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Neuroendocrine Tumors in 2019

1. Neuroendocrine tumors (NETs) are increasing in incidence and are often metastatic at diagnosis. They originate from neuroendocrine cells and secrete hormones. 2. Somatostatin analogues are first-line treatment for symptomatic control in NETs but resistance can develop. Chemotherapy has limited efficacy except in high-grade tumors. 3. Emerging biomarkers and molecular targeted therapies such as inhibitors of angiogenesis are improving outcomes beyond traditional approaches.

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Neuroendocrine Tumors Management & Treatment Update Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Sandostatin LAR Launch Event Sofitel Hotel, Cairo Thursday, 20/12/2018
Member of Advisory Board, Consultant, and Speaker for: • Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly Speaker Disclosures:
NEN Classification: As Time Goes By… Siegfried Oberndorfer WHO 1980 WHO AJCC/WHO 2000 ENETS UICC 2010 UICC & WHO 2017 1907 1963 1980 1995 2000 2006/7 2009 2010 2017 AJCC, American Joint Committee on Cancer; ENETS, European Neuroendocrine Tumor Society; UICC, Union for International Cancer Control
Origin of NET: Neuro Endocrine DCGs No Synapse Mono-Amines  SSTR Oronsky et al. Neoplasia (2017) 19, 991–1002 Schimmack et al. March 2011. Langenbeck s Archives of Surgery 396(3):273-98
NEN: On the Rise! Dasari A, et al. JAMA Oncol. 2017;3(10):1335-1342.
Incidence of NEN: The SEER Data Modlin IM, et al. Cancer. 2003;97(4):934-959. Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. AI/AN, American Indian/Alaskan native; ERG, End Results Group; SEER, Surveillance, Epidemiology, and End Results Program; TNCS, Third National Cancer Survey
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.
NEN Diagnosis: A Matter ofAge? Quaedvlieg PF, et al. Ann Oncol. 2001;12(9):1295-1300. 700 600 500 400 300 200 100 0 11- 15 16- 20 21- 30 31- 40 41- 50 51- 60 61- 70 71 - 80 >81 Age, Years Lepage C, et al. Gut.2004;53(4):549-553. Ratesper100,000 Plöckinger U, et al. Neuroendocrinology. 2009; 90(2):159-61.
NEN: Incidence Specifics Huguet I, et al. Neuroendocrinology. 2017;104(2):105-111. Niederle MB, et al. Endocr Relat Cancer. 2010;17(4):909-918.
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 registriesYao 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
Hormonal Syndrome in NET:
Altered Tryptophan Metabolism in NET Tryptophan 5-Hydroxytryptophan Serotonin Tryptophan Hydroxylase Aromatic L-Amino Acid Decarboxylase G Blood Stream Platelets5-HIAA Monoamine Oxidase Aldehyde Dehydrogenase
GH TSH Insulin Glucagon Somatostatin Enzymes Bicarbonates Gastrin Secretin CCK VIP Motilin Neurotensin Gastric acid Pepsin Blood flow Motility Nutrient, ion absorption Mucosal proliferation T4 T3 Calcitonin Excitation of many neurons General arousal Hyperkinesia Rigidity Catalepsy Autonomic effects Patel YC. General aspects of the biology and function of somatostatin. In: Somatostatin. Basic and Clinical Aspects of Neuroscience, vol 4. Berlin, Heidelberg: Springer; 1992. Somatostatin Principal Actions of Somatostatin
Pathogenesis of Carcinoid: TRYPTOPHAN METABOLISM NORMAL NET 1% SEROTONIN 70% SEROTONIN FOREGUT MIDGUT HINDGUT Aromatic L- Amino Acid Decarboxylase
Somatostatin Receptors Baledelli et al. Frontiers in Endocrinology. February 2014 | Volume 5 | Article 7
Pathogenesis of Carcinoid
Carcinoid Heart Disease: • 50% of all cases • 20% at presentation • CHF • Valve surgery is the only approved treatment
Halperin et al: Lancet Oncol 2017; 18: 525–34 Entire Group of NET Patients G 1 – 2 NET Patients
Biomarker Dilemma: Oberg et al. Lancet Oncol 2015; 16: e435–46
Chromogranin A (CgA): A Marker of DiseaseBurden... Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827. Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Welin S, et al. Cancer. 2011;117(20):4617- 4622. Korse CM, et al. Eur J Cancer. 2012;48(5):662-671. ... & Differentiation Somatostatin receptor expression
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:
Categories of Circulating Neuroendocrine Neoplasia Biomarkers Oberg et al. Lancet Oncol 2015; 16: e435–46
NET – Test: Modlin et al. Endocrine Connections. (2014)3,215-223 PCR-based 51-transcript signature to detect tumors
NET – Test: “Correct Prediction” Modlin et al. Endocrine Connections. (2014)3,215-223 APP, appendix; CgA, chromogranin A; CR, colorectum; CUP, carcinoid of unknown primary; DUO, duodenum; G, gastric; GEP-NET, gastroenteropancreatic NET; PANC, pancreas; SI, small intestine.
NET Test: “False Positive Results” Modlin et al. Endocrine Connections. (2014)3,215-223
Principals of Syndrome Management 1. Reduce hormone secretion/productionHormones 2. Reduce effects of secreted hormones NET 3. Control tumor growth Clinical signs/symptoms related to hormone excess
Human Somatostatin Versus Synthetic OctapeptideAnalogue Octreotide S S Human somatostatin ala gly cys lys asn phe phe trp lys thr phe thrcys ser Amino acids essential for receptor binding S S ph e cys cys thr lys D trp D ph e thr - ol SST1 none SST2 high SST3 none SST4 none SST5 moderate 1993-1995 SST binding affinity 1982-1988 Octreotide / Lanreotide “classical SSA” SSA, somatostatin analogue Personal data
Diarrhea: 42% mean reduction Flushing: 84% mean reduction Rubin et al, J Clin Oncol, 1999
SSA-resistant Carcinoid Syndrome ◆ Tachyphylaxis to SSA develops in some 6-18 months ― Downregulation or internalization of SSTR ― Upregulation of other SSTR subtypes ― Variable SSTR phosphorylation patients after ― Heterodimerization of SSTR with other receptors Oberg, Clin Oncol, 2012; Susini & Buscail, Ann Oncol, 2006; Loughrey et al, Endocrinol Metab Clin N Am, 2018
◆ Retrospective chart review of 239 patients who received octreotide LAR > 30 mg/month – – – 62% of pts had dose escalation for control of syndrome 73/90 (81%) pts noted improvement/resolution in flushing 85/107 (79%) pts noted improvement/resolution in diarrhea Strosberg et al, Oncologist 2014
SSAs: Antiproliferative Efficacy CR, complete response; PR, partial response; SD, stable diseaseToumpanakis C, Caplin ME. Semin Oncol. 2013;40(1):56-68. Study Number of Patien ts SSA SD % PR/CR % Arnold, et al. 52 Octreotide 36 -- Saltz, et al. 34 Octreotide 50 -- di Bartolomeo, et al. 58 Octreotide 46 PR: 3 Ricci, et al. 15 Octreotide 40 PR: 7 Aparicio, et al. 35 Octreotide/lanreotide 57 -- Faiss, et al. 30 Lanreotide 37 PR: 3.3 CR: 3.3 Faiss, et al. 25 Lanreotide 28 PR: 4 Ducreaux, et al. 39 Lanreotide 48.7 PR: 5 Bianchi, et al. 23 Lanreotide autogel 65.3 8.7 Massuti, et al. 30 Lanreotide autogel 88.9 3.7
SSAs: Benefits and Challenges • Symptom relief for flushing and/ or diarrhea in 60%-80% of the patients with CS or functioning pNET • Low toxicity and good long-term tolerability • Convenient application once monthly • High tumor burden • Tachyphylaxis • Insulinoma (paradoxical effects) • Prevention of CHD? • Moderate decrease of biomarkers (eg, 5-HIAA) • No value in SSTR-negative NET LimitationsBenefits CHD, coronary heart disease
Consensus Guidelines for Carcinoid Syndrome ENETS 20161 Carcinoid Syndrome or NCCN 20182 1. 2. Pavel et al. Neuroendocrinology 2016;103:172–85. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. Version 3.2018 – Sept 11, 2018 Octreotide Lanreotide
Objective response rate: <20 % n = 367 STZ, streptozotocin; 5FU, 5-flurouracil; DOX, doxorubicin Moertel CG, et al. Cancer Clin Trials. 1979;2(4):327-334. Engstrom PF, et al. J Clin Oncol. 1984;2(11):1255-1259. Bukowski RM, et al. Cancer. 1987;60(12):2891-2895. Sun W, et al. J Clin Oncol. 2005;23(22):4897-4904. Öberg K, Chemotherapy Is Not Effective in NETs Grade 1/ Grade 2 of the Midgut (Carcinoids)Reference Type of tumor Regimen No. of patients Objective response Response duration (months) Median survival (months) Moertel and Carcinoids 5FU + cyclophosphamide 47 33 – – Hanley STZ + 5FU 42 33 – – Engstrom et al Carcinoids STZ + 5FU 80 22 8 16 DOX 81 21 6.5 12 Bukowski et al Carcinoids STZ + DOX + 5FU + cyclophosphamide STZ + 5FU + 56 9 31 22 – – – 10.8 cyclophosphamide Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7 STZ + 5FU 27 16 5.3 24.3
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: Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA. J Clin Oncol. 2008;26(8):1316.
https://f6publishing.blob.core.windows.net/f93a39ca- 2719- 42d5-a41d-4cd9c9803317/WJCO-7-149-g001.jpg Sunitinib Octreotide , lanreotide pasireotide 177-Lu DOTATATE 90Y- DOTATOC Everolimu s Pazopanib Cabozantinib Lenvatinib Axitinib Cell proliferation Cell survival IFN-a receptor 1 IFN-a receptor 2 TYK2 JAK1 Interferon-α Targeted Therapies in NETs VEGF Bevacizumab
OS benefit (n.s.) 148 (73%) crossed over to open label Everolimus Yao JC, et al. N Engl J Med. 2011;364(6):514-523. Yao JC, et al. J Clin Oncol. 2016;364(6):514-523. Primary endpoint PFS significantly prolonged Everolimus in pNETs Placebo-Controlled Trial in 410 Patients With pNETs (RADIANT-3)
Everolimus in Nonpancreatic NETs Everolimus vs Placebo in nonfunctioning GI and lung NETs (RADIANT-4; primary endpoint met) Everolimus +/- pasireotide in lung and thymic NETs (LUNA) Everolimus + octreotide in carcinoids with carcinoid syndrome (RADIANT-2; primary endpoint not met)
Everolimus in Advanced Nonfunctional NETs of the Lung or GI Tract: RADIANT-4 Study Yao JC, et al. Lancet. 2016;387(1022):968-977. Primary Endpoint PFS significantly prolonged 302 patients; EVE vs PLB 2:1 randomization PFS 11 months (EVE) vs 3.9 months (PLB) Interim OS analysis in favor of everolimus
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.
Everolimus: Real World Trial: • Med PFS = 12 months • Med OAS = 32 months • Pancreatic = Non Pancreatic
A Watch & Wait Strategy Seems to be Justified in… Nonfunctioning tumor in patients with • Low tumor burden • Low proliferative activity of the tumor (NET G1, low G2) • Stable disease patients • and those not being afraid of it…. (patients and physicians…)
Don’t Forget NET & NOT Adenocarcinoma with Neuroendocrine Differentiation in Histopathology (Synaptophysin - Crg)M0 M1 Possible R0 Surgery + Follow Up R1/Irresectable G 1 G 2 G 3 • mTOR – LASRA • TKI • PRRT • Clinical Trial Chemotherapy: • Platinum/Etoposide • Capecitabine/Temodal • Streptozocin/5-Fu
Summary and Conclusions • SSAs (octreotide and lanreotide) are established therapies for syndrome control and inhibition of tumor growth in low grade tumors • Frequently, SSAs are used as first-line antiproliferative therapy in patients with unknown growth behavior or slowly growing (G1/low G2) tumors, particularly in GI and pNETs • Watch and wait policy may be applied in indolent nonfunctioning NETs with low grade and low tumor burden • Targeted drugs (everolimus and sunitinib) and PRRT represent treatment options in progressive disease
Thank You

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Neuroendocrine Tumors in 2019

  • 1.
    Neuroendocrine Tumors Management &Treatment Update Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Sandostatin LAR Launch Event Sofitel Hotel, Cairo Thursday, 20/12/2018
  • 2.
    Member of AdvisoryBoard, Consultant, and Speaker for: • Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly Speaker Disclosures:
  • 4.
    NEN Classification: AsTime Goes By… Siegfried Oberndorfer WHO 1980 WHO AJCC/WHO 2000 ENETS UICC 2010 UICC & WHO 2017 1907 1963 1980 1995 2000 2006/7 2009 2010 2017 AJCC, American Joint Committee on Cancer; ENETS, European Neuroendocrine Tumor Society; UICC, Union for International Cancer Control
  • 5.
    Origin of NET: NeuroEndocrine DCGs No Synapse Mono-Amines  SSTR Oronsky et al. Neoplasia (2017) 19, 991–1002 Schimmack et al. March 2011. Langenbeck s Archives of Surgery 396(3):273-98
  • 6.
    NEN: On theRise! Dasari A, et al. JAMA Oncol. 2017;3(10):1335-1342.
  • 7.
    Incidence of NEN:The SEER Data Modlin IM, et al. Cancer. 2003;97(4):934-959. Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. AI/AN, American Indian/Alaskan native; ERG, End Results Group; SEER, Surveillance, Epidemiology, and End Results Program; TNCS, Third National Cancer Survey
  • 8.
    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.
  • 9.
    NEN Diagnosis: AMatter ofAge? Quaedvlieg PF, et al. Ann Oncol. 2001;12(9):1295-1300. 700 600 500 400 300 200 100 0 11- 15 16- 20 21- 30 31- 40 41- 50 51- 60 61- 70 71 - 80 >81 Age, Years Lepage C, et al. Gut.2004;53(4):549-553. Ratesper100,000 Plöckinger U, et al. Neuroendocrinology. 2009; 90(2):159-61.
  • 10.
    NEN: Incidence Specifics HuguetI, et al. Neuroendocrinology. 2017;104(2):105-111. Niederle MB, et al. Endocr Relat Cancer. 2010;17(4):909-918.
  • 11.
    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 registriesYao 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
  • 12.
  • 13.
    Altered Tryptophan Metabolismin NET Tryptophan 5-Hydroxytryptophan Serotonin Tryptophan Hydroxylase Aromatic L-Amino Acid Decarboxylase G Blood Stream Platelets5-HIAA Monoamine Oxidase Aldehyde Dehydrogenase
  • 14.
    GH TSH Insulin Glucagon Somatostatin Enzymes Bicarbonates Gastrin Secretin CCK VIP Motilin Neurotensin Gastric acid Pepsin Blood flow Motility Nutrient,ion absorption Mucosal proliferation T4 T3 Calcitonin Excitation of many neurons General arousal Hyperkinesia Rigidity Catalepsy Autonomic effects Patel YC. General aspects of the biology and function of somatostatin. In: Somatostatin. Basic and Clinical Aspects of Neuroscience, vol 4. Berlin, Heidelberg: Springer; 1992. Somatostatin Principal Actions of Somatostatin
  • 15.
    Pathogenesis of Carcinoid: TRYPTOPHANMETABOLISM NORMAL NET 1% SEROTONIN 70% SEROTONIN FOREGUT MIDGUT HINDGUT Aromatic L- Amino Acid Decarboxylase
  • 16.
    Somatostatin Receptors Baledelli etal. Frontiers in Endocrinology. February 2014 | Volume 5 | Article 7
  • 17.
  • 18.
    Carcinoid Heart Disease: •50% of all cases • 20% at presentation • CHF • Valve surgery is the only approved treatment
  • 20.
    Halperin et al:Lancet Oncol 2017; 18: 525–34 Entire Group of NET Patients G 1 – 2 NET Patients
  • 21.
    Biomarker Dilemma: Oberg etal. Lancet Oncol 2015; 16: e435–46
  • 22.
    Chromogranin A (CgA):A Marker of DiseaseBurden... Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827. Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Welin S, et al. Cancer. 2011;117(20):4617- 4622. Korse CM, et al. Eur J Cancer. 2012;48(5):662-671. ... & Differentiation Somatostatin receptor expression
  • 23.
    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:
  • 25.
    Categories of Circulating NeuroendocrineNeoplasia Biomarkers Oberg et al. Lancet Oncol 2015; 16: e435–46
  • 26.
    NET – Test: Modlinet al. Endocrine Connections. (2014)3,215-223 PCR-based 51-transcript signature to detect tumors
  • 27.
    NET – Test: “CorrectPrediction” Modlin et al. Endocrine Connections. (2014)3,215-223 APP, appendix; CgA, chromogranin A; CR, colorectum; CUP, carcinoid of unknown primary; DUO, duodenum; G, gastric; GEP-NET, gastroenteropancreatic NET; PANC, pancreas; SI, small intestine.
  • 28.
    NET Test: “False PositiveResults” Modlin et al. Endocrine Connections. (2014)3,215-223
  • 29.
    Principals of SyndromeManagement 1. Reduce hormone secretion/productionHormones 2. Reduce effects of secreted hormones NET 3. Control tumor growth Clinical signs/symptoms related to hormone excess
  • 30.
    Human Somatostatin VersusSynthetic OctapeptideAnalogue Octreotide S S Human somatostatin ala gly cys lys asn phe phe trp lys thr phe thrcys ser Amino acids essential for receptor binding S S ph e cys cys thr lys D trp D ph e thr - ol SST1 none SST2 high SST3 none SST4 none SST5 moderate 1993-1995 SST binding affinity 1982-1988 Octreotide / Lanreotide “classical SSA” SSA, somatostatin analogue Personal data
  • 31.
    Diarrhea: 42% mean reduction Flushing:84% mean reduction Rubin et al, J Clin Oncol, 1999
  • 37.
    SSA-resistant Carcinoid Syndrome ◆Tachyphylaxis to SSA develops in some 6-18 months ― Downregulation or internalization of SSTR ― Upregulation of other SSTR subtypes ― Variable SSTR phosphorylation patients after ― Heterodimerization of SSTR with other receptors Oberg, Clin Oncol, 2012; Susini & Buscail, Ann Oncol, 2006; Loughrey et al, Endocrinol Metab Clin N Am, 2018
  • 38.
    ◆ Retrospective chartreview of 239 patients who received octreotide LAR > 30 mg/month – – – 62% of pts had dose escalation for control of syndrome 73/90 (81%) pts noted improvement/resolution in flushing 85/107 (79%) pts noted improvement/resolution in diarrhea Strosberg et al, Oncologist 2014
  • 39.
    SSAs: Antiproliferative Efficacy CR,complete response; PR, partial response; SD, stable diseaseToumpanakis C, Caplin ME. Semin Oncol. 2013;40(1):56-68. Study Number of Patien ts SSA SD % PR/CR % Arnold, et al. 52 Octreotide 36 -- Saltz, et al. 34 Octreotide 50 -- di Bartolomeo, et al. 58 Octreotide 46 PR: 3 Ricci, et al. 15 Octreotide 40 PR: 7 Aparicio, et al. 35 Octreotide/lanreotide 57 -- Faiss, et al. 30 Lanreotide 37 PR: 3.3 CR: 3.3 Faiss, et al. 25 Lanreotide 28 PR: 4 Ducreaux, et al. 39 Lanreotide 48.7 PR: 5 Bianchi, et al. 23 Lanreotide autogel 65.3 8.7 Massuti, et al. 30 Lanreotide autogel 88.9 3.7
  • 40.
    SSAs: Benefits and Challenges •Symptom relief for flushing and/ or diarrhea in 60%-80% of the patients with CS or functioning pNET • Low toxicity and good long-term tolerability • Convenient application once monthly • High tumor burden • Tachyphylaxis • Insulinoma (paradoxical effects) • Prevention of CHD? • Moderate decrease of biomarkers (eg, 5-HIAA) • No value in SSTR-negative NET LimitationsBenefits CHD, coronary heart disease
  • 41.
    Consensus Guidelines forCarcinoid Syndrome ENETS 20161 Carcinoid Syndrome or NCCN 20182 1. 2. Pavel et al. Neuroendocrinology 2016;103:172–85. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. Version 3.2018 – Sept 11, 2018 Octreotide Lanreotide
  • 42.
    Objective response rate:<20 % n = 367 STZ, streptozotocin; 5FU, 5-flurouracil; DOX, doxorubicin Moertel CG, et al. Cancer Clin Trials. 1979;2(4):327-334. Engstrom PF, et al. J Clin Oncol. 1984;2(11):1255-1259. Bukowski RM, et al. Cancer. 1987;60(12):2891-2895. Sun W, et al. J Clin Oncol. 2005;23(22):4897-4904. Öberg K, Chemotherapy Is Not Effective in NETs Grade 1/ Grade 2 of the Midgut (Carcinoids)Reference Type of tumor Regimen No. of patients Objective response Response duration (months) Median survival (months) Moertel and Carcinoids 5FU + cyclophosphamide 47 33 – – Hanley STZ + 5FU 42 33 – – Engstrom et al Carcinoids STZ + 5FU 80 22 8 16 DOX 81 21 6.5 12 Bukowski et al Carcinoids STZ + DOX + 5FU + cyclophosphamide STZ + 5FU + 56 9 31 22 – – – 10.8 cyclophosphamide Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7 STZ + 5FU 27 16 5.3 24.3
  • 43.
    Chemotherapy for G3NET: NORDIC Trial: Annals of Oncology 24: 152–160, 2013
  • 44.
    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
  • 45.
    Molecular Events &Therapeutic Implications: Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA. J Clin Oncol. 2008;26(8):1316.
  • 46.
    https://f6publishing.blob.core.windows.net/f93a39ca- 2719- 42d5-a41d-4cd9c9803317/WJCO-7-149-g001.jpg Sunitinib Octreotide , lanreotide pasireotide 177-LuDOTATATE 90Y- DOTATOC Everolimu s Pazopanib Cabozantinib Lenvatinib Axitinib Cell proliferation Cell survival IFN-a receptor 1 IFN-a receptor 2 TYK2 JAK1 Interferon-α Targeted Therapies in NETs VEGF Bevacizumab
  • 47.
    OS benefit (n.s.) 148(73%) crossed over to open label Everolimus Yao JC, et al. N Engl J Med. 2011;364(6):514-523. Yao JC, et al. J Clin Oncol. 2016;364(6):514-523. Primary endpoint PFS significantly prolonged Everolimus in pNETs Placebo-Controlled Trial in 410 Patients With pNETs (RADIANT-3)
  • 48.
    Everolimus in NonpancreaticNETs Everolimus vs Placebo in nonfunctioning GI and lung NETs (RADIANT-4; primary endpoint met) Everolimus +/- pasireotide in lung and thymic NETs (LUNA) Everolimus + octreotide in carcinoids with carcinoid syndrome (RADIANT-2; primary endpoint not met)
  • 49.
    Everolimus in AdvancedNonfunctional NETs of the Lung or GI Tract: RADIANT-4 Study Yao JC, et al. Lancet. 2016;387(1022):968-977. Primary Endpoint PFS significantly prolonged 302 patients; EVE vs PLB 2:1 randomization PFS 11 months (EVE) vs 3.9 months (PLB) Interim OS analysis in favor of everolimus
  • 50.
    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
  • 51.
    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.
  • 52.
    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.
  • 53.
    Everolimus: Real WorldTrial: • Med PFS = 12 months • Med OAS = 32 months • Pancreatic = Non Pancreatic
  • 54.
    A Watch &Wait Strategy Seems to be Justified in… Nonfunctioning tumor in patients with • Low tumor burden • Low proliferative activity of the tumor (NET G1, low G2) • Stable disease patients • and those not being afraid of it…. (patients and physicians…)
  • 55.
    Don’t Forget NET &NOT Adenocarcinoma with Neuroendocrine Differentiation in Histopathology (Synaptophysin - Crg)M0 M1 Possible R0 Surgery + Follow Up R1/Irresectable G 1 G 2 G 3 • mTOR – LASRA • TKI • PRRT • Clinical Trial Chemotherapy: • Platinum/Etoposide • Capecitabine/Temodal • Streptozocin/5-Fu
  • 56.
    Summary and Conclusions •SSAs (octreotide and lanreotide) are established therapies for syndrome control and inhibition of tumor growth in low grade tumors • Frequently, SSAs are used as first-line antiproliferative therapy in patients with unknown growth behavior or slowly growing (G1/low G2) tumors, particularly in GI and pNETs • Watch and wait policy may be applied in indolent nonfunctioning NETs with low grade and low tumor burden • Targeted drugs (everolimus and sunitinib) and PRRT represent treatment options in progressive disease
  • 57.