Hot of the press. Γρηγόριος Καλτσάς MD FRCP Καθηγητής Παθολογίας Ενδοκρινολογίας ΕΚΠΑ

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1 Hot of the press Γρηγόριος Καλτσάς MD FRCP Καθηγητής Παθολογίας Ενδοκρινολογίας ΕΚΠΑ

2 Outline Diagnostic developments Histopathology Molecular Therapeutic developments Results on PRRT Telotristat in carcinoid syndrome Carcinoid heart disease Results on MTT

3 2017 WHO classification Distant Metastasis M1a: Hepatic only M1b: Extrahepatic only M1c: Hepatic and extrahepatic Jejunum/Ileum N1: Less than 12 LN metastasis without mesenteric mass(es) greater than 2 cm in sizes N2: 12 more regional LN and/or mesenteric mass(es) greater than 2 cm in maximum dimensions

4 Classification of Grade 3 (G3) Well-differentiated NETs (WD-NET) and poorly differentiated NEC (PD-NEC) of the pancreas WHO classification Histopathology (morphology) Proliferation rate (Ki-67) Not clear distinction WD-NETs vs. PD-NEC 33 pnets with proliferative markers 20/33 primaries & 13/33 metastases WD-NET Small cell & large cell NEC (PD-NEC) Ambiguous Genetic Loss DAXX/ATRX expression= WD-NET Abnormal p53, Rb, SMAD4 = PD-NEC Evaluation by 3 pathologists Morphological assessment 33% (11/33) agreement 6 WD-NET 5 PD-NEC 67% (20/33) ambiguous (WD-NET/PD-NEC) Proliferative markers 35% WT-NET (Ki-67>55%) 33% PD-NEC (Ki-67<55%) Genetic markers DAXX/ATXP (n=10) WD-NET P53/Rb/SMAD4 (n=11) PD-NEC Mutually exclusive 8/20 ambiguous unclassified Tumour heterogeneity G1/G2 areas or prior diagnosis a G1/G2 WD-NET (progression from G1/2 to G3)

5 WD-NET PD-NEC-SCC Ambiguous p NETs PD-NEC-LCC Am J SurgPathol, 2016

6 Mean Ki-67: WT-NET (46%, 30-80%) vs. PD-NEC (72%, 26-93%) Median disease specific survival: WD-NET (n=20) vs. PD-NEC (n=12) 75 vs. 11 months Am J SurgPathol, 2016

7 2017 WHO classification proportion pts worse outcome G1-2 if Ki67 5% rather than 2% No stat significance NETs Ki67 > 20% Well differentiated NET: Ki67 40% Poorly differentiated SCUC,LCNEC: Ki67 70% MANEC MINEN/MENEN (Mixed Endocrine non Endocrine Neoplasms) MINEN: non-endocrine component other than adenoca (squamous cell, acinar cell) MENEN: Each component 30% at least

8 pnets: Molecular subtypes with distinctive Clinical, Metastatic, Developmental & Metabolic characteristics Cancer Discov 2015, 5(12):

9 Cancer Discov 2015, 5(12):

10 NETTER -1 Study Objectives and Design Aim Design Evaluate the efficacy and safety of 177 Lu-Dotatate + SSAs (symptoms control) compared to Octreotide LAR 60mg (off-label use) 1 in patients with inoperable, somatostatin receptor positive, midgut NET, progressive under Octreotide LAR 30mg (label use) International, multicenter, randomized, comparator-controlled, parallel-group Treatment and Assessments Progression free survival (Recist criteria) every 12 weeks Dose 1 Dose 2 Dose 3 Dose 4 Baseline and Randomizatio n n = 115 n = administrations of 7.4 GBq of 177 Lu-Dotatate every 8 weeks + SSAs (symptoms control) Octreotide LAR (high dose - 60mg every 4 weeks 1 ) 5 Years follow up 1. FDA and EMA recommendation NEJM 2017, 12:376(2):

11 Progression-Free Survival N = 229 (ITT) Number of events: Lu-Dotatate: 23 Oct 60 mg LAR: Lu-Dotatate Median PFS: Not reached Hazard ratio : 0.21 [ ] p < % reduction in the risk of disease progression/death Estimated Median PFS in the 177 Lu-Dotatate arm 40 months Octreotide LAR 60 mg Median PFS: 8.4 months All progressions centrally confirmed and independently reviewed for eligibility (SAP) 11

12 Tumour (Response Rate (currently evaluable patients) 177 Lu-Dotatate (n=101) Octreotide LAR 60mg (n=100) Complete Response (n) 1 0 Partial Response (n) 18 3 Objective Response Rate (CI 95%) 19% (11-26) 3% (0-6) * Progressive Disease (n, %) 5 (4%) 27 (24%) Stable Disease (n, %) 77 (66%) 70 (62%) *p=

13 Overall Survival (interim analysis) 0. 5 N = 229 (ITT) Number of deaths: Lu-Dotatate: 13 Octreotide 60 mg LAR: 22 p=

14 Somatostatin receptor antagonists for imaging and therapy Comparison of 177Lu-DOTA-JR11 vs. 177Lu- DOTATE in a metastatic G2 NET ileum Tumor dosages GyGBq vs Gy/GBq J Nucl Med 2017, 58(9)

15 Serotonin from tryptophan through TrOH (tryptophan hydroxylase) Telotristat blocks the binding of Tryptopahn to TrOH reducing serotonin production by carcinoid tumours Telotristat

16 TERLOTRISTAT (135): Placebo, vs mg, mg JCO 2017, 35(1):14-23

17 Stepwise management of CS Pasireotide Consider cytoreductive techniques to reduce tumour load

18 R Recommendations on pharmacotherapy for CHD and control of carcinoid syndrome symptoms Watchful waiting in asymptomatic patients Treatment with somatostatin analogues to reduce 5-HIAA <300 mmol/24 h in all cases. Diuretics with different mode of action and fluid and salt restriction, to improve oedema. Digoxin may be beneficial with respect to right ventricular contractility. In cases of carcinoid syndrome resistant to somatostatin analogues, interferon alfa, or the new agent, telotristat ethyl, whilst TAE and hepatic debulking surgery should be performed with caution. J Am Col Cardiol 2017, 69(10):

19 Indications for valve replacement surgery Symptomatic right heart failure Performed early rather than later Fatigue and dyspnoea leading to oedema, ascites Progressive asymptomatic right ventricular enlargement/dysfunction Prior to hepatic surgery? Type of prosthesis (Biological vs. mechanical) J Am Col Cardiol 2017, 69(10):

20 Everolimus RADIANT 4: Everolimus in lung NETs Post hoc analysis: 90/302 pts lung NETs PFS: Everolimus 9.2 ms ( ) Placebo 3.6 ms ( ) HR: 0.5 (benefit 5.6 ms) 13% Response rate RADIANT 4: Functional Assessment of Cancer Therapy General (FACT-G) FACT-G: Baseline, every 8/52 up 48/52 Everolimus: (n=70) ms P=0.31 Placebo: (n=22) 9.23 ms Preservation of Quality of Life Cancer Sci 2017 Oct An Oncol 2017

21 Everolimus RADIANT 3: Everolimus effect on secretory component Gastrin: > 50% reduction Glucagon: 40% reduction Effect on syndrome? RADIANT 2: Everolimus&Octreotide LAR effect on overall survival (OS) No difference OS after adjusting for imbalances in baseline covariates Pancreas 2017, June An Oncol 2017, 289(7):

22 Sunitinib Overall survival N=171 (86 sunitinib and 85 placebo) 5 years OS Sunitinib : 38.6 ms Placebo : 29.1 ms Sunitinib& autophagy 69% placebo crossed over p=0.35 Autophagy inhibitors (chloroquine) Blocks autophagy& increases sunitinib efficacy An Oncol 2017, 28(2): Mol Cancer Ther, 2017, 16(11):2502

23 Perforation - Dissemination N n perforations (%) Mean follow up (mos) Overall Survival (%) ANEN survival (25%) (10%) 60* (8%) 18* (21%) (6%) (9%) (5%) (14%) patients: 103 perforations Most simple appendectomy alone No peritoneal metastases 3 deaths but no peritoneal involvement Ann Surg Oncol 2015, 22:

24 Distant metastases & deaths from ANENs Reference n Histology Ki67 CS/5HIA A/CHD Site Disease related deaths Anderson Carcinoid NA - Liver - NA Follow-up Moertel Typical Carcinoid NA - NA 2 29 years Mc Gillvary Serotonin (+) NA - Liver - NA Quaedvlieg All ANETs (0.6%) NA NA McGory Carcinoid NA NA Liu Carcinoid WHO 2%, 2-15% - Liver, bone, lung? 3 40 months Mullen Malignant carcinoid tumour Hsu Malignant carcinoid tumour NA years NA NA Glasberg ENETS classification 2%, 4% 1 Liver 0 NA Kleiman Well differentiated NET (WHO) ENETS classification < 5% NA Liver 0 18 months 2%, 8% 1 Liver months Br J Surg 1985;72:545-6 Surgery 1992;111: NEJM 1987; 317; J Surg Oncol 2013;107: Neuroendocrinol 2013; 98:31-37 Dis Colon Rectum 2015;58:

25 CONCLUSIONS - RECOMMENDATIONS Prognostic factors Evidence Recommendation RHC Size > 2cm Most robust data but? % Consider R1 No definite data Consider G2, size Grade Evolving data but? cut-off Consider G2 Size 1 2 cm LN MAI VI Serosa penetration No convincing data No evidence No convincing data No evidence No evidence Location base No evidence Consider if R1

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28 Met-NET 2 trial Metformin exerts an antiproliferativeeffect GI and lung G1-2 well differentiated Follow-up for 3 years PEP: Side effect SEP: Response (RESIST 1) Prognostic, predictive genetic biomakers

29 Unmet needs Initiation of treatment with SSAs & dosing Adjuvant treatment with SSAs Drug free intervals Anti-proliferative effect of increased doses of SSAs Re-institution of SSAs following response to other treatments Chemotherapy Molecular targeted therapy

30 Unmet needs Role of SSAs in well differentiated lung NETs Role of PRRT pnets Lung NETs Evolving therapies Immunotherapies Newer Molecular Targeted Therapies Chemo-radiosensitisation