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Recognition, Diagnosis, and Management of Neuroendocrine Tumors James C. Yao, MD Associate Professor and Deputy Chair, Gastrointestinal Medical Oncology.

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Presentation on theme: "Recognition, Diagnosis, and Management of Neuroendocrine Tumors James C. Yao, MD Associate Professor and Deputy Chair, Gastrointestinal Medical Oncology."— Presentation transcript:

1 Recognition, Diagnosis, and Management of Neuroendocrine Tumors James C. Yao, MD Associate Professor and Deputy Chair, Gastrointestinal Medical Oncology University of Texas M. D. Anderson Cancer Center

2 Learning Objectives After completing this activity, participants should be able to: –Outline patient signs and symptoms that should lead to an evaluation for NETs –Describe the diagnostic work-up that can confirm a suspected diagnosis of NET –Review current treatment approaches for NETs and expected patient outcomes –Analyze recent clinical trial data demonstrating improved outcomes beyond symptom control in patients with advanced NETs NET = neuroendocrine tumor

3 Epidemiology Signs and symptoms of NETs NETs: A Not-So-Rare Disease

4 197319741975197619771978197919801981 19821983198419851986198719881989199019911992199319941995199619971998 199920002001200220032004 0.00 1.00 2.00 3.00 4.00 5.00 6.00 0 100 200 300 400 500 600 Incidence per 100,000 - NETs Incidence per 100,000 – All malignant neoplasms All malignant neoplasms Neuroendocrine tumors Yao JC et al. J Clin Oncol. 2008;26:3063-3072. Incidence of NETs Increasing

5 ColonNeuroendocrineStomachPancreasEsophagusHepatobiliary 0 100 1100 1200 103,312 cases (35/100,000) Cases (thousands) 29-year limited duration prevalence analysis based on SEER. Yao JC et al. J Clin Oncol. 2008;26:3063-3072. SEER = Surveillance, Epidemiology, and End Results NETs Are Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the US, 2004 Median survival (1988 – 2004) Localized 203 months Regional 114 months Distant 39 months

6 Autopsy Studies Carcinoid 1,2 –2 studies > 15,000 cases each –0.7% to 1.2% Islet cell 3 –> 11,000 cases from Hong Kong –0.1% 1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:322-330. 2. Moertel CG et al. Cancer. 1961;14:291-293. 3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.

7 Vague abdominal symptoms Primary tumor Flushing Metastases Diarrhea Death NETs Are Often Diagnosed Late Time Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

8 Missed Symptoms and Late Diagnosis Flushing –No sweating –First sip of alcohol Diarrhea –Especially nocturnal Wheezing Irritable bowel syndrome Bloating Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

9 Pathologic confirmation Assess disease burden Assess functional status Diagnosis and Initial Work-Up

10 Anatomic Imaging: CT Std VenousDelayed Arterial Imaging studies property of James Yao, MD. CT: computed tomography.

11 Anatomic Imaging: MRI MRI = magnetic resonance imaging Imaging studies property of James Yao, MD.

12 Anatomic CT and Indium-111 Pentetreotide Scintigraphy Imaging studies property of James Yao, MD.

13 Tumor Markers General NET markers – Chromogranin A Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function – Neuron-specific enolase Midgut (small bowel, appendix, cecum) – 5 HIAA (24-hr urine collection) – Serotonin (blood, more variable) 5-HIAA = 5-hydroxyindoleacetic acid

14 Other Markers in Functional Tumors Gastrinoma Gastrin Glucagonoma Glucagon Insulinoma InsulinPro-insulinC-peptide VIPoma Vasoactive intestinal peptide Fasting measurements when possible

15 Principles of Marker Assessment Lots of markers; expression can change over time –Chromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, pancreatic polypeptide Take large panel of markers at key points –Diagnosis or relapse Follow a few elevated markers over time Not necessary to check every marker at each visit

16 Somatostatin analogs Chemotherapy for pancreatic NETs Regional therapy approaches Current Treatment Approaches

17 Limited Options for Advanced NETs Octreotide LAR + chemotherapy Chemotherapy Octreotide LAR No standard Functional Nonfunctional Midgut No syndrome Non-midgut No syndrome pNET Carcinoid Carcinoid syndrome Disease progression Hepatic artery embolization Investigational agents (No approved therapies available) LAR = long-acting release; pNET = pancreatic NET

18 pNET: Streptozocin-Based Chemotherapy Imaging studies property of James Yao, MD.

19 Median survival –Carcinoid43 months –pNET27 months Carcinoid –No approved drugs for tumor control pNET –Streptozocin approved but perceived to be toxic –No agreed-upon standard treatment for tumor control Survival Patients with distant NET (1988-2004) Limited Options Need for Tumor Control Agents Remains High Carcinoid Pancreatic NET Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

20 Somatostatin receptor Peptide receptor radiotherapy Angiogenesis mTOR Emerging Therapeutic Approaches mTOR = mammalian target of rapamycin

21 Targeting NETs Somatostatin receptors highly expressed by NETs –Targeting SST receptors can provide symptom and disease control New targets could change treatment paradigm : –mTOR, PI3K, VEGF inhibitors –Other antiangiogenic agents High potential for combinations PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

22 PROMID: Octreotide LAR Slows Progression in Midgut NETs Octreotide LAR vs placebo P =.000072 HR = 0.34 [95% CI: 0.20–0.59] Octreotide LAR (n = 42) Median 14.3 months Placebo: (n = 43) Median 6.0 months Time (months) Proportion without progression 0 0.25 0.5 0.75 1 06121824303642485460667278 Based on conservative ITT analysis HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP = time to progression Rinke A et al. J Clin Oncol. 2009;27:4656-4663. TTP in Midgut NET

23 No Standard Potential Management of Advanced NETs Post-PROMID Octreotide LAR + chemotherapy Chemotherapy Octreotide LAR Consider octreotide LAR No standard Functional Nonfunctional Midgut No syndrome Non-midgut No syndrome pNET Carcinoid Carcinoid syndrome Disease progression Investigational agents (No approved therapies available)

24 Systemic radiotherapy targeting somatostatin receptors Compounds vary by isotope and carrier molecule 177 Lu DOTATATE 1 and 90 Y DOTATOC 2 : promising results in phase 2 studies Peptide Receptor Radiotherapy (PRRT) 111 In pentetreotide DTPA-CO-NH-D-Phe-Cys S S Thr(ol)-Cys Phe D-Trp Lys Thr 111 In DOTA-CO-NH-D-Phe-Cys S S Thr(ol)-Cys Tyr D-Trp Lys Thr 90 Y DOTATOC 90 Y 177 Lu DOTATATE DOTA-CO-NH-D-Phe-Cys S S Thr-Cys Tyr D-Trp Lys Thr 177 Lu 177 Lu-DOTATATE: 177 Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid 0 (DOTA), Tyr 3 -octreotate; 90 Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.

25 90 Y-DOTATOC, 90 Y-Edotreotide Multiple studies –Various doses: 6 GBq/m 2, 7.4 GBq/m 2, 13.3 GBq/m 2 –Various schedules of 3-4 treatments RRs from smaller studies: 23% 1 & 24% 2 RR from larger study (N = 90): 4.4% 3 Waldherr C et al. J Nucl Med. 2002;43:610-616. Waldherr C et al. Ann Oncol. 2001;12:941-944. Bushnell DL et al. J Clin Oncol. 2010;28:1652-1659.

26 N = 504 27.8-29.6 GBq in 4 cycles Efficacy in 310 pts, NOT ITT RR: 30% Median TTP: 40 months 177 Lu DOTATATE Phase 2 Study ITT = intent-to-treat; RR = response rate; TTP = time to progression Imaging studies property of James Yao, MD. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

27 If ITT principle applied to response: –91 responses among 504 patients –RR drops to 18% High reported TTP calculated only for 249 who did not have PD as best treatment outcome PRRT clearly active; strong need for rigorous phase 3 study 177 Lu DOTATATE: What Does It Mean? PD = progressive disease Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

28 NET: Bevacizumab fCT Baseline Day 2 after bevacizumab Imaging studies property of James Yao, MD.

29 Bevacizumab: Randomized Phase 2 Trial Stable dose of octreotide x 2 months Random assignment Bevacizumab + PEG interferon α-2b (+ octreotide) Protocol starts here Bevacizumab (+ octreotide) PEG interferon α-2b (+ octreotide) 18 wks Bevacizumab (n = 22) PEG interferon (n = 22) PR (confirmed) 40 SD1716 PD16 ITT by assignment P =.019 (2-sided exact) Additional responses: 1 pt with PD on PEG interferon had PR after addition of bevacizumab 1 pt with SD on PEG interferon had PR after addition of bevacizumab PR = partial response; SD = stable disease Yao JC et al. J Clin Oncol. 2008;26:1316-1323.

30 Sunitinib: Phase 2 Open-Label Study Carcinoid, n (%) (n = 41) Islet cell, n (%) (n = 66) All pts, n (%) (N = 107) PR (confirmed)1 (2)11 (17)12 (11) SD34 (83)45 (68)78 (73) PD1 (2)5 (8)6 (6) Not evaluable5 (12)5 (8)10 (9) Kulke MH et al. J Clin Oncol. 2008;26:3403-3410.

31 Carcinoid: SWOG 0518 Phase 3 Study Poor prognosis (N = 283) Octreotide + interferon Octreotide + bevacizumab Supported by CTSU Endorsed by ECOG, CALGB, NCCTG R CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group

32 Sunitinib Phase 3 pNET Study Islet cell w/PD over prior 12 months (340 planned, 171 accrued) Sunitinib 37.5 mg continuous dosing Placebo Stopped early at unplanned time point March 12, 2009 Investigator-reported PFS: 11.4 mo with sunitinib vs 5.5 mo with placebo R PFS = progression-free survival Raymond E et al. ASCO GI 2010; Abstract 127.

33 mTOR Signaling Pathways SOS Grb MetabolismAngiogenesis Growth & Proliferation Nutrients & Metabolites 4EBP1 Rheb Receptor Tyrosine Kinase p70S6K PI3K IRS-1 RAS P P TSC1/2 AKT eIF4E Protein Synthesis Cyclin D, p27 Glut 1 VEGF, PDGF-β P P HIF-1α Everolimus mTORC1

34 Angiomyolipomas Subependymal giant-cell astrocytoma Islet cell carcinoma Imaging studies property of James Yao, MD.

35 MDACC: Everolimus + Octreotide LAR Response Per protocol Overall N = 60 Carcinoid n = 30 Islet cell n = 30 PR13 (22%)5 (17%)8 (27%) SD42 (70%)24 (80%)18 (60%) PD5 (8%)1 (3%)4 (13%) PFS (median) 60 wks63 wks50 wks ITT RR: 20% MDACC = M. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318.

36 RADIANT-1: Study Design Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy –Stratum 1: No octreotide LAR 60d before enrollment Received everolimus 10 mg/d –Stratum 2: Octreotide LAR ≥ 3mo before enrollment Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d) Treatment until progression; CT or MRI at baseline & q3mo Primary endpoint RR stratum 1 Secondary endpoints RR stratum 2 Response duration Safety PFS Survival PK Stratum 1 n = 115 SCREENSCREEN Stratum 2 n = 45 Everolimus + octreotide LAR Everolimus PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors Yao JC et al. J Clin Oncol. 2010;28:69-76.

37 RADIANT-1: Best Change from Baseline Central Radiology Review Stratum 1: Everolimus (n = 115) Stratum 2: Everolimus + Octreotide LAR (n = 45) Central radiologyITT, n (%) PR11 (9.6) SD78 (67.8) Clinical benefit (PR + SD) 89 (77.4) PD16 (13.9) Unknown10 (8.7) Central radiologyITT, n (%) PR2 (4.4) SD36 (80.0) Clinical benefit (PR + SD) 38 (84.4) PD0 (0.0) Unknown7 (15.6) Yao JC et al. J Clin Oncol. 2010;28:69-76.

38 RADIANT-1 PFS by Central Review EverolimusEverolimus + octreotide LAR 846 n = 115 Median PFS = 9.7 mo 0 20 40 60 80 100 Probability (%) 26021012141618202224 Time, mo 5481580115111362515125331 Patients at risk 24 0 Patients at risk 846 n = 45 Median PFS = 16.7 mo 0 20 40 60 80 100 Probability (%) 0210121416182022 Time, mo 21322245391914108331 Yao JC et al. J Clin Oncol. 2010;28:69-76.

39 Octreotide LAR + Everolimus Octreotide LAR + placebo Advanced carcinoid with syndrome in progression (N = 429) Pivotal Phase 3 Trials with Everolimus in NETs R Accrual completed Best supportive care + everolimus* Best supportive care + placebo* Advanced pNET in progression (N = 410) R Accrual completed *Octreotide LAR included as best supportive care.

40 Conclusions NETs not that rare Progress being made Somatostatin analogs effective in controlling hormonal syndrome PROMID suggests octreotide LAR controls tumor growth in midgut carcinoids Phase 2: VEGF and mTOR inhibitors have single-agent activity in NETs Confirmatory phase 3 studies ongoing


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