Treatment Algorithm (ESMO)

Treatment Algorithm (ESMO)

ENETS 2016 Consensus Guidelines for the Management of Patiens with Intestinal(midgut) Neuroendocrine Tumors. Pavel et al., Neuroendocrinology Jan 2016

ΘΕΡΑΠΕΙΑ ΥΠΟΤΡΟΠΗΣ ΜΕΡΙΚΗ ΑΝΤΑΠΟΚΡΙΣΗ (PR) ΙΑΝ 2014-ΔΕΚ 2014 OCTREOTIDE LAR 30mg/28d CgA :105,6 ng/ml 2-3 κενώσεις/d

ΙΑΝ2015 ΠΡΟΟΔΟΣ ΝΟΣΟΥ CgA :1050ng/mL 4-5 υδαρείς κενώσεις /24 h

ΘΕΡΑΠΕΥΤΙΚΗ ΑΝΤΙΜΕΤΩΠΙΣΗ. ΠΡΟΟΔΟΣ ΝΟΣΟΥ Μετά από θεραπεία με ανάλογο σωματοστατίνης. Σημαντική πρόοδος της ηπατικής μεταστατικής νόσου (αύξηση παλαιών,εμφάνιση νέων εστιών) Πρωτοεμφανιζόμενη εξωηπατική νόσος (οστικές μέτα) Λειτουργικός όγκος + εκτεταμένη ΔΕ ημικολεκτομή. Σακχ.Διαβήτης,Αρτ.υπέρταση. Αντιμετώπιση υψηλού ογκολογικού φορτίου

Management of locoregional unresectable and/or metastatic disease Complete resection possible Resect Primary + metastases Distant metastases IMAGING Multiphasic CT or MRI Consider Octreoscan BIOCHEMICAL Consider 5-HIAA Consider CgA Asymptomatic Low tumor burden Locally symptomatic from primary tumor Clinically significant tumor burden Observe with markers and imaging every 3-6 mo or SSA s Consider Resection of Primary tumor SSA s 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 Carcinoid syndrome SSA s ECHOcardiogram Consider chemotherapy if no other options feasible 39

RADIANT-2 Study Design Phase III Double Blind Placebo Controlled Trial Patients with advanced NET and a history of symptoms attributed to carcinoid syndrome, N = 429 R A N D O M I Z E 1:1 Everolimus 10 mg/d + Octreotide LAR 30 mg/28 days n = 216 Crossover Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression Multi-phasic CT or MRI performed every 12 weeks Primary endpoint: PFS (RECIST) Secondary endpoints: Tumour response, OS, biomarkers, safety, Enrollment January 2007 - March 2008

Central Local Central Local PFS extension 11.3 16.4 months 8.6 12 months HR / risk reduction 0.77 / 23% 0.78 / 22% total events 223 284 p value 0.026 0.018

RADIANT4 Primary Endpoint: PFS by Central Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 Probability of Progression-free Survival (%) 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 15 18 21 24 27 30 No.of patients still at risk Censoring Times Everolimus (n/n = 113/205) Placebo (n/n = 65/97) Kaplan-Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Months Everolimus Placebo 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0 P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. Yao JC et al. Lancet 2016;387:968-977.

RADIANT4 PFS HR by Pre-defined Subgroups Per Central Review Subgroups All Age <65 65 Sex Male Female Race Caucasian Asian Other Tumor grading Grade 1 Grade 2 Treatment naive* Yes No Prior chemotherapy Yes No Baseline CgA >2xULN 2xULN Baseline NSE >ULN ULN No. 302 159 143 142 160 230 50 22 194 107 117 185 77 225 139 138 87 188 Hazard Ratio (95% CI) 0.56 (0.41-0.77) 0.55 (0.36-0.83) 0.59 (0.37-0.94) 0.78 (0.51-1.22) 0.39 (0.25-0.60) 0.83 (0.56-1.21) 0.19 (0.09-0.40) 0.26 (0.08-0.85) 0.57 (0.39-0.84) 0.49 (0.29-0.83) 0.65 (0.39-1.08) 0.51 (0.35-0.76) 0.35 (0.19-0.64) 0.60 (0.42-0.86) 0.40 (0.25-0.62) 0.70 (0.45-1.11 0.77 (0.45-1.34) 0.44 (0.29-0.66) 0.1 0.4 1 10 Everolimus Better Placebo Better Yao C et al. Lancet 2016;387:968-977.

RADIANT4 PFS Treatment Effect by Primary Tumor Per Central Review PFS events Hazard Ratio [95% CI] Everolimus n/n (%) Placebo n/n (%) Lung (N=90) 0.50 [0.28-0.88] 42/63 (66.7) 18/27 (66.7) Stomach (N=11) 0.31 [0.06-1.75] 3/7 (42.9) 4/4 (100) Primary tumor origin Rectum (N=40) Ileum (N=71) Jejunum (N=22) 0.17 [0.08-0.38] 1.34 [0.63-2.87] 0.38 [0.11-1.34] 21/25 (84.0) 22/47 (46.8) 5/16 (31.3) 14/15 (93.3) 11/24 (45.8) 5/6 (83.3) CUP (N=36) 0.60 [0.24-1.51] 11/23 (47.8) 8/13 (61.5) Other (N=32) 0.38 [0.12-1.15] 9/24 (37.5) 5/8 (62.5) 0.1 0 2 3 Everolimus Placebo 4 5 In favor of All hazard ratios presented for these subgroup analyses were unstratified and unadjusted for any covariates. Everolimus demonstrated a consistent positive treatment effect across multiple primary tumor locations In the ileum subgroup only 22 progression events were reported out of 47 patients in the everolimus arm vs 11 out of 24 patients in the placebo arm The better prognosis for the ileum subgroup in relation to the median duration of follow-up may have been insufficient to demonstrate the potential benefit of treatment Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20 44

Trans-arterial Chemoembolization for metastatic NETs with high tumour burden < 75% tumour load n(%) > 75% tumour load Patients 133 68 G1/2 118 (98%) 62 (98%) No TACE (average) 260 (1.9) 138 (2.03) Functional syndrome Carcinoid syndrome Median OS (months) Median OS post TACE (months) 98 (74%) 74 (56%) 59.2 30 57 (84%) 40 (59%) 64.1 28 Radiology response SD 28% PR 49% NA 23% SD 23.5% PR 58.8% NA 16.2% Symptomatic response 88(77.9%) 58 (85.2%) < Average length stay (days) 2.35 2.98 Number of complications 20 (17.7%) 15 (21.7%) 30-day mortality 5% 5 (7%) Contraindications TACE Poor performance status Bilirubin > 2mg/dl Vessel occlusion Ann Surg Oncol, 2016 23:4008-4015

ECC 2015; Late-breaker abstract 6LBA NETTER-1: study design Presented By Jonathan Strosberg at 2016 ASCO Annual Meeting

Stage IV NETs G3 (WHO) Αντι-νεοπλασματική θεραπεία - Χημειοθεραπεία Clinical Evidence based on Ph II studies

Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. This is the largest reported series of NETs (65pts) treated with capecitabine and temozolomide in daily practice and shows that this combination is a promising treatment option for both grade 1/2 pnets and non-pnets. Crespo et al. Future Oncol. 2016 Nov 2.

ENETS 2016 Consensus Guidelines for the Management of Patiens with Intestinal(midgut) Neuroendocrine Tumors. Pavel et al., Neuroendocrinology Jan 2016

ΣΥΝΔΥΑΣΜΕΝΗ ΘΕΡΑΠΕΙΑ ΠΡΟΟΔΟΥ ΤΗΣ ΝΟΣΟΥ. TACE + Octreotide Lar30mg /21d

Σταδιοποίηση μετά από TACE CgA : 1650ng/mL

Κλινική συμπεριφορά κ σταδιοποίηση(grading) Most primary small bowel NETs are G1 tumours (Ki67<2%). However, when these tumors metastasize to the liver, they may become highly proliferative. More than two-thirds of the patients who had G1 primary tumor developed G2 or G3 liver metastases. Chi et al, Am J Clin Pathol, March 2015

Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours. Response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT. Childs et al:endocr Relat Cancer. 2016 Jul;23(7):563-70

Comparison of the impact of 68Ga-DOTATATE and 18F-FDG PET/CT on clinical management in patients with neuroendocrine tumors. in PD NETs, 18F-FDG PET/CT plays a significant clinical role in combination with 68Ga- DOTATATE. 68Ga DOTATATE SUVmax values relate to tumor grade and Ki67 index and can be used prognostically. Panagiotidis et al. J Nucl Med. 2016 Aug 11.

ΣΥΝΔΥΑΣΜΕΝΗΘΕΡΑΠΕΙΑ ΠΡΟΟΔΟΥ ΤΗΣ ΝΟΣΟΥ. ΦΕΒ2015-ΙΟΥΝ2015 Carboplatin-etoposide 6 κύκλοι θεραπείας Τοξικότητα Grade 2/3 ναυτία Grade 2 θρομβοπενία ουδετεροπενία Νεφρική ανεπάρκεια GFR (Gates) 45ml/min Aνταπόκριση CgA 122ng/ml Aπεικονιστική σταθεροποίηση της νόσου.

ΣΥΝΔΥΑΣΜΕΝΗΘΕΡΑΠΕΙΑ ΠΡΟΟΔΟΥ ΤΗΣ ΝΟΣΟΥ. ΑΥΓ 2015-MAR 2017 4 συνεδρίες TACE 2 σε κάθε λοβό του ήπατος Προσθήκη θεραπείας με διφωσφονικά Συνέχιση θεραπείας με Lanreotide autogel120mg.

ΠΑΡΟΥΣΑ ΝΟΣΟΣ 2017 Χολολιθίαση Λαπ.χολoκυστεκτομή Βιοψία από μεγάλη μετα εστία του ήπατος. Μετάσταση από ΝΕΤ 3-7 μιτώσεις/10 oppm Ki 67 :15%

Eπανασταδιοποίηση μετά TACE + Lanreotide 120mg 18F-FDG PET C/T SCAN

Eπανασταδιοποίηση μετά TACE +Lanreotide 120mg 18F-FDG PET CT

ΘΕΡΑΠΕΙΑ ΠΑΡΟΥΣΑΣ ΝΟΣΟΥ. EVEROLIMUS 10mg /d Στοματίτιδα grade 2 Rash grade 2-3 Σταθερή νόσος PS ECOG :1

Επανασταδιοποίηση μετά θεραπεία με EVEROLIMUS

SHOOT THE EXPERT 1)Στην αντιμετώπιση προόδου της νόσου είναι πάντα καθοριστικό το Grading του όγκου η το Staging η η εκτασή της; (ταχύτητα αναδιπλασιασμού) 2) Υπάρχουν αμεσα κριτήρια ανταπόκρισης για ΤACE (αριθμός συνεδριών κατηγορία χημειοθεραπευτικού); 3) Ογκολογικά κριτήρια ανταπόκρισης στη συστηματική θεραπεία (CR,PR,ORR) και επιλογή θεραπείας (διαδοχική θεραπεία);