SORAFENIB/VEGFR2 INHIBITOR What to do with patients who progress but maintain good performance status Most patients respond to frontline TKI therapy but then progress in a new lesion or a subset of lesions TARGETS OF KINASE INHIBITORS: TARGETS OF KINASE INHIBITORS Compound Name VEGFR BRAF PDGFR KIT RET Other Sorafenib (Nexavar) + + + + + FLT-3 Sunitinib ( Sutent ) + + + FLT-3 Axitinib (AG-013736) + + + Motesanib (AMG-706) + + + + Pazopanib (GW786034) + + + Vandetanib ( Zactima ) + + EGFR Cabozotanib (XL184) + + C-MET Lenvatinib (E7080) + + + + FGFR TARGETED AGENTS PHASE II CLINICAL DATA: MSB 05/30/09 TARGETED AGENTS PHASE II CLINICAL DATA Drug Key Baseline Characteristics n PFS Months PR SD PD Sorafenib (Brose) DTC+ PDTC(90%), 47 20 38% 47% 2% Sunitinib (Cohen) DTC (74%); MTC (26%) 51 - 17% DTC 74% DTC 9% DTC Axitinib (Cohen) Papillary (50%); Medullary (18%); Follicular/Hurthle (25%/18%); Anaplastic (3%) 60 18.1 30% 48% 7% Motesanib (Sherman) Papillary (61%); Follicular/Hurthle (34%) 93 10 14% 67% 8% Pazopanib (Bible) PD and DTC (Progression <6months) 37 12 49% - - Lenvatinib (E7080, Sherman) DTC 100% 58 13.3 45% 46% 5% TARGETING CELL SIGNALLING IN THYROID CANCER: 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 SIGNALLING 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 UPCC 19309: EVEROLIMUS + SORAFENIB FOR DTC PATIENTS WHO PROGRESS ON SORAFENIB ALONE: 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 UPCC 18310: NO25530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor Vemurafenib in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine: Eligibility criteria: Locally advanced or metastatic DTC Progression within 14 months RAI refractory UPCC 18310: NO25530 : An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor Vemurafenib in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine Vemurafenib 960mg BID Primary Endpoint: Best Overall response Rate (BORR) (RECIST 1.1) (Partial and complete RR) in sorafenib naïve pts Independent review Secondary Endpoints: PFS, TTP, OS, TTP, in sorafenib naïve pts BORR, CB, TTP, PFS and OS, in soraefnib exposed patients Informed Consent BRAF V600E testing + First Line Sorafenib Naïve (n=25) Second Line Prior Sorafenib ( n=25) + PowerPoint Presentation: E7080 ( len v a t ini b ) pha s e I I re s ul t s S her m a n e t a l . AS CO 20 1 1 , ab str 5503 O v e rall ( n = 58 ) C R 0 PR 2 6 ( 45% ) SD 2 7 ( 46% ) PD 3 ( 5 % ) DC R 5 3 ( 91% ) PowerPoint Presentation: Over c oming s o r afenib r es i s tan c e T arge t ing al t erna t i v e pa t h w a y s J C li n O n c o l 31 , 201 3 ( s upp l ; ab str 6024) CLINICAL TRIALS ONGOING FOR METASTATIC DIFFERENTIATED THYROID CANCER: MSB 10/16/10 CLINICAL TRIALS ONGOING FOR METASTATIC DIFFERENTIATED THYROID CANCER Compound Name DTC/MTC Status Sorafenib ( Nexavar ) DTC First Line – International Phase III – Positive Study Lenvatinib (E7080) DTC First and Second Line – Phase III Vemurafenib (BRAF V600E inhibitor) DTC (PTC) First and Second Line Phase II – (Phase III?) Everolimus+Sorafenib DTC Second Line – Phase II Cabozantinib DTC First Line – Phase I complete First Line and Second Line Phase II– Pending Pioglitazone (PPAR γ ) DTC (FTC*) First and Second Line - Phase II Pazopanib (GW786034) DTC First and Second line – Phase II Done Sunitinib ( Sutent ) DTC First line Phase II – Done. PowerPoint Presentation: Are there better s trategi es ? R e st ora t ion of R adioiodine S en s i t i v i t y Ho e t a l . N E ng l J M e d 2013 ; 368 : 6 2 3 - 32. TAKE HOME MESSAGES-I: TAKE HOME MESSAGES-I Multiple VEGFR agents in DTC have activity that affect the vast majority of patients with advanced RAI-refractory thyroid cancer needing therapy Results of phase III trial with sorafenib (DECISION) showing that patients treated with sorafenib have a longer progression free survival than those on placebo. We look forward to a future major oncology meeting for these results. Results from the Phase III trial of lenvatinib (SELECT ) are likely to follow in another year. Molecular markers ( eg . BRAF V600E mutation) are newer targets being tested in Phase II clinical trials. If positive, patients will need routine molecular testing for these mutations Many studies for second line treatment of DTC are underway and now a primary focus of our research program at the Abramson Cancer Center and at other sites. These trials target new molecular mechanisms and hope to add to the success of the VEGFR inhibitors in this disease. Take Home Messages-II: Take Home Messages-II Patients with progressive RAI-refractory TC should be referred to an oncologist with access to all the available and investigational kinase inhibitors. Treatment with a kinase inhibitor should be initiated in patients with progressive, measurable disease. The physician managing these patients should be comfortable with and skilled in managing the adverse events related to kinase inhibitors. Many clinical trials are now available for patients progressing on frontline kinase inhibitor therapy. PowerPoint Presentation: Ta k e Home Mes s age W ho To Tr ea t? W ho Not To Tr e a t? • Ra d ioi od ine Re f rac to ry • No ra d io g ra p h ic d ise a se ( TG on ly ) RAI Sen siti v e No p r o g r e ss i o n Ve ry sl o w p ro g ression w ith o u t t h r ea t e ne d s y m p t o m s – – Neg a t iv e R A I S c an P r o g r e s s i on De s p i te Re c e n t R A I > 6 0 0 m Ci pri o r R A I • • • – • • No n - s u r g ical c and id a t e s E st a b l i s he d P ro g ression – T hre a t e n e d S y m p t o m s REFERENCES: REFERENCES Giuffrida D, Prestifilippo A, et al; Journal of Oncology Volume 2012, Article ID-391629, “New Treatment in Advanced Thyroid Cancer” Brose M, Nutting C, et al; BMC Cancer 2011, 11:349 “Rationale and design of DECISION: a double blind, randomized, placebo controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic, RAI-refractory, differentiated thyroid cancer” Harris P, Bible K; Expert Opinion Investigational Drugs; October 2011 20(10): 1357-1375; “Emerging Therapeutics for Advanced Thyroid Malignancies: Rationale and Targeted Approaches” Gupta-Abramson V, Troxel A, et al; JCO 2008 Vol. 26: 4714 “Phase II Trial of Sorafenib in Advanced Thyroid Cancer” Kojic K, Kojic S & Wiseman S; Expert Reviews in Anticancer Therapy 2012 Vol.12(3):345; “Differentiated thyroid cancers: a comprehensive review of novel targeted therapies

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