ΕΠΙΘΕΤΙΚΕΣ ΘΕΡΑΠΕΙΕΣ ΑΡΓΑ ΑΝΝΑ ΚΟΥΜΑΡΙΑΝΟΥ MD PhD ΠΑΘΟΛΟΓΟΣ ΟΓΚΟΛΟΓΟΣ ΑΙΜΑΤΟΛΟΓΙΚΗ-ΟΓΚΟΛΟΓΙΚΗ ΜΟΝΑΔΑ Δ’ ΠΑΝΕΠΙΣΤΗΜΙΑΚΗ ΠΑΘΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΓΠΝΑ ΑΤΤΙΚΟΝ NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Approved non-surgical therapies for the treatment of advanced pNET FDA approval: Lanreotide in GEP-NET7 Octreotide Depot 9 FDA approval: Sunitinib in pNET4 1982 1990 2006 2011 2010 2014 2011 2015 FDA approval: SFZ in pNET1,2 FDA/EMA approval: Everolimus in pNET5,6 Temozolomide8 1. Zanosar® (streptozocin) SmPC 2011; 2. Blumenthal GM et al. Oncologist 2012;17:1108–1113; 3. Sutent® (sunitinib) SmPC, 2014; 4. Sutent® (sunitinib) PI 2011; 5. Afinitor® (everolimus) PI 2011; 6. Afinitor® (everolimus) SmPC 2015; 7.Somatuline® depot (lanreotide) PI 2014; 8. Strosberg JR, et al. Gastrointest Cancer Res 2008;2:113-125; 9 Rinke JCO 2009 NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP Στόχοι θεραπείας Achieve best radiological response Stabilise disease Improve overall survival Maintain/improve QoL NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Biology of tumor (WHO classification, grading) Guides management Biology of tumor (WHO classification, grading) Extent of disease (TNM, stage) NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Survival according to differentiation 1.0 G1 0.8 Grading NET* Grade Mitotic count (10 HPF) Ki67 index (%) G1 ≤ 2 G2 3–20 G3 > 20 G2 0.6 Chance of survival 0.4 G1 vs G2 G1 vs G3 G2 vs G3 P = 0.040 P < 0.001 P < 0.001 0.2 Retrospective data from 158 patients with histopathological confirmed diagnosis of gastric, duodenal or pancreatic NET underwent survival analysis according to the ENET/AJCC grading system. The analysis indicated that survival was significantly poorer for patients who had grade 3 tumours compared with patients who had grade 1 and grade 2 tumours and for patients who had grade 2 tumours compared with patients who had grade 1 tumours. References: 1. Rindi G, Klöppel G, Alman 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. G3 0.0 * ENET and AJCC grading system 50 100 150 200 250 Time (months) Rindi G, et al. Virchows Arch. 2006;449:395-401. Rindi G, et al. Virchows Arch. 2007;451:757-762. Pape UF, et al. Cancer. 2008;113:256-265. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 6

TNM classification for GEP-NETs Stage 0* Τis N0 M0 Stage I T1** Stage IIa T2 IIb T3 Stage IIIa T4 IIIb Any Τ Ν1 Μ0 Stage IV Any Ν Μ1 Classification according to the anatomic origin NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Molecular Biology Underlying NET Yao JC, et al. Cancer Res 2013;73:1449-1453.

Radical resection vs. other therapies Radical resection (n= 90) Other therapies (n= 83) p = 0.0001 Median: 40.4 months NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Systemic therapy of advanced pNET: the patient continuum Favour chemotherapy Disease volume Rate of progression Favour targeted therapy/SSA Ki-67 + circulating tumour cells? + molecular profiling? + circulating biomarkers? Figure adapted from Lamarca A et al. TJOP 2014;2:15–25 Diez M et al. Ann Gastroenterol 2013;26(1):29-36

Neuroendocrine Tumors (NET) Most patients are diagnosed with advanced NET. Conventional chemotherapy has limited efficacy for patients with advanced grade 1 & 2 NET. Octreotide LAR and Lanreotide are the first targeted therapies that are historically used for symptom control & prolong time to progression Neuroendocrine tumours can arise in a variety of primary sites in the foregut, midgut, and hindgut regions. The numerous sites of origin demonstrate the heterogeneous nature of the disease. Currently, octreotide LAR is approved by the health authorities for the treatment of secretory symptoms caused by neuroendocrine tumours. However, currently there are no approved agents for anti-tumour therapy for patients with neuroendocrine tumours.   Reference: Yao et al. J Clin Oncol. 2008;26(May 20 suppl):3063-3072. Modlin IM, et al. J Clin Gastroenterol. 2006;40:572-582. Rinke A, et al. J Clin Oncol. 2009;27:4656-4663. Yao JC, et al, J Clin Oncol. 2008;26:3063-3072 11

Somatostatin receptors are highly expressed in NET Somatostatin analogues Targeting somatostatin receptors provides symptom and tumour control References: 1. Susini C, Buscail L. Ann Oncol. 2006;17(12):1733-1742 2. Mougey AM, Adler DG. Hosp Phys. November 2007:12-20,5 3. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Eur J Nucl Med. 1993;20(8):716-731. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

SST 1-5 Expression in NETs   NETs Pancreas Small bowel sst1 68 80 sst2 86 95 sst3 46 65 sst4 93 35 sst5 57 75 sst1 sst2 sst3 sst4 sst5 Kulakasiz et al. ont étudié l’expression des récepteurs sst avec des Ac dans des cellules de TNE in vitro. Nasir A et al. Cancer Control 2006;13: 52 -60 Öberg K et al. Annals Oncol 2004;15:966-973; Kulakasiz H et al. Gut 2002;50:52-60 NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 13

NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP Ασθενής με επεισόδιο flushing NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Antitumoral effects Somatostatin DIRECT EFFECT INDIRECT EFFECT Octreotide Lanreotide sst2 Modulation of immune system (Natural killers) Inhibition of secretion of trophic factors Arrest of cell cycle Cell death by apoptosis L’effet antitumoral de la somatostatine peut être direct ou indirect. On entend par « effets directs » la régulation par la somatostatine via son interaction avec un ou plusieurs de ses récepteurs exprimés à la surface de la cellule tumorale cible, de voies de signalisation conduisant à une inhibition de la progression tumorale (arrêt du cycle cellulaire, induction de l’apoptose), stimulée par des facteurs de croissance que la cellule tumorale sécrète elle-même ou présents dans son microenvironnement au sein de la tumeur. On entend par « effet indirect » l’inhibition par la somatostatine de la sécrétion de facteurs trophiques pro-tumoraux (de croissance, angiogénique) sécrétés par les cellules tumorales ou des cellules du microenvironnement qui jouent un rôle dans la progression tumorale (notamment les cellules endothéliales et le système immunitaire). Inhibition of growth factors Inhibition of angiogenesis (VEGF) Buscail et al 1994, Sharma et al. 1998, Danesi et al. 1997, Albini et al. 1998, Pages et al. 1999, Florio et al 2003 NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 15

NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP Dong M, et al. Clin Cancer Res 2012;18:1830-1836

Octreotide LAR 30 mg extends TTP in patients with functioning or non-functioning tumours Patients with non-functioning tumours Patients with functioning tumours Octreotide LAR: 25 patients / 9 events Median TTP 28.8 months Placebo: 27 patients / 24 events Median TTP 5.91 months Octreotide LAR: 17 patients / 11 events Median TTP 14.26 months Placebo: 16 patients / 14 events Median TTP 5.45 months 1 1 0.75 0.75 0.5 0.5 Proportion without progression Proportion without progression . 0.25 0.25 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time (months) Time (months) P=0.0008; HR=0.25 [95% CI: 0.10–0.59] P=0.0007; HR=0.23 [95% CI: 0.09–0.57] Rinke A et al. J Clin Oncol 2009

NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP Somatostatin analogs Μονοθεραπεία Αναβολή επιθετικών θεραπειών για αργότερα NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Management of locoregional unresectable and/or metastatic disease Distant metastases IMAGING Multiphasic CT or MRI Consider Octreoscan BIOCHEMICAL Consider 5-HIAA Consider CgA Complete resection possible Asymptomatic Low tumor burden Locally symptomatic from primary tumor Clinically significant tumor burden Carcinoid syndrome Resect Primary + metastases Observe with markers and imaging every 3-6 mo or SSA’s Consider Resection of Primary tumor SSA’s ECHOcardiogram Clinically Significant Progressive disease *SSAs, if not already receiving Consider hepatic regional therapy: - Arterial embolization - Chemoembolization - Radioembolization - Ablative therapy) Consider Cytoreductive surgery Consider everolimus 10mg/day Consider chemotherapy if no other options feasible

Management of locoregional unresectable and/or metastatic disease Locoregional unresectable disease and/or distant metastases Complete resection possible Asymptomatic Low tumor burden and STABLE disease Symptomatic or Clinically significant tumor burden or Clinically significant progressive disease Resect Primary + metastases Observe with markers and imaging every 3-12 months Manage clinically significant symptoms as appropriate Clinically Significant Progressive disease Everolimus 10mg/day Sunitinib 37,5mg/day Cytotoxic Chemotherapy Hepatic regional therapy - Arterial ermbolization - Chemoembolization - Radioembolization - Ablative therapy Cytoreductive surgery Consider SSA’s if not already receiving Lanreotide NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Stage IV NETs – ηπατικέs μεταστάσεις NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Treatment Decisions in GEP-NETs Options may depend on: Type of GEP-NET TNM stage (I-IV), degree hepatic involvement Tumor grade (G1-3) Functional status of tumour Growth rate Presence familial syndrome (MEN1) Patient: organ function, ECOG PS, comorbidity Access to various options ECOG: Eastern Cooperative Oncology Group; PS: performance status NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 24

Treatment Decisions in GEP-NETs Treatment decisions require discussion by a multidisciplinary team Options may depend on: Type of GEP-NET TNM stage (I-IV), degree hepatic involvement Tumor grade (G1-3) Functional status of tumour Growth rate Presence familial syndrome (MEN1) Patient: organ function, ECOG PS, comorbidity Access to various options ΔΙΕΠΙΣΤΗΜΟΝΙΚΗ ΟΜΑΔΑ ΚΑΙ ΟΓΚΟΛΟΓΙΚΑ ΣΥΜΒΟΥΛΙΑ!!! ECOG: Eastern Cooperative Oncology Group; PS: performance status NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 25

Systemic therapy of advanced pNET: the patient continuum Favour chemotherapy Disease volume Rate of progression Favour targeted therapy/SSA Ki-67 + circulating tumour cells? + molecular profiling? + circulating biomarkers? Figure adapted from Lamarca A et al. TJOP 2014;2:15–25 Diez M et al. Ann Gastroenterol 2013;26(1):29-36

Systemic therapy of advanced pNET: the patient continuum Favour chemotherapy Disease volume Rate of progression Favour targeted therapy/SSA Ki-67 Figure adapted from Lamarca A et al. TJOP 2014;2:15–25 Diez M et al. Ann Gastroenterol 2013;26(1):29-36

Treatment options for advanced pNET Advanced/inoperable Via MDT – consider clinical trials G1/G2 G3 Somatostatin analogs Chemotherapy Chemotherapy Platinum/etoposide Streptozocin-based; Temozolomide/capecitabine Targeted agent Everolimus Sunitinib PRRT (if uptake on scan) 177-Lu 90-Y 131-MIBG Liver-directed Surgical: transplantation/resection Embolic: HAE/TACE /RE

GEP NET Functioning SS analogs GI NET Non-functioning Functioning pNET Investigational drugs ** Functioning SS analogs High volume* Slow growth SS analogs Investigational drugs Chemotherapy PRRT GI NET High volume* Rapid growth Non-functioning Everolimus ? PRRT Low volume Rapid growth Low volume Slow growth SS analogs GEP NET Functioning SS analogs, PPi, everolimus High volume Slow growth* MT** pNET PRRT Investigational drugs Second line chemotherapy High volume* Rapid growth Chemotherapy Non-functioning Low volume Rapid growth *Cytoreductive techniques **MT=Molecular targeted therapy Low volume Slow growth MT** NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

Treatment decisions: criteria for choosing the right systemic treatment for advanced pNET Criteria for choosing chemotherapy Criteria for choosing somatostatin analogues Criteria for choosing targeted therapies Bulky disease More rapid disease progression G2/G3 tumours (occasionally G1 tumours) Radiological response required Functional tumours Low-volume disease G1 and subset of G2 (Ki67 <10%) Little/no disease progression Aim is to delay time to disease progression Low-volume disease G1/G2 tumours (Ki67 <20%) Low rate of disease progression Aim is to delay time to disease progression

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NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP