Mohamed Abdulla, profile picture
Uploaded byMohamed Abdulla
PPTX, PDF8,263 views

Neuroendocrine tumors in 2015

1) The document discusses the role of targeted therapy in neuroendocrine tumors. It covers topics such as the evolution of terminology and classification of NETs, the use of biomarkers and imaging in diagnosis and monitoring, and current therapeutic approaches including somatostatin analogs. 2) Somatostatin analogs like octreotide and lanreotide are effective in controlling hormonal symptoms in NET patients by binding to somatostatin receptors that are prevalent on many NETs. They have also shown inhibitory effects on tumor proliferation. 3) A phase III study showed octreotide LAR extended time to tumor progression compared to placebo in treatment-naïve patients with well-differentiated midgut NETs

Embed presentation

Downloaded 433 times
ROLE OF TARGETED THERAPY IN NEUROENDOCRINE TUMORS Mohamed Abdulla M.D. Prof. of Clinical Oncology Kasr Al-Aini School of Medicine Cairo University Target Therapy: Future Directions Helnan Palestine Hotel Thursday, 30/04/2015
Origin: Neuroendocrine Cells Neuropeptides Catecholamines Hormonal Syndromes Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1.
descendin g colon (<1%) sigmoid colon (- 12%) Primary Tumor Localizations est. % of all NEN thymus bronchus esophagus stomach duodenum pancreas jejunum/ileum cecum appendix colon rectum <1 15 <1 15 4 15 15 2 15 1 10 thymus (1%) bronchus (-15%) esophagus (<1%) pancreas (-15%) duodenum (-4%) ascending colon (- 1%) jejunum (-5%) ileum (-10%) cecum (-2%) appendix (-15%) rectum (-10%) stomach (-15%) Pape UF, et al. Gastroenterol up2date. 2011;7:313- 339.
2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973 0.00 1.00 2.00 3.00 4.00 5.00 6.00 0 100 200 300 400 500 600 Incidenceper100,000-NETs Incidenceper100,000–Allmalignantneoplasms All malignant neoplasm Neuroendocrine tumors Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. Increasing Incidence Plateau 1.09 5.25
Incidence of NETs Is Increasing* 5 5 SEER = Surveillance, Epidemiology, and End Results (for malignant NETs) *Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry IncidencePer100,000 1.40 Year NET Site 1.20 1.00 0.80 0.60 0.40 0.20 0 Lung Colon Small intestine Rectum Pancreas Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
Colon Neuroendocrine Stomach 29-year limited duration prevalence analyses based on SEER Pancreas Esophagus Hepatobiliary 0 100 1,100 NET Prevalence in the US, 2004 1,200 Median survival (1988 – 2004)103,312 cases (35/100,000) No.ofcases (thousands) Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. NETs Are the 2nd-Most Prevalent Gastrointestinal Tumor: • Localized • Regional • Distant 203 months 114 months 39 months
NET: Demographics: Lepage C, et al. Gut. 2004;53(4):549-553.
Niederle MD, et al. Endocr Relat Cancer. 2010;17(4):909-918. Biologicalbehavior Malignant Uncertain Benign NET: Not all the same:
[TITLE] Presented By Pamela L. Kunz, MD at 2012Annual Meeting
Key Issues in The Management: 1. How do we define the disease? Nomenclature, Classification & Pathology. 2. Who needs treatment and when? Patient Selection. 3. Which treatment and in what sequence? Treatments. 4. What is the role of combined biologics, somatostatin analogues, cytotoxics and biomarkers? Unanswered Questions.
1.How do we define the disease? Nomenclature, Classification and Pathology
Evolution of Terminology & Classification: Historic Evolution: 1907 1963 1970 1980 1995 Carcinoid Williams & Sandler Soga & Tazawa Histologic WHO Granular Stain Techniques Capella Size & Invasion • Benign. • Benign or Low Grade Malignant. • Low Grade Malignant. • High Grade Malignant. No Prognostic or Predictive Validation
Evolution of Terminology & Classification: Histopathologic Differentiation: Well Differentiated Poorly Differentiated
Evolution of Terminology & Classification: AJCC Criteria of Grading: Grade Mitotic Count (per 10 HPF) Ki 67 Index (%) G1 < 2 < 2 G2 2 – 20 3 – 20 G3 > 20 > 20 AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
Evolution of Terminology & Classification: Correlation of Tumor Grade With Survival: 1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Survival Time (mo) 0.0 0.2 0.4 0.6 0.8 1.0 CumulativeSurvival G1 G2 G3 G1 vs G2 G1 vs G3 G2 vs G3 P=0.040 P<0.001 P<0.001 N=193
Scarpa A, et al. Mod Pathol. 2010;23(6):824- 833. Prognostic Influence of Ki67- Labelling < 2% 15% 75% Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798- 7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221- 232.
Evolution of Terminology & Classification: Correlation of TNM Staging With Survival: 17 17 La Rosa S, Klersy C, Uccella S, et al. Hum Pathol. 2009;40:30-40. Patients With Well-Differentiated Pancreatic NET Stage I P<0.001 ProportionAlive Stage II Stage III Stage IV I (n = 44) II (n = 44) III (n = 34) IV (n = 33) Time (mo) 0.00 0.25 0.50 0.75 1.00 0 48 96 144 192 240
Evolution of Terminology & Classification: Metastatic Disease Is Common at Presentation: Localized Metastatic 50% 27% 23% Distant metastases Regional spread Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. *These data are of the cases in which stage was reported. 20% of cases did not provide disease stage information
Evolution of Terminology & Classification: NETs Are Often Diagnosed Late: Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889. 1 2 3 4 5 6 7 8 9 Time (yr) Primary tumour growth Metastases Flushing Diarrhea Death Vague abdominal symptoms Estimated time to diagnosis: 5 to 7 yr * * *Symptoms of carcinoid syndrome
2. Role of Biomarkers & Imaging:
Pan-neuroendocrine markers Cytosolic NSE, PGP 9.5 Related to secretory granules Chromogranin Related to synaptic vesicles Synaptophysin, VMAT Intermediate filaments NF, CK HMW Adhesion molecules N-CAM Immunohistochemical NE markers:
 Chromogranin A* (in 70%-90% increased in metast. NET)  Pancreatic Polypeptide, PP (in 40%-55 % elevated);  a-HCG, β-HCG (in ~ 30% elevated)  Neuron specific enolase (NSE) (in ~33% elevated) *The height of Chromogranin A level correlates with tumor load, an increase over time indicates tumor progression Circulating Tumor Markers:
CgA correlates with hepatic tumor load Heigher CgA levels indicate lower survival Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827 Prognostic Value of CgA:
HR = 0.25 95% CI: 0.13-0.51 P = .00004 Median PFS Early response = 13.3 mos. No early response = 7.5 mos. 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 HR = 0.25 95% CI: 0.10-0.58 P = .00062 CgA NSE Median PFS Early response = 8.6 mos. No early response = 2.9 mos. PFS(%) 0 20 40 60 80 100 0 20 40 60 80 100 Time Since Study Start, months Time Since Study Start, months Pts at Risk Pts at Risk Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0 Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0 Yao JC, et al. J Clin Oncol. 2010;28(1):69-76. RADIANT-1 (Stratum I) Predictive Value of Biomarkers: PFS by Early CgA and NSE Responses:
Modlin IM, et al. Ann Surg Oncol. 2010;17(9):2427-2443. PPI Chronic Atrophic Gastritis PPI H2RAs Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer Chronic atrophic gastritis Pancreatitis Inflammatory bowel disease Irritable bowel syndrome Liver cirrhosis Chronic hepatitis Colon cancer HCC Pancreatic adenocarcinoma Pheochromocytoma Hyperparathyroidism Pituituary tumors Medullary thyroid carcinoma Hyperthyroidism CgA ENDOCRINE DISEASE GASTRO- INTESTINAL DISORDERS NON-GI CANCER Arterial hypertension Cardiac insufficiency Acute coronary syndrome Giant cell arteritis CARDIOVASCULAR DISEASE Systemic rheumatoid arthritis Systemic inflammatory response syndrome Chronic bronchitis Airway obstruction in smokers INFLAMMATORY DISEASES Renal Insufficiency RENAL DISORDERS DRUGS Causes of Chromogranin A Elevation:
Diagnosis: Imaging Primary Tumor/Tumor Spread:  Whole body Screening & Staging  Endocrine Pancreatic tumor < 1cm  Routine imaging  Primary tumour Screening & Staging (optional)  Octreoscan (111Indium-DTPA- Octreotide)/ SPECT: 1. choice  Endoscopic ultrasonography  ultrasonography of the liver  CT (+ angiography), MRI  Positron emission tomography (PET) with 11C-5 HTP,11C-L-dopa or 18F-FDG  SMS-R-PET: 68Gallium-DOTATOC- PET  PET/CT ENETS-Guidelines 2011
3. Therapy for Advanced Disease
Therapy of NETs Three principles • Control of hormonal symptoms • Control of tumor growth • Improvement of survival? Symptomatic therapy Surgical therapy Antiproliferative therapy • Cure • Debulking • Treatment / Prevention of complications
Somatostatin Receptors (SSTR) Are Expressed by the Majority of NETs • SSTR2 is most prevalent in GEP-NETs and induces inhibitory effects on hormone secretion and proliferation in NETs • Somatostatin is effective in controlling NET-related hormonal symptoms • Clinical use of somatostatin is limited by its short half life Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther. 2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat Cancer. 2006;13(3):955-962. Prevalence on NET type: SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Pancreas 68% 95% 46% 93% 57% Midgut 80% 86% 65% 35% 75% Inhibitory effect: Hormone secretion + + + Proliferation + + + + Induction of apoptosis + +
• Octreotide and lanreotide show high affinity for the SSTR2 and are approved for antisecretory treatment in NETs LAR, long lasting release Susini C, et al. Ann Oncol. 2006;17(12):1733- 1742. Octreotide LAR (10-30 mg / 28 days im) Lanreotide (60-120 mg / 28 days sc) Octreotide (2-3 x 50-500 ug sc / d) Biotherapy of Functional Active NETs With Somatostatin Analogs (SSA) S S a l a g l y ly asn s cys p h e p h e p h e tr p l y s t h r p h e t h r s e r cys D-phe c y s phe l y s c th y r s Octreotide acetate D-trp Thr - ol D-phe c l y s v al c y y s S ty r s Lanreotid e D-trp Thr - NH2 S Somatostatin S S
Phase III Study of Octreotide LAR: Patients: • Well-differentiated midgut NET • Treatment-naïve • Locally inoperable or metastasized N = 85 Octreotide LAR 30 mg im/28 days Placebo im/28 days Primary endpoint: • Median time to tumour progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. 1:1 R A N D O M I Z E Secondary endpoints: •Objective tumour response rate • Symptom control • Overall survival Treatment until CT/MRI documented tumour progression or death Randomized, Double-blind, Placebo-controlled Study
Octreotide LAR 30 mg Significantly Prolongs TTP: HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumours; TTP = time to progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. Octreotide LAR vs placebo HR=0.34 P=0.000072 [95% CI: 0.20–0.59] Based on conservative ITT analysis ProportionWithout Progression 1.0 .75 .50 .25 0 0 6 12 18 24 30 36 42 Time (mo) 48 54 60 66 72 78 Octreotide LAR (n = 42) Median 14.3 mo Placebo (n = 43) Median 6.0 mo
Octreotide LAR 30 mg Extends TTP in Patients With Functioning and Nonfunctioning Tumours: 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Based on the per-protocol analysis P=0.0008; HR=0.25 (95% CI: 0.10–0.59) ProportionWithoutProgression P=0.0007; HR=0.23 (95% CI: 0.09–0.57) ProportionWithoutProgression Patients with nonfunctioning tumours Patients with functioning tumours Time (mo)Time (mo) Octreotide LAR 30 mg: 17 pts/11 events Median TTP 14.26 mo Placebo: 16 pts/14 events Median TTP 5.45 mo Octreotide LAR 30 mg: 25 pts/9 events Median TTP 28.8 mo Placebo: 27 pts/24 events Median TTP 5.91 mo 1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508. 2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
Octreotide LAR: Symptomatic Relief: J Clin Oncol. 2009, 27:4656-4663.
Lanreotide Acetate in NET: • Patient Characteristics: Clarinet Trial: • Well to Moderately differentiated. • Ki 67 < 10% • Pancreas, mid-gut, hind-gut, or Unknown origin. N Engl J Med 2014;371:224-33.
The SYM-NET StudyDESIGNASSESSMENTS A non-interventional cross sectional study to assess SYMptom control in neuroendocrine tumors (NET) Non-interventional, cross-sectional study 273 patients suffering from NET, already treated with lanreotide for at least 3 months and with history of diarrhea due to carcinoid syndrome were enrolled Subject questionnaires Investigator review of medical record Likert scales • Patient satisfaction • Symptom severity • Perception change diarrhea • Feelings about conse- quences on daily life QoL • EORTC C30 • EORTC GI- NET21 Demography Medical history Treatment with lanreotide Diarrhea Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ characteristics • At Tt initiation • Day of visit Other clinical data • At Tt initiation • Day of visit Qol = quality of life
SYM-NET Study – Results and Conclusion Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ • An improvement was observed for the majority of patients in all symptoms – 76 % patient satisfaction with diarrhea control (primary objective) – 73 % patient satisfaction with flushing control – QoL questionnaires showed a high level of activity capacity and low symptoms score • Patient-reported "subjective" information was consistent with investigator’s observation • Confirms in real life setting the satisfactory effect of lanreotide on symptoms of hormonal excess in GEP- NETs
Chemotherapy for Well-Differentiated NETs of the Pancreas and Duodenum: Author Turner NC, et al. Br J Cancer. 2010;102(7) 1106-1112. Chemotherapy Pt (n) RR mOS (%) (months) Cheng (1999)1 & Mc Collum (2003)2 STZ + DOX 16 & 16 8 ----- Eriksson (1990)3 Dealunoit (2004)4 Rivera et al. (1998)5 Kouvaraki et al. (2004)6 Turner et al. (2010)7 STZ + DOX STZ + DOX STZ + 5-FU + DOX STZ + 5-FU + DOX STZ + 5-FU + cispl. 84 45 12 84 47 36 ------ 36 24 55 21 39 37 38§ 31.5 1. Cheng PN, et al. Cancer. 1999;86(6):944-948. 2. McCollum AD, et al. Am J Clin Oncol. 2004;27(5):485-488. 3. Eriksson B, et al. J Intern Med. 1990;228(2):103-113. 4. Delaunoit T, et al. Eur J Cancer. 2004;40(4):515- 520. 5. Rivera E, et al. Am J Clin Oncol. 1998;21(1):36-38. 6. Kouvaraki MA, et al. J Clin Oncol. 2004;22(23):4762-4771. 7.
Chemotherapy for G3 NET: NORDIC Trial: Annals of Oncology 24: 152–160, 2013
Temozolomide in Pancreatic Neuroendocrine Carcinoma Strosberg JR, et al. Cancer 2011;117(2):268-275 Capecitabine Temozolomide every 28 days 750 mg/m2 x 2 x tgl. (days 1– 14) 200 mg/m2 x 1 (days 10–14); n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1 glucagonoma; 1 gastrinoma/glucagonoma 70% PR (RECIST ) Median PFS: 18 months Retrospective analysis G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver enzymes 100 80 60 40 20 0 –20 –40 –60 –80 –100 Progressive Disease Partial Response
Molecular Events & Therapeutic Implications: 1. Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR
Neuroendocrinal Tumors: Molecular Events & Therapeutic Implications: 2. mTOR Inhibitor: Mammalian Target of Rapamycin Cellular Growth Protein Synthesis Autophagy Resistance to Apoptosis ++ Proliferation Altered Metabolism
RADIANT-3 PFS by Investigator Review: • P value obtained from stratified 1-sided log-rank test • Hazard ratio is obtained from stratified unadjusted Cox model %Event-free 0 2 4 6 8 10 No. of patients still at risk Kaplan-Meier median PFS Everolimus: Placebo: 11.0 mo 4.6 mo Hazard ratio = 0.35; 95% CI 0.27–0.45 P value: <.0001 PFS rate (18 mos.) Everolimus 34.2% Placebo 8.9% Yao JC, et al. N Engl J Med. 2011;364(6):514- 12 14 16 18 Time (mo) 100 80 Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 60 40 20 0 20 22 24 26 28 30
RADIANT-3: Treatment-Related G3/4 AE: Yao JC, et al. N Engl J Med. 2011;364(6):514- 523. *Related toxicities grouped for calculation Occurring in >10% Everolimus n = 204 All Grades (%) Grade 3/4 (%) Placebo n = 203 All Grades (%) Grade 3/4 (%) Stomatitis* 64 7 17 0 Rash 49 <1 10 0 Diarrhea 34 3 10 0 Fatigue 31 2 14 <1 Nausea 20 2 18 0 Infections* 23 3 6 1 Peripheral edema 20 <1 3 0 Decreased appetite 20 0 7 1
RADIANT-2 Study Design: Everolimus 10 mg/day + Octreotide LAR 30 mg/28 days n = 216 Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression R A N D O M I Z E 1:1 Multiphasic CT or MRI performed every 12 wk Crossover Primary endpoint: • PFS (RECIST) Secondary endpoints: • Tumour response, OS, biomarkers, safety, PK Enrollment January 2007–May 2008 Phase III, Double-blind, Placebo-controlled Trial Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8. Patients with advanced NET (N=429) • Advanced low- or intermediate- grade NET • Radiologic progression <12 months • History of secretory symptoms (flushing, diarrhea) • Prior antitumour therapy allowed • WHO PS ≤2
PFS by Central Review:* Time (mo) No. of patients still at risk E + O P + O 216 213 202 202 167 155 129 117 120 106 102 84 81 72 69 65 63 57 56 50 50 42 42 35 33 24 22 18 17 11 11 9 4 3 1 1 1 0 0 0 * Independent adjudicated central review committee • P-value is obtained from 1-sided log-rank test • HR is obtained from unadjusted Cox model E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 PercentageEvent-free Kaplan-Meier median PFS Everolimus + octreotide LAR: 16.4 mo Placebo + octreotide LAR: 11.3 mo HR = 0.77; 95% CI (0.59–1.00) P=0.026 Total events = 223 Censoring times E + O (n/N = 103/216) P + O (n/N = 120/213) Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
Subgroup PFS Analysis: *Independent adjudicated central review HR = everolimus + octreotide/placebo + octreotide Unstratified Cox model was used to obtain HR E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR Subgroups (N) Central review *(429) Local investigator review (429) Age group <65 yr (286) ≥65 yr (143) Gender Male (221) Female (208) WHO Performance Status WHO = 0 (251) WHO > 0 (176) Tumour histology grade Well-diff. (341) Moderately diff. (68) Primary tumour site Small intestine (224) Lung (44) Colon (28) Other (132) Prior long-acting SSA Yes (339) No (90) Prior chemotherapy Yes (130) No (299) HR Median PFS (mo) E + O P + O 0.77 16.4 11.3 0.78 12.0 8.6 0.78 19.2 13.0 0.75 13.9 11.0 0.85 13.7 13.0 0.73 17.1 11.1 0.67 21.8 13.9 0.81 13.6 8.3 0.74 18.3 13.0 0.82 13.7 7.5 0.77 18.6 14.0 0.72 13.6 5.6 0.39 29.9 13.0 0.77 14.2 11.0 0.81 14.3 11.1 0.63 25.2 13.6 0.70 13.9 8.7 0.78 19.2 12.0 Hazard Ratio Favors E + O Favors P + O 0 10.4 0.8 1.4 Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
5050 Sunitinib vs Placebo in Advanced pNET: • Phase III randomized, placebo-controlled, double-blind trial • Trial stopped after early unplanned analysis showed efficacy and safety benefit Primary Endpoint: PFS Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported outcomes Patients with advanced pNET, N = 171/340 patients enrolled Sunitinib 37.5 mg/day orally Continuous daily dosing* n = 86 Placebo* n = 85 *With best supportive care Somatostatin analogues were permitted Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 1:1 R A N D O M I Z E
51 51 0.8 0.6 0.4 0.2 0 1.0 ProportionofPatients 5 10 15 20 250 Sunitinib 39 19 4 0 086Sunitinib 28 7 2 1 085Placebo Number at risk Time (mo) Placebo Kaplan-Meier median PFS Sunitinib: 11.4 mo Placebo: 5.5 mo HR = 0.42 (95% CI, 0.26–0.66) P<0.001 Progression-free Survival:* Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. * Local review
1.0 PRRT Objective response: Stable disease: Median survival: 34% 5% 94.6 months Open phase II study, 1,109 patients with progressive NET (within 12 months), 2,472 cycles 90Y-DOTA- TOC-therapy, median follow up 23 months • Objective response rates 30% - 40% • Survival benefit in responders likely • Limitations: safety concerns (renal, bone marrow toxicity), limited availability, lacking randomized studies 0 2 4 6 8 10 12 Time Since Start of Treatment, years 14 0.2 0.4 0.6 0.8 OverallSurvival,probability Imhof A, et al. J Clin Oncol. 2011;29(17):2416- 1423. No. of patient s No. of deaths Median survival Hazard ratio P Disease control 671 280 3.8 years 0.41 vs progress <.001 Progress 438 211 1.4 years
Final Take Home Message: • NET not rare. • Surgery is the Cornerstone in Curative Management. • Serum Biomarkers Are Still There to Share. • Tissue Markers Should be more Highlighted. • Molecular Targeted Therapies are The Hope for Tomorrow.

More Related Content

PPTX
Role of Chemotherapy, Targeted therapy and Immunotherapy in NSCLC Part I
byMohammed Fathy
 
PPTX
Neuroendocrine Tumors in 2019
byMohamed Abdulla
 
PPTX
Carcinoid and pancreatic neuro endocrine tumor
byAlok Gupta
 
PPTX
MANAGEMENT OF TRIPLE NEGATIVE BREAST CANCER.pptx
byCancer surgery By Royapettah Oncology Group
 
PPTX
Non small cell lung cancer copy
byankitapandey63
 
PPTX
Hodgkins lymphoma treat
byLAKSHMI DEEPTHI GEDELA
 
PPTX
Cervix landmark trials- kiran
byKiran Ramakrishna
 
PPTX
Small cell lung cancer
byDrAyush Garg
 
Role of Chemotherapy, Targeted therapy and Immunotherapy in NSCLC Part I
byMohammed Fathy
 
Neuroendocrine Tumors in 2019
byMohamed Abdulla
 
Carcinoid and pancreatic neuro endocrine tumor
byAlok Gupta
 
MANAGEMENT OF TRIPLE NEGATIVE BREAST CANCER.pptx
byCancer surgery By Royapettah Oncology Group
 
Non small cell lung cancer copy
byankitapandey63
 
Hodgkins lymphoma treat
byLAKSHMI DEEPTHI GEDELA
 
Cervix landmark trials- kiran
byKiran Ramakrishna
 
Small cell lung cancer
byDrAyush Garg
 

What's hot

PPTX
Triple Negative Breast Cancer
byMohamed Abdulla
 
PPTX
Neuroendocrine Tumors in 2016
byMohamed Abdulla
 
PPTX
Cancer of unknown primary: Knowing the unknown
byMary Ondinee Manalo Igot
 
PPTX
Immunotherapy advances in lung cancer
byAlok Gupta
 
PPTX
Portec 4a
byShruthi Shivdas
 
PPT
Chapter 24.3 metronomic chemotherapy
byNilesh Kucha
 
PPTX
Cross trial esophagus updated result
byBharti Devnani
 
PPTX
EVOLUTION OF CHEMOTHERAPY IN BREAST CANCER
byIsha Jaiswal
 
PPTX
Oncotype dx presentation
byahmed mjali
 
PPTX
PARP inhibitor in Ca Ovary
byChandan K Das
 
PPTX
chemotherapy for gastric cancer.pptx
bySujan Shrestha
 
PPTX
Principles of radiotherapy in gastric carcinoma
byAnil Gupta
 
PPTX
Molecular diagnostics of colorectal cancer
byAddisu Alemu
 
PPTX
Tailorx Trial
byDr.Bhavin Vadodariya
 
PPTX
DLBCL
byikramdr01
 
PPTX
Glioblastoma multiforme (GBM) Radiotherapy planning and management principles
byGebrekirstos Hagos Gebrekirstos, MD
 
PPTX
SBRT PROSTATE PLANNING
byKanhu Charan
 
PPT
Molecular biology of colo rectal cancers
byNeha Seth
 
PPTX
Landmark trials in Ovarian Cancer
byPradeep Dhanasekaran
 
PPTX
LONG TERM TOXICITIES AND QUALITY OF LIFE AFTER RADIATION TO CENTRAL NERVOUS ...
bySubhash Thakur
 
Triple Negative Breast Cancer
byMohamed Abdulla
 
Neuroendocrine Tumors in 2016
byMohamed Abdulla
 
Cancer of unknown primary: Knowing the unknown
byMary Ondinee Manalo Igot
 
Immunotherapy advances in lung cancer
byAlok Gupta
 
Portec 4a
byShruthi Shivdas
 
Chapter 24.3 metronomic chemotherapy
byNilesh Kucha
 
Cross trial esophagus updated result
byBharti Devnani
 
EVOLUTION OF CHEMOTHERAPY IN BREAST CANCER
byIsha Jaiswal
 
Oncotype dx presentation
byahmed mjali
 
PARP inhibitor in Ca Ovary
byChandan K Das
 
chemotherapy for gastric cancer.pptx
bySujan Shrestha
 
Principles of radiotherapy in gastric carcinoma
byAnil Gupta
 
Molecular diagnostics of colorectal cancer
byAddisu Alemu
 
Tailorx Trial
byDr.Bhavin Vadodariya
 
DLBCL
byikramdr01
 
Glioblastoma multiforme (GBM) Radiotherapy planning and management principles
byGebrekirstos Hagos Gebrekirstos, MD
 
SBRT PROSTATE PLANNING
byKanhu Charan
 
Molecular biology of colo rectal cancers
byNeha Seth
 
Landmark trials in Ovarian Cancer
byPradeep Dhanasekaran
 
LONG TERM TOXICITIES AND QUALITY OF LIFE AFTER RADIATION TO CENTRAL NERVOUS ...
bySubhash Thakur
 

Viewers also liked

PPT
7 capdevila
byEuropean School of Oncology
 
PPT
MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours
byEuropean School of Oncology
 
PPT
NIH Presentation Nov 2016 Neuroendocrine Tumor Clinical Trials
byCACSNETS
 
PPT
Pancreatic neuroendocrine tumours
byAtit Ghoda
 
PPT
Radionuclide neuroendocrine tumors functional imaging
byHussein Farghaly
 
PPT
5. Carcinoid Tumour Biochemical And Radiological Testing
byensteve
 
PDF
Dr Ed. Wolin July 16 2016 DC Neuroendocrine Tumor Support Group Presentation
byCACSNETS
 
PPT
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS
bydrfarhanali2008
 
PPTX
pancreatic neuroendocrine tumors
byShankar Zanwar
 
PPTX
Understanding GEP NET Cancer
byBill Claxton
 
PPTX
Pancreatic neuroendocrine tumors
bysuhas k r
 
PPT
Carcinoid Tumour
byAhmed Almumtin
 
PPTX
Neuroendocrine tumors of pancreas
byDr Amit Goswami MS, FNB,FIAGES,FCLS
 
PPTX
Recent advances in lung tumors and tumor like lesions
byEkta Jajodia
 
PPTX
Apu domas & carcinoid syndrome
byDhritiman Chakrabarti
 
PPTX
Benign and malignant tumors of GIT
by리나 카
 
PPTX
Carcinoid tumours of small intestine; surgical aspect
byDaifallah Almansouri
 
PDF
Nets 2008 Carlos F Pinto
byCarlos Frederico Pinto
 
PPTX
Finding the Answer to NET Cancer
byDana-Farber Cancer Institute
 
PDF
C hoeffel imaging of gastroenteropancreatic neuroendocrine tumors jfim hanoi ...
byJFIM - Journées Francophones d'Imagerie Médicale
 
7 capdevila
byEuropean School of Oncology
 
MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours
byEuropean School of Oncology
 
NIH Presentation Nov 2016 Neuroendocrine Tumor Clinical Trials
byCACSNETS
 
Pancreatic neuroendocrine tumours
byAtit Ghoda
 
Radionuclide neuroendocrine tumors functional imaging
byHussein Farghaly
 
5. Carcinoid Tumour Biochemical And Radiological Testing
byensteve
 
Dr Ed. Wolin July 16 2016 DC Neuroendocrine Tumor Support Group Presentation
byCACSNETS
 
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS
bydrfarhanali2008
 
pancreatic neuroendocrine tumors
byShankar Zanwar
 
Understanding GEP NET Cancer
byBill Claxton
 
Pancreatic neuroendocrine tumors
bysuhas k r
 
Carcinoid Tumour
byAhmed Almumtin
 
Neuroendocrine tumors of pancreas
byDr Amit Goswami MS, FNB,FIAGES,FCLS
 
Recent advances in lung tumors and tumor like lesions
byEkta Jajodia
 
Apu domas & carcinoid syndrome
byDhritiman Chakrabarti
 
Benign and malignant tumors of GIT
by리나 카
 
Carcinoid tumours of small intestine; surgical aspect
byDaifallah Almansouri
 
Nets 2008 Carlos F Pinto
byCarlos Frederico Pinto
 
Finding the Answer to NET Cancer
byDana-Farber Cancer Institute
 
C hoeffel imaging of gastroenteropancreatic neuroendocrine tumors jfim hanoi ...
byJFIM - Journées Francophones d'Imagerie Médicale
 

Similar to Neuroendocrine tumors in 2015

PPTX
Gastrointestinal-Pancreatic NET management
byChandan K Das
 
PPTX
Pancreatic Neuroendocrine Tumors
byDr Junish Singh Bagga
 
PPTX
Pancreatic neuro endocrine tumours
bydamuluri ramu
 
PPTX
Carcinoid tumors
byNilesh Kucha
 
PPTX
Neuroendocrine tumors of pancreas
byvipul1992bhu
 
PPT
Pathology NET.ppt
byNirupama kothari
 
PPTX
Neuroendocrine tumors
byBHUSHANBHALGAT1
 
PPT
Rare Solid Cancers: An Introduction - Slide 14 - E. Baudin - Neuroendocrine t...
byEuropean School of Oncology
 
PPTX
Neuroendocrine tumors (Gastroduodenal)
byjrajbomman
 
PPTX
Carcinoid tumor
byadiadochokinesia
 
PPTX
Pancreatic neuroendocrine tumors (pnets)
byDr Priyanka Vishwakarma
 
PPTX
NEUROENDOCRINE TUMORS OF GIT-1 neuro endo
bysurimallasrinivasgan
 
PPTX
Optimizing Neuroendocrine Tumor Outcomes: Closing the Gaps in Diagnosis and Care
byi3 Health
 
PPT
Git endocrine tumors
byMarwa Khalifa
 
PPTX
GI NETs- a type of ppt of gastroenterology neuroendocrine tumors
byshauryagoyal87
 
PPTX
Bea lehming memorial lectures cacs - washington dc 11-15-2014
byCACSNETS
 
PDF
Infographic - Optimizing Neuroendocrine Tumor Outcomes
byi3 Health
 
PPTX
Carcinoid tumor - Descriptive Slides for Undergraduates
byAjilAntony12
 
PPTX
Neuroendocrine tumors by dr. abhishek b po
byyumiizafar0505
 
PPTX
Treatment of Pancreatic Neuroendocrine Neoplasms
byDhaval Mangukiya
 
Gastrointestinal-Pancreatic NET management
byChandan K Das
 
Pancreatic Neuroendocrine Tumors
byDr Junish Singh Bagga
 
Pancreatic neuro endocrine tumours
bydamuluri ramu
 
Carcinoid tumors
byNilesh Kucha
 
Neuroendocrine tumors of pancreas
byvipul1992bhu
 
Pathology NET.ppt
byNirupama kothari
 
Neuroendocrine tumors
byBHUSHANBHALGAT1
 
Rare Solid Cancers: An Introduction - Slide 14 - E. Baudin - Neuroendocrine t...
byEuropean School of Oncology
 
Neuroendocrine tumors (Gastroduodenal)
byjrajbomman
 
Carcinoid tumor
byadiadochokinesia
 
Pancreatic neuroendocrine tumors (pnets)
byDr Priyanka Vishwakarma
 
NEUROENDOCRINE TUMORS OF GIT-1 neuro endo
bysurimallasrinivasgan
 
Optimizing Neuroendocrine Tumor Outcomes: Closing the Gaps in Diagnosis and Care
byi3 Health
 
Git endocrine tumors
byMarwa Khalifa
 
GI NETs- a type of ppt of gastroenterology neuroendocrine tumors
byshauryagoyal87
 
Bea lehming memorial lectures cacs - washington dc 11-15-2014
byCACSNETS
 
Infographic - Optimizing Neuroendocrine Tumor Outcomes
byi3 Health
 
Carcinoid tumor - Descriptive Slides for Undergraduates
byAjilAntony12
 
Neuroendocrine tumors by dr. abhishek b po
byyumiizafar0505
 
Treatment of Pancreatic Neuroendocrine Neoplasms
byDhaval Mangukiya
 

More from Mohamed Abdulla

PPTX
Management of metastatic colorectal cancer
byMohamed Abdulla
 
PPTX
metastatic colorectal cancer; a new chapter in the story
byMohamed Abdulla
 
PPTX
Colon cancer sidedness 2018
byMohamed Abdulla
 
PPTX
ovarian cancer - angiogenesis
byMohamed Abdulla
 
PPTX
Ovarian Cancer; What is Behind the Scene
byMohamed Abdulla
 
PPTX
Msd msi high solid tumors
byMohamed Abdulla
 
PPTX
CRPC management
byMohamed Abdulla
 
PPTX
mHSPC Feb 2023.pptx
byMohamed Abdulla
 
PPTX
Rectal Cancer
byMohamed Abdulla
 
PPTX
Basic principles of cancer immunotherapy
byMohamed Abdulla
 
PPTX
Continuum of care of metastatic colorectal cancer
byMohamed Abdulla
 
PPTX
Role of Apalutamide in management of M0 CRPC
byMohamed Abdulla
 
PPTX
Cancer immunotherapy different modes of action - astra zeneca - jordan
byMohamed Abdulla
 
PPTX
Impact of 1ry tumor location on treatment guidelines of mCRC
byMohamed Abdulla
 
PPTX
Expanding treatment platform in m crc bayer - asyut 2018
byMohamed Abdulla
 
PPTX
BTC - Durvalumab - AZ 2023.pptx
byMohamed Abdulla
 
PPTX
angiogenesis; a key player in all chapters of metastatic crc story2
byMohamed Abdulla
 
PPTX
Prostate cancer the androgenic fortified dogma
byMohamed Abdulla
 
PPTX
Ihof heterogenity &amp; personalized treatment crpc 2019
byMohamed Abdulla
 
PPTX
Astellas meeting, crpc- what we have in 2019
byMohamed Abdulla
 
Management of metastatic colorectal cancer
byMohamed Abdulla
 
metastatic colorectal cancer; a new chapter in the story
byMohamed Abdulla
 
Colon cancer sidedness 2018
byMohamed Abdulla
 
ovarian cancer - angiogenesis
byMohamed Abdulla
 
Ovarian Cancer; What is Behind the Scene
byMohamed Abdulla
 
Msd msi high solid tumors
byMohamed Abdulla
 
CRPC management
byMohamed Abdulla
 
mHSPC Feb 2023.pptx
byMohamed Abdulla
 
Rectal Cancer
byMohamed Abdulla
 
Basic principles of cancer immunotherapy
byMohamed Abdulla
 
Continuum of care of metastatic colorectal cancer
byMohamed Abdulla
 
Role of Apalutamide in management of M0 CRPC
byMohamed Abdulla
 
Cancer immunotherapy different modes of action - astra zeneca - jordan
byMohamed Abdulla
 
Impact of 1ry tumor location on treatment guidelines of mCRC
byMohamed Abdulla
 
Expanding treatment platform in m crc bayer - asyut 2018
byMohamed Abdulla
 
BTC - Durvalumab - AZ 2023.pptx
byMohamed Abdulla
 
angiogenesis; a key player in all chapters of metastatic crc story2
byMohamed Abdulla
 
Prostate cancer the androgenic fortified dogma
byMohamed Abdulla
 
Ihof heterogenity &amp; personalized treatment crpc 2019
byMohamed Abdulla
 
Astellas meeting, crpc- what we have in 2019
byMohamed Abdulla
 

Recently uploaded

PDF
Antibiotics: Cephalosporins & Monobactams.pdf
byPrerana Jadhav
 
PPTX
adrenaldiseases.faciomaxillarysurgery.pptx
byDr Kingshika Joylin
 
PDF
Beta Lactam Antibiotics Penicillin .pdf
byPrerana Jadhav
 
PDF
2. Structural organization of Proteins & denaturation of proteins
byDr. Santhosh Kumar. N
 
PPTX
Pharmacovigilance in Rare Diseases by Sahil Srivastava.pptx
bySahil Srivastava
 
PDF
Tetracycline Antibiotics: Classification & SAR.pdf
byPrerana Jadhav
 
PPTX
FACIAL NERVE AND ITS APPLIED ANATOMY BY Dr. AASTHA DUBEY
byAASTHA DUBEY
 
PPTX
Implant roadmap by Dr mohamed sidky.pptx
byssuseraa4a1e
 
PDF
Ibrutinib 140 mg Capsule Treatment Guide
byLetsMeds
 
PDF
Lenvatinib Tablets: Uses, Benefits, Diseases Treated & Availability in the Ph...
byLetsMeds
 
PPTX
composition, functions of Extra cellular matrix. ECM Proteins, glycoproteins ...
byDr. Santhosh Kumar. N
 
PPTX
Complications of Coronary angiography and PCI.pptx
byVishal Gaurab
 
PDF
Community Pharmacy Chapter Defination, scope of CP 1.pdf
bydhananjaymohite2410
 
PPTX
Obstructed labour presentation & its management
byeswari83
 
PPTX
2025 APVRS-PAO Diplopia After Cataract & Retina Surgery.pptx
byAlvina Pauline Santiago, MD
 
PPTX
SCOPE AND LIMITATIONS OF HOMOEOPATHY IN SURGICAL CONDITIONS
byDR.P.S SUDHAKAR
 
PDF
Partograph: It is a composite graphical recording of cervical dilatation and ...
byMayuriGamit2
 
PDF
UNIT-II Acid Base Titration neutralization curves
bysanjayudps2016
 
PDF
MIndsets in Career of Emergency Medicine
byChing-Hsing Lee
 
PPTX
Surgery instruments for MBBS Students, pptx
bycbmesurgery
 
Antibiotics: Cephalosporins & Monobactams.pdf
byPrerana Jadhav
 
adrenaldiseases.faciomaxillarysurgery.pptx
byDr Kingshika Joylin
 
Beta Lactam Antibiotics Penicillin .pdf
byPrerana Jadhav
 
2. Structural organization of Proteins & denaturation of proteins
byDr. Santhosh Kumar. N
 
Pharmacovigilance in Rare Diseases by Sahil Srivastava.pptx
bySahil Srivastava
 
Tetracycline Antibiotics: Classification & SAR.pdf
byPrerana Jadhav
 
FACIAL NERVE AND ITS APPLIED ANATOMY BY Dr. AASTHA DUBEY
byAASTHA DUBEY
 
Implant roadmap by Dr mohamed sidky.pptx
byssuseraa4a1e
 
Ibrutinib 140 mg Capsule Treatment Guide
byLetsMeds
 
Lenvatinib Tablets: Uses, Benefits, Diseases Treated & Availability in the Ph...
byLetsMeds
 
composition, functions of Extra cellular matrix. ECM Proteins, glycoproteins ...
byDr. Santhosh Kumar. N
 
Complications of Coronary angiography and PCI.pptx
byVishal Gaurab
 
Community Pharmacy Chapter Defination, scope of CP 1.pdf
bydhananjaymohite2410
 
Obstructed labour presentation & its management
byeswari83
 
2025 APVRS-PAO Diplopia After Cataract & Retina Surgery.pptx
byAlvina Pauline Santiago, MD
 
SCOPE AND LIMITATIONS OF HOMOEOPATHY IN SURGICAL CONDITIONS
byDR.P.S SUDHAKAR
 
Partograph: It is a composite graphical recording of cervical dilatation and ...
byMayuriGamit2
 
UNIT-II Acid Base Titration neutralization curves
bysanjayudps2016
 
MIndsets in Career of Emergency Medicine
byChing-Hsing Lee
 
Surgery instruments for MBBS Students, pptx
bycbmesurgery
 

Neuroendocrine tumors in 2015

  • 1.
    ROLE OF TARGETEDTHERAPY IN NEUROENDOCRINE TUMORS Mohamed Abdulla M.D. Prof. of Clinical Oncology Kasr Al-Aini School of Medicine Cairo University Target Therapy: Future Directions Helnan Palestine Hotel Thursday, 30/04/2015
  • 2.
    Origin: Neuroendocrine Cells Neuropeptides Catecholamines Hormonal Syndromes Lawrence B, GustafssonBI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1.
  • 3.
    descendin g colon (<1%) sigmoid colon (- 12%) PrimaryTumor Localizations est. % of all NEN thymus bronchus esophagus stomach duodenum pancreas jejunum/ileum cecum appendix colon rectum <1 15 <1 15 4 15 15 2 15 1 10 thymus (1%) bronchus (-15%) esophagus (<1%) pancreas (-15%) duodenum (-4%) ascending colon (- 1%) jejunum (-5%) ileum (-10%) cecum (-2%) appendix (-15%) rectum (-10%) stomach (-15%) Pape UF, et al. Gastroenterol up2date. 2011;7:313- 339.
  • 4.
  • 5.
    Incidence of NETsIs Increasing* 5 5 SEER = Surveillance, Epidemiology, and End Results (for malignant NETs) *Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry IncidencePer100,000 1.40 Year NET Site 1.20 1.00 0.80 0.60 0.40 0.20 0 Lung Colon Small intestine Rectum Pancreas Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
  • 6.
    Colon Neuroendocrine Stomach 29-yearlimited duration prevalence analyses based on SEER Pancreas Esophagus Hepatobiliary 0 100 1,100 NET Prevalence in the US, 2004 1,200 Median survival (1988 – 2004)103,312 cases (35/100,000) No.ofcases (thousands) Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. NETs Are the 2nd-Most Prevalent Gastrointestinal Tumor: • Localized • Regional • Distant 203 months 114 months 39 months
  • 7.
    NET: Demographics: Lepage C,et al. Gut. 2004;53(4):549-553.
  • 8.
    Niederle MD, etal. Endocr Relat Cancer. 2010;17(4):909-918. Biologicalbehavior Malignant Uncertain Benign NET: Not all the same:
  • 9.
    [TITLE] Presented By PamelaL. Kunz, MD at 2012Annual Meeting
  • 10.
    Key Issues inThe Management: 1. How do we define the disease? Nomenclature, Classification & Pathology. 2. Who needs treatment and when? Patient Selection. 3. Which treatment and in what sequence? Treatments. 4. What is the role of combined biologics, somatostatin analogues, cytotoxics and biomarkers? Unanswered Questions.
  • 11.
    1.How do wedefine the disease? Nomenclature, Classification and Pathology
  • 12.
    Evolution of Terminology& Classification: Historic Evolution: 1907 1963 1970 1980 1995 Carcinoid Williams & Sandler Soga & Tazawa Histologic WHO Granular Stain Techniques Capella Size & Invasion • Benign. • Benign or Low Grade Malignant. • Low Grade Malignant. • High Grade Malignant. No Prognostic or Predictive Validation
  • 13.
    Evolution of Terminology& Classification: Histopathologic Differentiation: Well Differentiated Poorly Differentiated
  • 14.
    Evolution of Terminology& Classification: AJCC Criteria of Grading: Grade Mitotic Count (per 10 HPF) Ki 67 Index (%) G1 < 2 < 2 G2 2 – 20 3 – 20 G3 > 20 > 20 AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
  • 15.
    Evolution of Terminology& Classification: Correlation of Tumor Grade With Survival: 1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Survival Time (mo) 0.0 0.2 0.4 0.6 0.8 1.0 CumulativeSurvival G1 G2 G3 G1 vs G2 G1 vs G3 G2 vs G3 P=0.040 P<0.001 P<0.001 N=193
  • 16.
    Scarpa A, etal. Mod Pathol. 2010;23(6):824- 833. Prognostic Influence of Ki67- Labelling < 2% 15% 75% Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798- 7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221- 232.
  • 17.
    Evolution of Terminology& Classification: Correlation of TNM Staging With Survival: 17 17 La Rosa S, Klersy C, Uccella S, et al. Hum Pathol. 2009;40:30-40. Patients With Well-Differentiated Pancreatic NET Stage I P<0.001 ProportionAlive Stage II Stage III Stage IV I (n = 44) II (n = 44) III (n = 34) IV (n = 33) Time (mo) 0.00 0.25 0.50 0.75 1.00 0 48 96 144 192 240
  • 18.
    Evolution of Terminology& Classification: Metastatic Disease Is Common at Presentation: Localized Metastatic 50% 27% 23% Distant metastases Regional spread Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. *These data are of the cases in which stage was reported. 20% of cases did not provide disease stage information
  • 19.
    Evolution of Terminology& Classification: NETs Are Often Diagnosed Late: Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889. 1 2 3 4 5 6 7 8 9 Time (yr) Primary tumour growth Metastases Flushing Diarrhea Death Vague abdominal symptoms Estimated time to diagnosis: 5 to 7 yr * * *Symptoms of carcinoid syndrome
  • 20.
    2. Role ofBiomarkers & Imaging:
  • 21.
    Pan-neuroendocrine markers Cytosolic NSE,PGP 9.5 Related to secretory granules Chromogranin Related to synaptic vesicles Synaptophysin, VMAT Intermediate filaments NF, CK HMW Adhesion molecules N-CAM Immunohistochemical NE markers:
  • 22.
     Chromogranin A* (in70%-90% increased in metast. NET)  Pancreatic Polypeptide, PP (in 40%-55 % elevated);  a-HCG, β-HCG (in ~ 30% elevated)  Neuron specific enolase (NSE) (in ~33% elevated) *The height of Chromogranin A level correlates with tumor load, an increase over time indicates tumor progression Circulating Tumor Markers:
  • 23.
    CgA correlates withhepatic tumor load Heigher CgA levels indicate lower survival Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827 Prognostic Value of CgA:
  • 24.
    HR = 0.25 95%CI: 0.13-0.51 P = .00004 Median PFS Early response = 13.3 mos. No early response = 7.5 mos. 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 HR = 0.25 95% CI: 0.10-0.58 P = .00062 CgA NSE Median PFS Early response = 8.6 mos. No early response = 2.9 mos. PFS(%) 0 20 40 60 80 100 0 20 40 60 80 100 Time Since Study Start, months Time Since Study Start, months Pts at Risk Pts at Risk Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0 Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0 Yao JC, et al. J Clin Oncol. 2010;28(1):69-76. RADIANT-1 (Stratum I) Predictive Value of Biomarkers: PFS by Early CgA and NSE Responses:
  • 25.
    Modlin IM, etal. Ann Surg Oncol. 2010;17(9):2427-2443. PPI Chronic Atrophic Gastritis PPI H2RAs Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer Chronic atrophic gastritis Pancreatitis Inflammatory bowel disease Irritable bowel syndrome Liver cirrhosis Chronic hepatitis Colon cancer HCC Pancreatic adenocarcinoma Pheochromocytoma Hyperparathyroidism Pituituary tumors Medullary thyroid carcinoma Hyperthyroidism CgA ENDOCRINE DISEASE GASTRO- INTESTINAL DISORDERS NON-GI CANCER Arterial hypertension Cardiac insufficiency Acute coronary syndrome Giant cell arteritis CARDIOVASCULAR DISEASE Systemic rheumatoid arthritis Systemic inflammatory response syndrome Chronic bronchitis Airway obstruction in smokers INFLAMMATORY DISEASES Renal Insufficiency RENAL DISORDERS DRUGS Causes of Chromogranin A Elevation:
  • 26.
    Diagnosis: Imaging PrimaryTumor/Tumor Spread:  Whole body Screening & Staging  Endocrine Pancreatic tumor < 1cm  Routine imaging  Primary tumour Screening & Staging (optional)  Octreoscan (111Indium-DTPA- Octreotide)/ SPECT: 1. choice  Endoscopic ultrasonography  ultrasonography of the liver  CT (+ angiography), MRI  Positron emission tomography (PET) with 11C-5 HTP,11C-L-dopa or 18F-FDG  SMS-R-PET: 68Gallium-DOTATOC- PET  PET/CT ENETS-Guidelines 2011
  • 27.
    3. Therapy forAdvanced Disease
  • 28.
    Therapy of NETs Threeprinciples • Control of hormonal symptoms • Control of tumor growth • Improvement of survival? Symptomatic therapy Surgical therapy Antiproliferative therapy • Cure • Debulking • Treatment / Prevention of complications
  • 29.
    Somatostatin Receptors (SSTR)Are Expressed by the Majority of NETs • SSTR2 is most prevalent in GEP-NETs and induces inhibitory effects on hormone secretion and proliferation in NETs • Somatostatin is effective in controlling NET-related hormonal symptoms • Clinical use of somatostatin is limited by its short half life Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther. 2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat Cancer. 2006;13(3):955-962. Prevalence on NET type: SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Pancreas 68% 95% 46% 93% 57% Midgut 80% 86% 65% 35% 75% Inhibitory effect: Hormone secretion + + + Proliferation + + + + Induction of apoptosis + +
  • 30.
    • Octreotide andlanreotide show high affinity for the SSTR2 and are approved for antisecretory treatment in NETs LAR, long lasting release Susini C, et al. Ann Oncol. 2006;17(12):1733- 1742. Octreotide LAR (10-30 mg / 28 days im) Lanreotide (60-120 mg / 28 days sc) Octreotide (2-3 x 50-500 ug sc / d) Biotherapy of Functional Active NETs With Somatostatin Analogs (SSA) S S a l a g l y ly asn s cys p h e p h e p h e tr p l y s t h r p h e t h r s e r cys D-phe c y s phe l y s c th y r s Octreotide acetate D-trp Thr - ol D-phe c l y s v al c y y s S ty r s Lanreotid e D-trp Thr - NH2 S Somatostatin S S
  • 31.
    Phase III Studyof Octreotide LAR: Patients: • Well-differentiated midgut NET • Treatment-naïve • Locally inoperable or metastasized N = 85 Octreotide LAR 30 mg im/28 days Placebo im/28 days Primary endpoint: • Median time to tumour progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. 1:1 R A N D O M I Z E Secondary endpoints: •Objective tumour response rate • Symptom control • Overall survival Treatment until CT/MRI documented tumour progression or death Randomized, Double-blind, Placebo-controlled Study
  • 32.
    Octreotide LAR 30mg Significantly Prolongs TTP: HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumours; TTP = time to progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. Octreotide LAR vs placebo HR=0.34 P=0.000072 [95% CI: 0.20–0.59] Based on conservative ITT analysis ProportionWithout Progression 1.0 .75 .50 .25 0 0 6 12 18 24 30 36 42 Time (mo) 48 54 60 66 72 78 Octreotide LAR (n = 42) Median 14.3 mo Placebo (n = 43) Median 6.0 mo
  • 33.
    Octreotide LAR 30mg Extends TTP in Patients With Functioning and Nonfunctioning Tumours: 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Based on the per-protocol analysis P=0.0008; HR=0.25 (95% CI: 0.10–0.59) ProportionWithoutProgression P=0.0007; HR=0.23 (95% CI: 0.09–0.57) ProportionWithoutProgression Patients with nonfunctioning tumours Patients with functioning tumours Time (mo)Time (mo) Octreotide LAR 30 mg: 17 pts/11 events Median TTP 14.26 mo Placebo: 16 pts/14 events Median TTP 5.45 mo Octreotide LAR 30 mg: 25 pts/9 events Median TTP 28.8 mo Placebo: 27 pts/24 events Median TTP 5.91 mo 1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508. 2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
  • 34.
    Octreotide LAR: SymptomaticRelief: J Clin Oncol. 2009, 27:4656-4663.
  • 35.
    Lanreotide Acetate inNET: • Patient Characteristics: Clarinet Trial: • Well to Moderately differentiated. • Ki 67 < 10% • Pancreas, mid-gut, hind-gut, or Unknown origin. N Engl J Med 2014;371:224-33.
  • 36.
    The SYM-NET StudyDESIGNASSESSMENTS Anon-interventional cross sectional study to assess SYMptom control in neuroendocrine tumors (NET) Non-interventional, cross-sectional study 273 patients suffering from NET, already treated with lanreotide for at least 3 months and with history of diarrhea due to carcinoid syndrome were enrolled Subject questionnaires Investigator review of medical record Likert scales • Patient satisfaction • Symptom severity • Perception change diarrhea • Feelings about conse- quences on daily life QoL • EORTC C30 • EORTC GI- NET21 Demography Medical history Treatment with lanreotide Diarrhea Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ characteristics • At Tt initiation • Day of visit Other clinical data • At Tt initiation • Day of visit Qol = quality of life
  • 37.
    SYM-NET Study –Results and Conclusion Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ • An improvement was observed for the majority of patients in all symptoms – 76 % patient satisfaction with diarrhea control (primary objective) – 73 % patient satisfaction with flushing control – QoL questionnaires showed a high level of activity capacity and low symptoms score • Patient-reported "subjective" information was consistent with investigator’s observation • Confirms in real life setting the satisfactory effect of lanreotide on symptoms of hormonal excess in GEP- NETs
  • 38.
    Chemotherapy for Well-Differentiated NETsof the Pancreas and Duodenum: Author Turner NC, et al. Br J Cancer. 2010;102(7) 1106-1112. Chemotherapy Pt (n) RR mOS (%) (months) Cheng (1999)1 & Mc Collum (2003)2 STZ + DOX 16 & 16 8 ----- Eriksson (1990)3 Dealunoit (2004)4 Rivera et al. (1998)5 Kouvaraki et al. (2004)6 Turner et al. (2010)7 STZ + DOX STZ + DOX STZ + 5-FU + DOX STZ + 5-FU + DOX STZ + 5-FU + cispl. 84 45 12 84 47 36 ------ 36 24 55 21 39 37 38§ 31.5 1. Cheng PN, et al. Cancer. 1999;86(6):944-948. 2. McCollum AD, et al. Am J Clin Oncol. 2004;27(5):485-488. 3. Eriksson B, et al. J Intern Med. 1990;228(2):103-113. 4. Delaunoit T, et al. Eur J Cancer. 2004;40(4):515- 520. 5. Rivera E, et al. Am J Clin Oncol. 1998;21(1):36-38. 6. Kouvaraki MA, et al. J Clin Oncol. 2004;22(23):4762-4771. 7.
  • 39.
    Chemotherapy for G3NET: NORDIC Trial: Annals of Oncology 24: 152–160, 2013
  • 40.
    Temozolomide in Pancreatic NeuroendocrineCarcinoma Strosberg JR, et al. Cancer 2011;117(2):268-275 Capecitabine Temozolomide every 28 days 750 mg/m2 x 2 x tgl. (days 1– 14) 200 mg/m2 x 1 (days 10–14); n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1 glucagonoma; 1 gastrinoma/glucagonoma 70% PR (RECIST ) Median PFS: 18 months Retrospective analysis G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver enzymes 100 80 60 40 20 0 –20 –40 –60 –80 –100 Progressive Disease Partial Response
  • 41.
    Molecular Events &Therapeutic Implications: 1. Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR
  • 42.
    Neuroendocrinal Tumors: Molecular Events& Therapeutic Implications: 2. mTOR Inhibitor: Mammalian Target of Rapamycin Cellular Growth Protein Synthesis Autophagy Resistance to Apoptosis ++ Proliferation Altered Metabolism
  • 43.
    RADIANT-3 PFS by InvestigatorReview: • P value obtained from stratified 1-sided log-rank test • Hazard ratio is obtained from stratified unadjusted Cox model %Event-free 0 2 4 6 8 10 No. of patients still at risk Kaplan-Meier median PFS Everolimus: Placebo: 11.0 mo 4.6 mo Hazard ratio = 0.35; 95% CI 0.27–0.45 P value: <.0001 PFS rate (18 mos.) Everolimus 34.2% Placebo 8.9% Yao JC, et al. N Engl J Med. 2011;364(6):514- 12 14 16 18 Time (mo) 100 80 Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 60 40 20 0 20 22 24 26 28 30
  • 44.
    RADIANT-3: Treatment-Related G3/4 AE: YaoJC, et al. N Engl J Med. 2011;364(6):514- 523. *Related toxicities grouped for calculation Occurring in >10% Everolimus n = 204 All Grades (%) Grade 3/4 (%) Placebo n = 203 All Grades (%) Grade 3/4 (%) Stomatitis* 64 7 17 0 Rash 49 <1 10 0 Diarrhea 34 3 10 0 Fatigue 31 2 14 <1 Nausea 20 2 18 0 Infections* 23 3 6 1 Peripheral edema 20 <1 3 0 Decreased appetite 20 0 7 1
  • 45.
    RADIANT-2 Study Design: Everolimus10 mg/day + Octreotide LAR 30 mg/28 days n = 216 Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression R A N D O M I Z E 1:1 Multiphasic CT or MRI performed every 12 wk Crossover Primary endpoint: • PFS (RECIST) Secondary endpoints: • Tumour response, OS, biomarkers, safety, PK Enrollment January 2007–May 2008 Phase III, Double-blind, Placebo-controlled Trial Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8. Patients with advanced NET (N=429) • Advanced low- or intermediate- grade NET • Radiologic progression <12 months • History of secretory symptoms (flushing, diarrhea) • Prior antitumour therapy allowed • WHO PS ≤2
  • 46.
    PFS by CentralReview:* Time (mo) No. of patients still at risk E + O P + O 216 213 202 202 167 155 129 117 120 106 102 84 81 72 69 65 63 57 56 50 50 42 42 35 33 24 22 18 17 11 11 9 4 3 1 1 1 0 0 0 * Independent adjudicated central review committee • P-value is obtained from 1-sided log-rank test • HR is obtained from unadjusted Cox model E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 PercentageEvent-free Kaplan-Meier median PFS Everolimus + octreotide LAR: 16.4 mo Placebo + octreotide LAR: 11.3 mo HR = 0.77; 95% CI (0.59–1.00) P=0.026 Total events = 223 Censoring times E + O (n/N = 103/216) P + O (n/N = 120/213) Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
  • 47.
    Subgroup PFS Analysis: *Independentadjudicated central review HR = everolimus + octreotide/placebo + octreotide Unstratified Cox model was used to obtain HR E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR Subgroups (N) Central review *(429) Local investigator review (429) Age group <65 yr (286) ≥65 yr (143) Gender Male (221) Female (208) WHO Performance Status WHO = 0 (251) WHO > 0 (176) Tumour histology grade Well-diff. (341) Moderately diff. (68) Primary tumour site Small intestine (224) Lung (44) Colon (28) Other (132) Prior long-acting SSA Yes (339) No (90) Prior chemotherapy Yes (130) No (299) HR Median PFS (mo) E + O P + O 0.77 16.4 11.3 0.78 12.0 8.6 0.78 19.2 13.0 0.75 13.9 11.0 0.85 13.7 13.0 0.73 17.1 11.1 0.67 21.8 13.9 0.81 13.6 8.3 0.74 18.3 13.0 0.82 13.7 7.5 0.77 18.6 14.0 0.72 13.6 5.6 0.39 29.9 13.0 0.77 14.2 11.0 0.81 14.3 11.1 0.63 25.2 13.6 0.70 13.9 8.7 0.78 19.2 12.0 Hazard Ratio Favors E + O Favors P + O 0 10.4 0.8 1.4 Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
  • 48.
    5050 Sunitinib vs Placeboin Advanced pNET: • Phase III randomized, placebo-controlled, double-blind trial • Trial stopped after early unplanned analysis showed efficacy and safety benefit Primary Endpoint: PFS Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported outcomes Patients with advanced pNET, N = 171/340 patients enrolled Sunitinib 37.5 mg/day orally Continuous daily dosing* n = 86 Placebo* n = 85 *With best supportive care Somatostatin analogues were permitted Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 1:1 R A N D O M I Z E
  • 49.
    51 51 0.8 0.6 0.4 0.2 0 1.0 ProportionofPatients 5 1015 20 250 Sunitinib 39 19 4 0 086Sunitinib 28 7 2 1 085Placebo Number at risk Time (mo) Placebo Kaplan-Meier median PFS Sunitinib: 11.4 mo Placebo: 5.5 mo HR = 0.42 (95% CI, 0.26–0.66) P<0.001 Progression-free Survival:* Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. * Local review
  • 50.
    1.0 PRRT Objective response: Stable disease: Median survival: 34% 5% 94.6 months Openphase II study, 1,109 patients with progressive NET (within 12 months), 2,472 cycles 90Y-DOTA- TOC-therapy, median follow up 23 months • Objective response rates 30% - 40% • Survival benefit in responders likely • Limitations: safety concerns (renal, bone marrow toxicity), limited availability, lacking randomized studies 0 2 4 6 8 10 12 Time Since Start of Treatment, years 14 0.2 0.4 0.6 0.8 OverallSurvival,probability Imhof A, et al. J Clin Oncol. 2011;29(17):2416- 1423. No. of patient s No. of deaths Median survival Hazard ratio P Disease control 671 280 3.8 years 0.41 vs progress <.001 Progress 438 211 1.4 years
  • 53.
    Final Take HomeMessage: • NET not rare. • Surgery is the Cornerstone in Curative Management. • Serum Biomarkers Are Still There to Share. • Tissue Markers Should be more Highlighted. • Molecular Targeted Therapies are The Hope for Tomorrow.