NET MASTERCLASS 2017

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1 NET MASTERCLASS 2017 NET εντέρου Κατευθυντήριες Οδηγίες και Αλληλουχία Θεραπειών Β. Μιχαλάκη Παθολόγος Ογκολόγος Β Χειρουργική Κλινική ΕΚΠΑ Αρεταίειο Νοσοκομείο

ENETS GUIDELINES ENETS GUIDELINES 2016 1. Rindi et al.

2 ENETS GUIDELINES ENETS GUIDELINES Rindi et al. Neuroendocrinology 2006; 2. Rindi et al. Virchows Arch 2007; 3. Salazar et al. Neuroendocrinology 2012

3 ENETS 2016 Consensus Guidelines (GEP)

4 ENETS CONSENSUS GUIDELINES UPDATE FOR NEUROENDOCRINE NEOPLASMS OF THE JEJUNUM AND ILEUM B. NIEDERLEA U.-F. PAPEB F. COSTAC D. GROSSD F. KELESTIMURE U. KNIGGEF K. ÖBERGG PAVELB A. PERRENH C. TOUMPANAKISI J. O CONNORJ D. O TOOLEK E. KRENNINGL REEDM R. KIANMANESHN ALL OTHER VIENNA CONSENSUS CONFERENCE PARTICIPANTS

5 NEUROENDOCRINE NEOPLASMS (NENS) OF THE SMALL INTESTINE /SI- NENS) SI-NENS DERIVE FROM SEROTONIN-PRODUCING ENTEROCHROMAFFIN CELLS. THE BIOLOGY OF THESE TUMORS IS DIFFERENT FROM OTHER NENS OF THE DIGESTIVE TRACT, CHARACTERIZED BY A LOW PROLIFERATION RATE [THE VAST MAJORITY ARE GRADE 1 (G1) AND G2], THEY ARE OFTEN INDOLENT; G3 TUMORS ARE EXCEPTIONAL.

6 THERAPEUTIC ALGORITHM FOR SI-NENS. Disease Localized Regional Distant Stage I/II III IV TNM T1 3N0M0 T4N0M0 T1 4N1M0 Surgical Radical resection treatment Local radical open (or in selected pts) laparoscopic resection* of t primary tumor(s)** t lymph nodes (dissection along the superior mesenteric root) Radical resection with curative intent Local radical open resection of t primary tumor(s) t lymph nodes (dissection along the superior mesenteric root) t in combination with: mets (liver) Aim Free from tumor Free from tumor TxNxM1 Palliative resection Local radical open (in selected pts) laparoscopic resection of t primary tumor(s) t lymph nodes (dissection along the superior mesenteric root) t t To avoid local complications (obstruction, bleeding etc.) To possibly improve prognosis* No resection Due to: t local inoperability t comorbidity Όλοι οι ασθενείς με Si- NENs θα πρέπει να θεωρούνται πιθανοί υποψήφιοι για θεραπευτική χειρουργική επέμβαση του πρωτοπαθούς όγκου και των τοπικά διηθημένων λεμφαδένων. Οι ασθενείς θα πρέπει να αξιολογούνται σε διεπιστημονικό ογκολογικό συμβούλιο. Θεραπευτική εκτομή του πρωτοπαθούς όγκου καθώς και των τοποπεριοχικών λεμφαδενικών μεταστάσεων. οδηγεί στη βελτίωση της έκβασης με άριστη 5- και 10- ετή επιβίωση

7 Παρηγορητική χειρουργική αντιμετώπιση του πρωτοπαθούς όγκου σε μεταστατική νόσο (Si-NEN) Σε περιπτώσεις απομακρυσμένων μεταστάσεων σε ασθενείς με Si-NEN, η απόφαση για το αν θα πραγματοποιηθεί εκτομή του πρωτοπαθούς όγκου ή όχι εξαρτάται από: Εάν η θεραπευτική προσέγγιση, συμπεριλαμβανομένου της θεραπευτικής εκτομής των απομακρυσμένων μεταστάσεων (κυρίως ηπατικών μεταστάσεων) μπορεί να επιτευχθεί εύλογα, τότε η χειρουργική αντιμετώπιση του όγκου θα πρέπει να γίνεται με τα πρότυπα ογκολογικής εκτομής. Σε συμπτωματικούς ασθενείς με συμπτώματα που οφείλονται στην απόφραξη ή την αιμορραγία του λεπτού εντέρου, η παρηγορητική εκτομή του πρωτοπαθούς όγκου είναι απαραίτητη για την πρόληψη της κλινικής επιδείνωσης Niederle B. Neuroendocrinology 2016

8 ENETS CONSENSUS GUIDELINES UPDATE FOR NEUROENDOCRINE NEOPLASMS OFTHE JEJUNUM AND ILEUM B. NIEDERLEA

9 ADVANCED GI NETS

10 MIDGUT WELL DIFFERENTIATED NET: SSA AS FIRST-LINE THERAPY Octreotide LAR 30 mg/4w SSA Lanreotide autogel 120 mg/4w PROMID trial CLARINET trial 1 SSA ARE AN ESTABLISHED THERAPY FOR ANTIPROLIFERATIVE PURPOSES IN INTESTINAL NET, BASED ON 2 PLACEBO CONTROLLED TRIALS (PROMID AND CLARINET STUDIES). BOTH DRUGS, OCTREOTIDE LAR AND LANREOTIDE AUTOGEL ARE RECOMMENDED AS FIRST LINE SYSTEMIC THERAPY IN MIDGUT NET, TO CONTROL TUMOR GROWTH ON THE CLARINET STUDY DESIGN, THE USE OF SSA IN GEP NET IS RECOMMENDED UP TO A KI 67 OF 10% THERE IS CONSENSUS THAT SSA SHOULD BE STARTED AT DIAGNOSIS IN CASES OF HIGH LIVER TUMOR BURDEN AND EXTENDED DISEASE SINCE THESE ARE WORSE PROGNOSTIC FACTORS.

11 Advanced non functioning well-differentiated GI NET

12 NOVEL TARGETED DRUGS EVEROLIMUS CAN BE RECOMMENDED IN ADVANCED NET OF NON PANCREATIC ORIGIN IN CASE OF DISEASE PROGRESSION (E.G. NET OF INTESTINAL OR LUNG ORIGIN). IT CAN BE USED IN MIDGUT NET AS SECOND OR THIRD LINE THERAPY AFTER FAILURE OF SSA AND/OR IFN ALPHA OR PRRT. THIS RECOMMENDATION IS BASED ON THE RESULTS OF THE RADIANT 4 TRIAL THAT REACHED ITS PRIMARY ENDPOINT, AND DEMONSTRATES SUPERIOR PFS WITH EVEROLIMUS COMPARED TO PLACEBO IN NON FUNCTIONING NET OF INTESTINAL OR LUNG ORIGIN. THE SEQUENCING OF EVEROLIMUS AS SECOND OR THIRD LINE THERAPY FOR ADVANCED INTESTINAL NEN WILL ALSO DEPEND ON OTHER ISSUES, INCLUDING ACCESSIBILITY OF PRRT SUNITINIB IN MIDGUT NET (SUNLAND STUDY), IS CURRENTLY EXPLORED IN PROSPECTIVE RANDOMIZED CLINICAL TRIALS BUT THEIR RESULTS ARE NOT AVAILABLE YET AND THEIR USE SHOULD BE RESTRICTED TO CLINICAL TRIALS.

13 MIDGUT NET: NETTER-1 PHASE III STUDY OF 177 LU-DOTATATE + OCTREOTIDE VS HIGH-DOSE OCTREOTIDE Treatment and assessments Tumor burden assessment (RECIST criteria) every 12 weeks Dose 1 Dose 2 Dose 3 Dose 4 Midgut NET n = administrations of 7.4 GBq of 177 Lu-Dotatate every 8 weeks + octreotide 30 mg Octreoscan positive Progression within 3 years n = 115 Octreotide LAR 60 mg every 4 weeks 5 years of followup THE REGISTRATIONAL TRIAL OF 177LU DOTATATE IN PROGRESSIVE MIDGUT NET (NETTER 1), HAS REACHED ITS PRIMARY ENDPOINT, WITH SIGNIFICANT PROLONGATION OF PFS COMPARED TO HIGH DOSE OCTREOTIDE (60 MG/MONTH). BASED ON THIS TRIAL, PRRT MAY BE RECOMMENDED IN MIDGUT NET AS SECOND LINE THERAPY AFTER FAILURE OF SSA IF THE GENERAL REQUIREMENTS TO APPLY PRRT ARE FULFILLED OR AS THIRD LINE THERAPY AFTER FAILURE OF EVEROLIMUS.

14 ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms J.K. Ramagea W.W. De Herderb G. Delle Favec P. Ferollad D. Feronee T. Itof P. Ruszniewskig A. Sundinh W. Weberi Z. Zheng-Peij B. Taalk A. Pascherl all other Vienna Consensus Conference participants

15 Algorithm for treating rectal NETs.

16 NEN ΣΚΩΛΗΚΟΕΙΔΟΎΣ PAPE UF NEUROENDOCRINOLOGY 2016

17 NEN ΣΚΩΛΗΚΟΕΙΔΟΎΣ PAPE UF NEUROENDOCRINOLOGY 2016

18 NEN ΣΚΩΛΗΚΟΕΙΔΟΎΣ PAPE UF NEUROENDOCRINOLOGY 2016

19 NEN ΣΚΩΛΗΚΟΕΙΔΟΎΣ PAPE UF NEUROENDOCRINOLOGY 2016

20 High grade GEP NECs

21 G3 (KI %) GEP NECS Prognostic factors Tumor morphology: Well vs. Poorly diff. Ki-67: < 55% vs. > 55% Primary site: pancreas vs. colorectal Milione et al., Neuroendocrinology 2016 Heetfeld et al., End Rel Cancer 2015 Basturk et al., Am J Clin Pathol2015 Velayoudome-Cephise et al., End Rel Cancer 2013 Sorbye et al., Ann oncol 2013

22 Type A Type B Overall survival of 136 patients with GEP NEC according to subtype Type C Type A = well diff. + Ki % Type B = poorly diff. + Ki % Type C = poorly diff. + Ki-67 > 55% Milione et al., Neuroendocrinology Mar 2016

23 GEP NEC HETEROGENEITY: POSSIBLE CLINICAL IMPLICATIONS WD = well differentiated; PD = poorly differentiated

24 ENETS 2016 GUIDELINES GEP NEC Minimal consensus statement on treatment For patients with localized disease, combination of platinum-based chemotherapy with local treatment consisting of surgery, radiotherapy or both probably offers the greatest likelihood of long-term survival. Debulking or surgical resect ion of metastasis are not recommended. Systemic chemotherapy is indicated in advanced inoperable disease, provided the patient has adequate organ function and perf ormance status and patients should be rapidly referred for consideration of palliative chem otherapy. The combination of cisplatin and etoposide, or alternative regimens substituting carboplatin for cisplatin, or irinotecan for etoposide, are recommended as first-line therapy. Since response rates of these regimens are lower in patients with Ki-67 in the lower range of G3 (20-55%), other treat ment options may be explored in these patients (especially perhaps for NEC of GI origin). While 2nd-line re gimens have not been evaluated rigorously, options include temozolomide-, irinotecan- or oxaliplatin- based schedules as main alternatives. There ar e no data to support the use of somatostatin analogs or PRRT in patients with GEP NECs expressing so matostatin receptors. Prophylactic cranial irrad iation is not indicated in patients with limited-stage disease in complete remission. Garcia-Carbonero et al., Neuroendocrinology Jan 2016

25 PHASE III TRIAL-RELATED EVIDENCE IN NET trial PROMID Presented/publishe d Rinke, JCO 2009 CLARINET Caplin, NEJM 2014 RADIANT-2 Pavel, Lancet 2012 therapy outcome setting OCT LAR vs. PLB LAN A vs. PLB EVE + OCT LAR vs. PLB + OCT LAR positive positive negative Well-diff midgut Well-diff enteropancreatic <10% Ki-67 Carcinoid syndrome-related RADIANT-3 Yao, NEJM 2011 EVE vs. PLB positive Well-diff pancreatic A Raymond, NEJM 2011 SUN vs. PLB positive RADIANT-4 Yao, Lancet 2015 EVE vs. PLB positive TELESTAR Kulke, JCO Oct 2016 Telotristat vs. PLB positive NETTER-1 Strosberg, ESMO 2015 SWOG Yao, ASCO 2015 PRRT+ OCT LAR vs. HD OCT LAR BEV + OCT LAR vs. IFN + OCT LAR positive negative Well-diff pancreatic Non functioning well-diff GI and LUNG Carcinoid syndrome refractory to SSA Midgut progressing on OCT LAR Mixed population

TREATMENT LANDSCAPE FOR ADVANCED NETS 2017 Site Octreotide Lanreotide 177 Lu- DOTATATE Streptozocin Sunitinib Everolimus Disease status Treatment naïve Stable Progressive over 3 years Historical

PROMID CLARINET NETTER-1 RADIANT-4 Colon CLARINET RADIANT-4 Rectum CLARINET RADIANT-4 Unknown 1 RADIANT-4 *RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months.

26 TREATMENT LANDSCAPE FOR ADVANCED NETS 2017 Site Octreotide Lanreotide 177 Lu- DOTATATE Streptozocin Sunitinib Everolimus Disease status Treatment naïve Stable Progressive over 3 years Historical Progressive over 12 months Progressive over 6 months* Lung RADIANT-4 Stomach CLARINET RADIANT-4 Duodenum CLARINET RADIANT-4 Pancreas CLARINET Historical Phase III RADIANT-3* Small bowel Appendix PROMID CLARINET NETTER-1 RADIANT-4 Colon CLARINET RADIANT-4 Rectum CLARINET RADIANT-4 Unknown 1 RADIANT-4 *RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months. RADIANT-4 requires documentation of PD during prior 6 months. Rinke A, et al. J Clin Oncol. 2009;27(28): Caplin ME, et al. N Engl J Med. 2014;371(3): Strosberg J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6. Raymond E, et al. N Engl J Med. 2011;364(6): Yao JC, et al. J Clin Oncol. 2008;26(26): Yao JC, et al. N Engl J Med. 364(6): Yao JC, et al. Lancet. 2016;387(10022):

27 Treatments Approved agents for oncologic control pnets: Everolimus, sunitinib, lanreotide GI NETs: Lanreotide, everolimus Other active agents pnets: Temozolomide GI NETs: Octreotide, [177]Lu-DOTATATE Approved agents for oncologic control before 2011 pnets: Streptozocin GI NETs: None / / /16 OCT SC CS 25,30 LAN symptom control 24 PROMID OCT LAR: Antitumor activity 9,31 CLARINET LAN GEP NET 16,17,29 RADIANT-4 EVE NF GI and lung NET 15, STZ pnet STZ combination: Survival benefit pnet 2 OCT LAR carcinoid tumors 23,26, /11 RADIANT-3 EVE in pnet 11,12,32,33 Sunitinib phase III pnet 13,31,34 ELECT LAN: Symptom control 27 TELESTAR telotristat etiprate CS 20 NDA filed 3/30/ RADIANT-2 EVE + OCT, LAR in mnet w/cs 14 NETTER-1 [177]Lu-Dotatate midgut NET 18 US approval US/EU approval EU approval AC, atypical carcinoid; AJCC; American Joint Committee on Cancer; CS, carcinoid syndrome; ENETS, European Neuroendocrine Tumor Society; ESMO; European Society for Medical Oncology; EVE, everolimus; GEP, gastroenteropancreatic; GI NETs, gastrointestinal neuroendocrine tumors; LAN, lanreotide; LAR, long-acting repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF, nonfunctional; OCT, octreotide; pnet, pancreatic NET; SC, subcutaneous; STZ, streptozocin; TC, typical carcinoid; UICC, Union for International Cancer Control; WHO, World HealthOrganization

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