Presentation on theme: "Recognition, Diagnosis, and Management of Neuroendocrine Tumors"— Presentation transcript:
1 Recognition, Diagnosis, and Management of Neuroendocrine Tumors James C. Yao, MDAssociate Professor and Deputy Chair, Gastrointestinal Medical OncologyUniversity of Texas M. D. Anderson Cancer Center
2 Learning ObjectivesAfter completing this activity, participants should be able to:Outline patient signs and symptoms that should lead to an evaluation for NETsDescribe the diagnostic work-up that can confirm a suspected diagnosis of NETReview current treatment approaches for NETs and expected patient outcomesAnalyze recent clinical trial data demonstrating improved outcomes beyond symptom control in patients with advanced NETsBullet 2: ... confirm a suspected diagnosis of NET (delete s)?NET = neuroendocrine tumor
3 NETs: A Not-So-Rare Disease EpidemiologySigns and symptoms of NETs
4 Incidence of NETs Increasing 6.00600All malignant neoplasms5.005004.00400Incidence per 100,000 - NETs3.00Incidence per 100,000 – All malignant neoplasms3002.00200TO PURCHASE – USE AS IS1.00100Neuroendocrine tumors0.0019731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004Yao JC et al. J Clin Oncol. 2008;26:44
5 NETs Are Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the US, 20041200Median survival (1988 – 2004)Localized 203 monthsRegional 114 monthsDistant 39 months103,312 cases (35/100,000)1100Cases (thousands)100RE-CREATE AS ISNote: the break in the colon cancer bar is correct, as it indicates a change in the scale used in the Y axis (because colon cancer is more common than the others by an order of magnitudeColonNeuroendocrineStomachPancreasEsophagusHepatobiliary29-year limited duration prevalence analysis based on SEER.Yao JC et al. J Clin Oncol. 2008;26:SEER = Surveillance, Epidemiology, and End Results555
6 Autopsy Studies Carcinoid1,2 Islet cell3 2 studies 0.7% to 1.2% > 15,000 cases each0.7% to 1.2%Islet cell3> 11,000 cases from Hong Kong0.1%1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:2. Moertel CG et al. Cancer. 1961;14:3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.
7 NETs Are Often Diagnosed Late Vague abdominal symptomsDeathDiarrheaFlushingMetastasesRE-CREATE AS ISPrimary tumorTimeVinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.
8 Missed Symptoms and Late Diagnosis FlushingNo sweatingFirst sip of alcoholDiarrheaEspecially nocturnalWheezingIrritable bowel syndromeBloatingKeep as is50% + 24% + 27% = 101% OK? [copyeditor note]Yes—these numbers are rounded from the original publication; keep as is.[SD note]Yao JC et al. J Clin Oncol. 2008;26:
9 Diagnosis and Initial Work-Up Pathologic confirmationAssess disease burdenAssess functional status
10 Anatomic Imaging: CT Std Arterial Venous Delayed 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 AAffected by somatostatin analogues, proton pump inhibitors, kidney function, liver functionNeuron-specific enolaseMidgut (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 Fasting measurements when possibleGastrinomaGastrinGlucagonomaGlucagonInsulinomaInsulinPro-insulinC-peptideVIPomaVasoactive intestinal peptide
15 Principles of Marker Assessment Lots of markers; expression can change over timeChromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, pancreatic polypeptideTake large panel of markers at key pointsDiagnosis or relapseFollow a few elevated markers over timeNot necessary to check every marker at each visit
16 Current Treatment Approaches Somatostatin analogsChemotherapy for pancreatic NETsRegional therapy approaches
17 Limited Options for Advanced NETs FunctionalOctreotide LAR + chemotherapypNETHepatic artery embolizationInvestigationalagents(No approved therapiesavailable)NonfunctionalChemotherapyCarcinoid syndromeOctreotide LARDisease progressionMidgut No syndromeCarcinoidNo standardRE-CREATE as isNon-midgut No syndromeNo standardLAR = long-acting release; pNET = pancreatic NET
18 pNET: Streptozocin-Based Chemotherapy Imaging studies property of James Yao, MD.
19 Need for Tumor Control Agents Remains High Survival Patients with distant NET ( )Limited OptionsCarcinoidNo approved drugs for tumor controlpNETStreptozocin approved but perceived to be toxicNo agreed-upon standard treatment for tumor controlCarcinoidPancreatic NETIMAGE ON THE LEFT – USE AS IS, NO PURCHASEMedian survivalCarcinoid 43 monthspNET 27 monthsYao JC et al. J Clin Oncol. 2008;26:
21 Targeting NETs Somatostatin receptors highly expressed by NETs Targeting SST receptors can provide symptom and disease controlNew targets could change treatment paradigm :mTOR, PI3K, VEGF inhibitorsOther antiangiogenic agentsHigh potential for combinationsUse image as isPI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor
22 PROMID: Octreotide LAR Slows Progression in Midgut NETs TTP in Midgut NETOctreotide LAR vs placebo P =HR = 0.34 [95% CI: 0.20–0.59]Octreotide LAR (n = 42)Median 14.3 monthsPlacebo: (n = 43)Median 6.0 monthsTime (months)Proportion without progression0.250.50.7516121824303642485460667278TO PURCHASE – USE AS ISIs the capitalization of the expanded form of PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors standard? (i.e. Capping Placebo, Octreotide, Randomized, MIDgut). [copyeditor note]Yes—the capitalized letters are those that spell out the acronym (in addition to LAR, which is always capped.) [SD note]Based on conservative ITT analysisHR = 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 progressionRinke A et al. J Clin Oncol. 2009;27:
23 Potential Management of Advanced NETs Post-PROMID FunctionalOctreotide LAR + chemotherapypNETNonfunctionalChemotherapyInvestigationalagents(No approved therapiesavailable)Carcinoid syndromeOctreotide LARDisease progressionMidgut No syndromeConsider octreotide LARCarcinoidNo StandardNon-midgut No syndromeNo standard
24 Peptide Receptor Radiotherapy (PRRT) 111In pentetreotideDTPA-CO-NH-D-Phe-CysSThr(ol)-CysPheD-TrpLysThr111InDOTA-CO-NH-D-Phe-CysTyr90Y DOTATOC90Y177Lu DOTATATEThr-Cys177LuSystemic radiotherapy targeting somatostatin receptorsCompounds vary by isotope and carrier molecule177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studiesInsert semicolon after 2001 in reference 2.[done – SD]177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide.1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26: Waldherr C et al. Ann Oncol. 2001;12:
25 90Y-DOTATOC, 90Y-Edotreotide Multiple studiesVarious doses: 6 GBq/m2, 7.4 GBq/m2, GBq/m2Various schedules of 3-4 treatmentsRRs from smaller studies: 23%1 & 24%2RR from larger study (N = 90): 4.4%3Semicolons are missing after 2001 and 2010 in references, and there’s an extra space after 43: in the first reference.[done – SD]Waldherr C et al. J Nucl Med. 2002;43:Waldherr C et al. Ann Oncol. 2001;12:Bushnell DL et al. J Clin Oncol. 2010;28:
26 177Lu DOTATATE Phase 2 Study N = 504GBq in 4 cyclesEfficacy in 310 pts, NOT ITTRR: 30%Median TTP: 40 monthsDoes intent-to-treat need hyphens? [Yes – per SD]Add colon after TTP in the last bullet point? [done –SD]Missing graphics? [? Not sure what this means –SD]ITT = intent-to-treat; RR = response rate; TTP = time to progressionImaging studies property of James Yao, MD.Kwekkeboom DJ et al. J Clin Oncol. 2008;26:
27 177Lu DOTATATE: What Does It Mean? If ITT principle applied to response:91 responses among 504 patientsRR drops to 18%High reported TTP calculated only for 249 who did not have PD as best treatment outcomePRRT clearly active; strong need for rigorous phase 3 studyIf ITT principle is applied to response (add ‘is’) ?High reported TTP calculated only for the (add ‘the’)?[note from SD: these changes not implemented b/c language is unambiguous as shown – this standard style is used to keep slide text brief]PD = progressive diseaseKwekkeboom DJ et al. J Clin Oncol. 2008;26:
28 NET: Bevacizumab fCT Baseline Day 2 after bevacizumab Move ‘MD’ up to same line as ‘Yao’Imaging studies property of James Yao, MD.28
29 Bevacizumab: Randomized Phase 2 Trial Stable dose of octreotidex 2 monthsRandom assignmentBevacizumab + PEG interferon α-2b(+ octreotide)Protocolstarts hereBevacizumabPEG interferon α-2b18 wksITT by assignmentBevacizumab(n = 22)PEG interferonPR (confirmed)4SD1716PD16P = .019 (2-sided exact)Additional responses:1 pt with PD on PEG interferon had PR after addition of bevacizumab1 pt with SD on PEG interferon had PR after addition of bevacizumabdelete space after 2008;PR = partial response; SD = stable diseaseYao JC et al. J Clin Oncol. 2008;26:29
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)PD5 (8)6 (6)Not evaluable5 (12)10 (9)Kulke MH et al. J Clin Oncol. 2008;26:
31 Carcinoid: SWOG 0518 Phase 3 Study Octreotide + interferonPoor prognosis(N = 283)RSupported by CTSUEndorsed by ECOG, CALGB, NCCTGAdded study # to titleOctreotide + bevacizumabCALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group31
32 Sunitinib Phase 3 pNET Study Stopped early at unplanned time pointMarch 12, 2009Sunitinib 37.5 mgcontinuous dosingRIslet cell w/PD over prior 12 months (340 planned,171 accrued)PlaceboClarified PFS rates and added reference.I’ve changed the word timepoint in the uber document; if those edits are accepted then the word should also be changed here. [SD note: made this change]Investigator-reported PFS:11.4 mo with sunitinib vs 5.5 mo with placeboPFS = progression-free survivalRaymond E et al. ASCO GI 2010; Abstract 127.
33 mTOR Signaling Pathways Receptor Tyrosine KinaseNutrients &MetabolitesRASIRS-1GrbSOSProtein SynthesisCyclin D, p27Glut 1VEGF, PDGF-βPHIF-1αPPPI3KAKTTSC1/2RhebEverolimusmTORC1Use as isWhy ‘Receptor’ in bold?p70S6K4EBP1eIF4EMetabolismAngiogenesisGrowth &Proliferation
34 Subependymal giant-cell astrocytomaIslet cell carcinomaAngiomyolipomasImaging studies property of James Yao, MD.
35 MDACC: Everolimus + Octreotide LAR Response Per protocolOverall N = 60Carcinoid n = 30Islet cell n = 30PR13 (22%)5 (17%)8 (27%)SD42 (70%)24 (80%)18 (60%)PD5 (8%)1 (3%)4 (13%)PFS (median)60 wks63 wks50 wksITT RR: 20%MDACC = M. D. Anderson Cancer Center; RR = response rateYao JC et al. J Clin Oncol. 2008;26:35
36 RADIANT-1: Study Design Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapyStratum 1: No octreotide LAR 60d before enrollmentReceived everolimus 10 mg/dStratum 2: Octreotide LAR ≥ 3mo before enrollmentReceived everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d)Stratum 1 n = 115SCREENStratum 2 n = 45Everolimus +octreotide LAREverolimusPrimary endpointRR stratum 1Secondary endpointsRR stratum 2Response durationSafetyPFSSurvivalPKWhy capping of all words in expanded form of RECIST? [SD note: Because those words spell out the acronym « RECIST »]Lowercase ‘e’ in ‘Primary endpoint’ and ‘Secondary endpoints’?Little horizontal line to the right of word ‘SCREEN’ overlaps vertical line slightlyTreatment until progression; CT or MRI at baseline & q3moPK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid TumorsYao 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)Central radiologyITT, n (%)PR11 (9.6)SD78 (67.8)Clinical benefit(PR + SD)89 (77.4)PD16 (13.9)Unknown10 (8.7)Stratum 2: Everolimus + Octreotide LAR(n = 45)Lowercase ‘f’ in ‘From’ in the title of this slideCentral 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 LAR10010080n = 11580n = 4560Probability (%)Probability (%)6040402020Median PFS = 16.7 moMedian PFS = 9.7 moTO PURCHASE BOTH IMAGES – USE AS IS246810121416182022242468101214161820222426Time, moTime, moPatients at riskPatients at risk11511181585436251512533145393222211914108331Yao JC et al. J Clin Oncol. 2010;28:69-76.38
39 Pivotal Phase 3 Trials with Everolimus in NETs Accrual completedOctreotide LAR + EverolimusAdvanced carcinoid with syndrome in progression(N = 429)ROctreotide LAR + placeboAccrual completedLowercase w in with in title of slideWhat does the superscript 1 in placebo refer to? Is a footnote to this slide missing?Best supportive care + everolimus*Advanced pNET in progression(N = 410)RBest supportive care + placebo**Octreotide LAR included as best supportive care.3939
40 Conclusions NETs not that rare Progress being made Somatostatin analogs effective in controlling hormonal syndromePROMID suggests octreotide LAR controls tumor growth in midgut carcinoidsPhase 2: VEGF and mTOR inhibitors have single-agent activity in NETsConfirmatory phase 3 studies ongoing