5 Introduction DEFINITION A subgroup of endocrine tumors formed by cells of epithelial origin, presenting with structural and functional characteristics similar to those of the normal endocrine cells specialised in the production of peptide hormones and aminesCapacity to express specific markers such as chromogranin A, synaptophysin, neuron-specific enolase and Neural Cel Adhesion MoleculeScoazec J-Y, 2009; Van Hootegem Ph, Acta Gastro Belgica 2009
6 What are Neuroendocrine Tumours? Neuroendocrine Tumours (NETs)Rare, heterogeneous, slow-growing tumours1Mainly sporadic, can be familial2,3Arise from cells with neuroendocrine origin1Can arise from most organs, commonly1:GI tract and pancreasEndocrine organsLungNETs may synthesise and secrete peptides/aminesSecreted peptides/amines can be used as tumour markers, and may lead to clinical symptoms4–6132Credits: 1BSIP, Estiot; 2Pasieka; 3BSIP, Vero/Carlo; Science Photo LibraryBuchanan KD Gastroenterol Today 2003; 13: 2–3Anderson RJ et al. Curr Opin Oncol 1997; 9: 45–54Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11Edney JA et al. Am J Surg 1990; 160: 625–629Neuman HPH et al. Sem Nephrol 2002; 22: 89–99Soga J et al. J Exp Clin Cancer Res 1998; 17: 389–400
7 IntroductionNeuroendocrine cells are distributed widely throughout the body, and neoplasms of these dispersed cells can arise at many sites.Broad spectrum:carcinoid tumors, pancreatic neuroendocrine tumors, medullary thyroid cancers, pheochromocytomas,…: characterized by slow growth and frequent secretion of hormones or vasoactive substancessmall cell carcinoma of the lung, Merckel cell tumor, poorly differentiated neuroendocrine carcinoma,… are highly aggressive neoplasms, and are usually advanced when diagnosed.
8 Indolent vs. Aggressive Biology Well differentiated neuroendocrine tumor (carcinoid, atypical carcinoid, many primary sites)Medullary carcinoma of the thyroidWell differentiated pancreatic neuroendocrine tumor (islet cell tumor)ParagangliomaPheochromocytomaPoorly differentiated neuroendocrine carcinoma (many primary sites)(Extra)pulmonary small cell carcinomaMerkel cell tumor of the skin skinNeuroblastoma, adrenalSmall cell lung cancer
9 Introduction RARE, BUT CHALLENGING All NETs have a malignant potential In general, they grow slower than adenocarcinomas of the GI tractMost NETs are functionally inactiveSome NETs never develop metastasesBiological behaviour is different and can change over timeNETs can arise solitarily or part of a genetic syndrome (e.g. MEN1)RARE, BUT CHALLENGINGVan Hootegem Ph, Acta Gastro Belgica 2009
10 Aetiology of NETs Majority of NETs are sporadic: Assumed to be sporadic mutationsNETs may also be familial:Autosomal dominant inherited syndromes1–4Multiple endocrine neoplasia I (MEN I)MEN IIvon Hippel Lindau (VHL) diseaseCarney complexAssociated with other familial conditions4–5Neurofibromatosis type ITuberous sclerosisBuchanan KD Gastroenterol Today 2003; 13: 2–3Neuman HPH et al. Sem Nephrol 2002; 22: 89–99Kaltsas GA et al. Endocr Rev 2004; 25: 458–511Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11Robbins SL et al. In Pocket Companion to Robbins Pathologic Basis of Disease (5th ed). WB Saunders Co, pp: 538
12 NET TerminologyClinicians often use ‘carcinoid’ to define non-pancreatic NETs arising from the GI tract (i.e. foregut, midgut, hindgut NETs)Clinicians use ‘carcinoid syndrome’ to describe symptomatic NETs with flushing of the skin, secretory diarrhoea, abdominal cramps and bronchoconstrictionPathologists often use ‘carcinoid’ to describe tumours with endocrine function (derived from enterochromaffin cells)
13 Carcinoid tumour distribution (%) based on 20,436 NETs1 NET TerminologyCarcinoids (~67% of NETS)Carcinoids secrete numerous peptides, including serotonin (5-HT) and tachykinins~10% carcinoids metastasise to liver and release 5-HT into the blood resulting in ‘carcinoid syndrome’ (cutaneous flushing, diarrhoea, abdominal pain)Carcinoid tumour distribution (%) based on 20,436 NETs11. SEER database 1973–2004
14 Pancreatic NETs by type based on 1,639 pancreatic NETs1 NET TerminologyPancreatic NETs (non-carcinoid):Functional (~40%) or non-functional (~60%)Functional pancreatic NETs usually defined by the predominant, clinically relevant hormone they secrete (eg insulin, gastrin, glucagon, VIP)Pancreatic NETs by type based on 1,639 pancreatic NETs1Solcia E et al. Pancreatic endocrine tumors: General concepts; Non-functioning tumors and tumors with uncommon function CRC PressÖberg K and Modlin IM S Annals Oncol 2009; 20 (Suppl 4): 147–149
15 Incidence of NETs All GEP-NETs: 2.5–5 cases/100,000/year1–2 Carcinoid tumoursBronchial carcinoids: 0.6 per 100,000/year3Midgut carcinoids: 2.4 per 100,000/year (based on 5-decade analysis of 13,715 carcinoids)2Racial differences exist24.5 per 100,000/year in black population2.6 per 100,000/year in white populationPancreatic NETs60% non-functional: 3.5–4 per million/year4Insulinomas: 2–4 per million/year5,6Gastrinomas: 0.5–4 new cases per million/year5,6Modlin IM et al. Lancet Oncol 2008; 9: 61–72Modlin IM et al. Cancer 2003; 97: 934–959Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 147–149Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 150–153Alexakis N et al. Best Pract Res Clin Gastroenterol 2008; 22: 183–205Öberg K and Eriksson B Best Pract Res Clin Gastroenterol 2005; 19: 753–781
16 Introduction GastroEnteropancreatic NETs (GEP) 55-70 % Thoracic NETs 25 – 30 %Other sites1-10 %NETs are rare, yearly incidence of 2-4 (?) per 105/year< 2 % of all GI malignancies are NETs10% -13% without primary tumorYao J, et al. J Clin Oncol, 2008; Van Hootegem Ph, Acta Gastro Belgica 2009
17 Improved diagnosis may underlie rising incidence of NETs Increasing Incidence of NETsBased on 35,618 patients with carcinoids in the US (SEER database, 1973–2004)1Improved diagnosis may underlie rising incidence of NETsYao JC et al. J Clin Oncol 2008; 26: 3063–3072
18 Classification of NETs Tumour-node-metastasis (TNM) classification system3,4Staging based on anatomical featuresApplied to gastroenteric tumours (foregut NETs3, midgut and hindgut NETs4)Major prognostic factor for survivalComplementary to pathological WHO classificationHelps clinicians to characterise tumours more precisely and to define most appropriate therapeutic strategyWHO classification systems1,2Based on macroscopic and histopathological featuresIntroduced for common NETs (digestive NETs, 20001; thoracic NETs , 20042)No specific classification for rare NETsClassification does not drive therapeutic strategySolcia E et al. (Eds) In WHO International histological classification of tumors, Edition 2. New York, Springer, 2000.De Lellis RA et al. (Eds) In WHO Classification of tumours. Pathology and genetics: Tumours of endocrine organs. IARC, Lyon, 2004Rindi G et al. Virchows Arch 2006; 449: 395‒401Rindi G et al. Virchows Arch 2007: 451: 757–762
19 TNM?The most recent 7th edition of the AJCC staging manual, which reflects a modification of proposal by ENETS , includes separate TNM staging systems for NETs of the appendix , pancreas ,stomach ,small bowel/ampulla of Vater and colorectal primary sites Although functionality may impact prognosis (eg, insulinomas are generally indolent tumors), the biologic behavior of most functioning NETs is defined by the grade and stage of the tumor.
20 Tumour-Node-Metastasis Classification of NETs1 Tumour (T): Size and location of primary tumourTX Primary tumour cannot be assessedTis In situ tumour/dysplasia (<0.5 mm) (only defined for stomach)T0 No evidence of primary tumourT1‒T4 Dependent on specificNode (N): Has the tumour spread to regional lymph nodes?NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasesN1 Regional lymph node metastasesMetastases (M): Has the cancer metastasised to other parts of the body?MX Distant metastases cannot be assessedM0 No distant metastasesM1 Distant metastasesRindi G et al. Virchows Arch 2006; 449: 395‒401
21 TNM classification used to define stage of specific NETs Staging of NETs1TNM classification used to define stage of specific NETsStageDescriptionTNMStage 0In situ tumour/dysplasia [for stomach only]TisN0M0Stage INETs with limited growthT1Stage IIANETs that are larger in size or more invasiveT2BT3Stage IIINETs that have invaded surrounding tissues or have regional node metastasesT4Any TN1Stage IVNETs with distant metastases always presentAny NM1Staging has been developed with some specificities for each digestive NET locationStaging helps clinicians to characterise tumours and to define most appropriate therapeutic strategyRindi G et al. Virchows Arch 2007: 451: 757‒762
23 Grading + IHCG1 en G2: goed gedifferentieerde NET, intense expressie van synaptophysin en Chromogranine A,Lokale necrose duidt meestal op G2G3: hooggradig met necrotische zones, meestal minder chromogranine A expressie maar behoudt de intense synaptophysine kleuring
24 Chromogranine A Chromogranin A, CgA a glycoprotein, stored in secretory granules‘first-line’ marker of NETssensitivity 84% and specificity 85-96%Borbath I et al. Acta Gastro Belgica 2009
25 Chromogranine AFor non-serotonin producing carcinoids and pancreatic neuroendocrine tumors, serum chromogranin A (CGA): more sensitive than 5-HIAA serum levels of CGA can also be elevated in non-neuroendocrine related conditions!
26 Serotonin, 5-hydroxy-indolic acid (5-HIAA) Serotonin & 5-HIAA- Serotonin (5-hydroxytryptamin)midgut (foregut) NETsdosage in blood is unreliable- 5-HIAASerotonin, 5-hydroxy-indolic acid (5-HIAA)main metabolite of serotoninat least once with midgut tumors24 h urinary collection is the gold standardcollection on chlorydric acidAVOID: bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, walnutsBorbath I et al. Acta Gastro Belgica 2009
27 Endocrine Tumours, WHO classification Well-differentiated Endocrine TumoursBenign BehaviourUncertain BehaviourIn general, slow-growing malignancies with low mitotic and proliferation indicesCells retain antigenic assets of their normal DES cell counterpartsWell-differentiated Endocrine CarcinomaPoorly differentiated Endocrine CarcinomaElevated proliferating and metastatic capacity.Cells of an abortive/incomplete endocrine phenotype.Mixed Endocrine Exocrine TumourTumour-Like LesionsSolcia et al. WHO international Histological Classification ot Tumours, Berlin 2000
28 NET Features Associated With Poor Prognosis Poorer prognosis associated with:Presence of metastases1*Poor differentiation2* ≥ 3 cm primary tumour size2*Non-functioning tumours2High proliferative (Ki67) index3Specific TNM classifications and gradesRisk of reduced survival in patients with NETs classified as TNM stage III–IV, or grade 2–34Tumour grading, mitotic rates and Ki67 index are inversely associated with survival for metastatic tumours5* Evidence based on duodenopancreatic tumoursSoga J J Exp Clin Cancer Res 2003; 22: 517–530Madeira I et al. Gut 1998; 43: 422–427Rindi G et al. Gastroenterology 1999; 116: 532–542Pape UF et al. Cancer 2008; 113: 256‒265Strosberg J et al. Hum Pathol [Epub ahead of print]
29 Survival rate depends on site of tumour origin and tumour spread 5 Year Survival Rate Decreases with Degree of Tumour Spread in Patients with Gastroenteric NETsSurvival rate depends on site of tumour origin and tumour spreadJanson ET et al. Ann Oncol 1997; 8: 685–690
31 Carcinoid tumoren:Carcinoid tumors have traditionally been classified based upon their origin from the embryonic divisions of the alimentary tract.
32 DistributionModlin IM et al. Gastroenterol, 2005
33 Abdominal obstruction Clinical Features: Carcinoid TumoursObstructive Jaundice1Non-functional (~90%)1Represent majority of carcinoid tumoursIncidental finding − e.g. liver ultrasoundAbdominal pain/obstructionGI bleedingObstructive jaundiceWeight lossFunctional (~10%)Symptoms due to excess hormone production − e.g. flushing, diarrhoea, wheezingAbdominal obstruction32Credits: 1Dr M.A. Ansary; 2GCA; 3Living Art Enterprises; Science Photo LibraryLiver metastasesKaltsas G and Grossman A In: Handbook of Neuroendocrine Tumours: Their Current and Future Management. BioScientifica, 2006, p. 98
34 Carcinoid SyndroomSymptomen veroorzaakt door het vrijzetten van een aantal polypeptiden, aminozuren en prostaglandines.Aminozuren: Serotonin, 5-Hydroxytryptophan, Norepinephrine, Dopamine, HistaminePolypeptides: Kallikrein, Pancreatic polypeptide, Bradykinin, Motilin, Somatostatin, Vasoactive intestinal peptide, Neuropeptide K, Substance P, Neurokinin AProstaglandins
37 Development of Carcinoid Syndrome and Crisis1 Carcinoid DiseaseCarcinoid SyndromeCarcinoid CrisisPrimary NETs usually asymptomatic for hormonal effectsMay present with obstructive symptoms (pain, nausea, and vomiting) despite normal radiologyUsually result of liver metastases exacerbating clinical symptomsHormone levels increase as tumour mass increases and liver function is compromisedAssociated with advanced diseaseRare sequel to carcinoid syndromeCharacterised by:Profound flushingBronchospasmTachycardiaHypotensionConfusionComaPrecipitated by:Anaesthetic inductionSurgical stressEmbolisationChemotherapyInsufficient somatostatin analogue coverRamage JK et al. Gut 2005; 54 (Suppl IV): 1–16
39 GASTRINOMA : duodenaal/pancreatisch Extreem zz: 0.5-3/millioen/jaarMeest frekwente functionele NET van pancreas…MEN 1 syndroom (hyperparathyroidie)Variabele agressiviteitDiagnose: uitstuiten HP, geen PPI gebruik tijdens test, pH meting samen met Gastrine serum bij nuchter patient
40 Gastrin Suspected ZES (gastrinoma) Serum Gastrin off PPI (1 week) multiple peptic ulcerspersonal or family history of hypercalcemia or pituitary tumorpost bulbar ulcerrecurrent PUD after surgeryPUD + diarrheaPUD refractory to conventional dose of PPIunexplained refractory diarrhealarge gastric foldGastrinSerum Gastrin off PPI (1 week)< 1000 pg/ml≥ 1000 pg/mlSecretin stimulation testGastric pH probeNegative, but reassessPositive≤ 4.0> STOPKaltas G, 2009
41 Insulinoma ZZ Vaak multipel, meestal benigne 1. Symptomen van hypoglycemie2. Glucose <40mg/dL3. verhoogd insuline72 uur vastentest met meten van glucose, C-pepetide en insuline: diagnose van autonoom functionerend en sereterend insulinoma
42 Insulinomaa homogeneous enhancing lesion (black arrow) in the uncinate process of the pancreas,just posterior to the superior mesenteric vein (white arrow).
44 Diagnosis & Staging‘The majority of patients doesn’t present with flushing, hypertension and/or secretory diarrhea’‘Most of them are asymptomatic or have vague and misleading symptoms’Need for performant diagnostic tools fo find the needle in the haystack!
45 Diagnosis & Staging: Imaging CT-scan and MRIpancreatic NETs : CTscan is performant- sensitivity 87%, specificity 83%, detection limit 1cm- hypovascular, large tumors with calcifications: malignantintestinal NETs : CTenteroclysis is a possible optionDiffusion MRI and CT perfusionsmall, benign and well-differentiated tumors =Highly vascularised, high blood flow and short mean transit timemalignant and high metastatic potential =Low blood flow and long mean transit timeVullerme M-P, 2009
46 Diagnosis & Staging: Imaging Endoscopic Ultrasound (EUS)pancreatic NETs : detection and localisation of small lesions- sensitivity > 90% for insulinomas- sensitivity ± 80% for gastrinomasintestinal NETs :detection, localisation, staging and guidance of therapy (rectal)EUS and Fine Needle Aspiration (FNA)cytology, but also histology and Ki-67 determinationO’Toole D, 2009
47 Diagnosis & Staging: Imaging - Somatostatin Receptor Scintigraphy - ‘Octreoscan’111Indium-pentetreotideimaging technique for detection & stagingCave: insulinoma & poorly differentiated NETsCave: spatial resolutionCave: lymphoma, meningioma, paraganglioma, pheochromocytoma, sarcoidosis, rheumatoid arthritisCave: > 4 weeks after last long acting analogueBorbath I et al. Acta Gastro Belgica 2009; Hoersch et al. ASCO 2009
48 Diagnosis & Staging: Imaging - 68Ga-labelled DOTATOC PET/CTgallium-68 is a positron emitterDOTATOC has 10 times more affinity for subtype 2 receptorPET/CT evaluation is possible17% addtional information(18-F-dihydroxy-phenyl-alanine [18F-DOPA] and 11-C-5-hydroxytryptophan [11-C-5-HTP])
49 Diagnosis & Staging: Imaging At diagnosisto identify the site of the primary tumourto evaluate the extent of local invasionsearch for metastatic disseminationassess the surgical resectability of the lesion(s)During follow-upto evaluate the rate of progressionassess the response to treatment(s)detect recurrences or late metastases
50 Diagnosis & Staging: Pathology A correct histological diagnosis, but alsoA correct histological stagingHE-stainingBehaviourInvasion of m. propriaDifferentiationSize (cm)AngioInvasionKI-67Benign-Well≤ 1< 2%Benign or Low-Grade≤ 2-/+Low-Grade+> 2> 2%High-GradePoorlyAny> 30%Ki67-stainingKloppel et al. Ann NY Acad Sci, 2004; Rindi et al. Neuroendocrinology, 2004
51 Diagnosis & Staging: Algoritm Suspected NET or SymptomsInherited disorder?Biochemical/Pathological DiagnosisImaging incl. DOTATOC PET CTMetastaticLocalized
52 Therapy multidisciplinary +++ Surgeryfunctioning vs. non-functioning tumoursresection, radiofrequency ablation (RFA)transplantationLocoregional and radioisotopic targeted treatmentSystemic treatmentchemotherapysomatostatin analogsinterferonmolecular therapy
53 Therapy : surgerySurgery is the sole option to cure a patient with GEP but,…R0-resection is mandatory (median survival 110 vs. 34 months)a small minority (± 20%) of patients present with a potentially resectable primary GEPresection of the primary might give a survival benefit even in metastatic patients (median survival 7.4 years vs. 4.0 years)Surgery is an option to control symptoms of patients with GEPbleedingbowel obstruction, especially in ileal NETsfunctioning tumoursRoeyen G et al. Acta Gastro Belgica 2009
54 Therapy : surgery Functioning minimal invasive (enucleation) for pancreatic NET with a lower malignant potential such as insulinomamore aggressive for pancreatic gastrinomaresection of primary and/or metastais to control symptomsLocalizednon-Functioningaggressive surgery for lesions more than 3 cmonly if patients develop symptomsLocalizedRoeyen G et al. Acta Gastro Belgica 2009
55 Aanpak van Levermetastasen Belangrijke –negatief- prognostische factorFrekwent bij presentatie (tot 50%)Pancreas: 5 jaars overleving van 30-60%GI: 60-90%Primary unknown in 5-10%
56 Levermetastasen: heelkunde? Bij alle operabele goed gedifferentieerde NET’sDuidelijk beter OS (in vergelijking met historische controles)Afwezigheid van extra abdominale metastasering of diffuse peritoneale carcinomatoseEventueel meerdere ingrepenOnvolledige debulking heelkunde? (meer dan 90% van tumor load)
57 Levermetastasen: RFARFA: effectief, maar moeilijk zo M groter dan 3 cm, problemen met localisatie (bloedvaten, nabijgelegen organen)Eventueel in combinatie met heelkundeLaser induced thermotherapy, cryotherapy, ethanol injectie, brachytherapy, …
58 Levertransplantatie?Met HCC de enige indicatie voor levertx in maligne ziekteUiteraard enkel leveraantasting5 jaars overleving van 36%(laaggradige NET’s, jonge patienten,…)
59 Levertransplantatie? INCLUSION EXCLUSION No Standard of Care! a low-grade NETsmall cell carcinoma and high-grade NETa primary NET drained by the portal system that was curatively resectedconditions contraindicating liver transplantationmetastatic liver involvement < 50%non-gastrointestinal NETs or tumors not drained by the portal systemstable disease for at least 6 monthsage below 55 yearsNo Standard of Care!Mazzaferro V et al. J Hepatol, 2007
60 Locoregional Approach Therapy : locoregional therapywell differentiatedKi-67 < 2%absence of angio- and/or perineural invasionno p53 overexpression< 2 mitoses/10 high power fieldsLocoregional ApproachLiver only metastatica) Hepatic artery embolization (HAE)No randomized trials!b) Hepatic arterial chemoembolization (HACE)c) Hepatic arterial radioembolization with Yttrium90Hendlisz A et al. Acta Gastro Belgica 2009
61 Hepatic Artery Embolisation/Chemoembolisation Used to target hepatic metastases by interrupting tumour blood supplyTechniqueCatheter passed into hepatic arteryArteriogram performed to identify artery supplying tumourEmbolising particles or gelfoam injected to block blood supply to tumourIn chemoembolisation, emulsion containing cytotoxic drug (e.g. streptozocin) precedes arterial block1In carcinoid syndrome, somatostatin analogues are co-administered to avoid carcinoid crisis1OutcomesTumour shrinkage observed in 50% patients and expected to reduce overall tumour massEffective procedure2,3 but significant side effects (e.g. fever, nausea, pain, abnormal liver function)4Angiogram of the hepatic artery in a patient with carcinoid liver metastasesCourtesy of Dr J. Ramage, North Hampshire Hospital, UKO’Toole D et al. Endocr Rel Cancer 2003; 10: 463–468Dominguez S et al. Eur J Gastroenterol Hepatol 2000; 12: 151–157Fiorentini G et al. J Chemother 2004; 16: 293–297Moertel CG et al. Ann Intern Med 1994; 120: 302–309
64 Somatostatin analogs (SSAs) Somatostatins = a family of peptide hormones (SST-14 & SST-28)SSTR-1-5inhibition of growth hormone and all GI hormonesgut motilitysplachnic flowabsorptioncell proliferationcell survivalangiogenesisSomatostatin analogs (SSAs)Verslype C et al. Acta Gastro Belgica 2009
65 Somatostatin analogs (SSAs) Therapy – ‘Somatostanine analogs’Novartis PharmaBeaufour IpsenOctreotide SC, 2-3x µg/dLanreotide IM, 30 mg/14 dOctreotide LAR IM, mg/28 dLanreotide autogel SC, mg/28 dSSTR2-5(3)Somatostatin analogs (SSAs)‘cornerstone’ in the management of patients with NETsymptom control, anti-proliferative (?)efficacy is dependent on tumor receptor expression (e.g. low in gastrinomas)
67 For metastatic NET patients SEER* registry Improved survivalPatients with metastic NETs diagnosed after 1988 showed a significant improvement in median survival duration“One possible explanation is that the introduction of octreotide in 1987 improved the control of carcinoid syndrome and changed the natural history of NETs”*Surveillance, Epidemiology and End ResultsYao J.C. et al. J Clin Oncol 2008;26:
69 PROMID – randomized, multicentric, phaseIII Octreotide LAR 30 mg i.m. every 4 weeksPlacebo i.m. every 4 weeksContinuation of treatment if no progressionInformed consentRandomization 1:1Month-1369121518ScreeningPrimary endpoint: time to tumor progressionTreatment was continued until CT or MRI documented tumor progressionFollow-up until deathCT and/or MRI was evaluated by a blinded central reader
70 PROMID – randomized, multicentric, phaseIII Histologically confirmed, locally inoperable or metastatic well-differentiated midgut NETsFunctionally active or inactive midgut NETsSandostatine LAR (n=42)Placebo (n=43)Complete response (n)Partial response (n)1Stable disease (n)2816Progressive disease (n)1023Unknown (n)3
79 Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET Study halted prior to complete accrual due to treatment benefitUnplanned Kaplan-Meier PFS analysis1.0P < .001; HR: (95% CI: to 0.649)0.80.6Sunitinib: PFS 11.1 moSurvival probability0.4Placebo: PFS 5.5 mo0.2SunitinibPlaceboEfficacy endpoint variable value (mo)Placebo, nSunitinib, nRaymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.
81 RADIANT-3: PFS by Investigator Review Kaplan-Meier median PFSEverolimus: 11.0 monthsPlacebo: 4.6 monthsHR = 0.35; 95% CI [ ] P < .00011008060% Event-free4020Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)24681012141618202224262830Time (mo)No. of patients still at riskEverolimusPlacebo20720318917715398126591145280244916367284213102612111P-value obtained from stratified one-sided log rank testHazard ratio is obtained from stratified unadjusted Cox modelYao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.