UCLH Cancer Collaborative Pancreas Update Meeting 12 th July 2017 Pancreatic Neuroendocrine Tumours Dr. Christos Toumpanakis MD PhD FRCP Consultant in Gastroenterology/Neuroendocrine Tumours Hon. Senior Lecturer University College of London Neuroendocrine Tumour Unit - ENETS Centre of Excellence ROYAL FREE HOSPITAL, London,UK
Disclosures NOVARTIS : advisory board, research grants, educational grants IPSEN : advisory board, research grants, educational grants PFIZER : advisory board, educational grants
Sporadic Pancreatic Neuro-endocrine Tumours With MEN-1: a. Parathyroid adenomas b. Pituitary tumours With other genetic syndromes Von Hippel Lindau (VHL) Neurofibromatosis (NF-1) Tuberous sclerosis.
Name Peptide Secreted Incidence New cases/million population Tumour Location Malignant % Associated with MEN-1 Zollinger-Ellison Syndrome Insulinoma Gastrin Insulin 1-1.5 1-2 Duodenum 60% Pancreas 40% Pancreas 60-90% 10% 25% 5% VIPoma (Verner Morrison) VIP 0.1 Pancreas 90% 40-70% 5% Glucagonoma Glucagon 0.01-0.1 Pancreas 50-80% 10% Somatostatinoma GRFoma Somatostatin Growth hormone <0.1 <0.1 Pancreas 55% Duodenum 45% Pancreas 30% Lung 50% Jejunum 15% 70% 60-70% 45% 15% ACTHoma ACTH <0.1 Pancreas 90% 95% Rarely Non- Functional (Pancreatic polypeptide) 2-4 Pancreas 100% 60-80% 20-40%
Specific symptoms Pancreatic NETs Gastrinoma Recurrent/resistant to treatment peptic ulcers, not related to H.pylori & NSAIDs Chronic diarrhoea responding to PPIs Insulinoma Fasting hypoglycaemia, low blood glucose, and improvement after administration of glucose (Whipple s triad) VIPoma Chronic diarrhoea, hypokalaemia and dehydration Glucagonoma New onset of DM, weight loss and migratory necrolytic erythema
Classification of NETS WHO 2010 classification (a) well- differentiated neuroendocrine tumours of G1-grade (Ki67< 2%) (b) well-differentiated neuroendocrine tumours of G2-grade (Ki67 2-20%) (c) poorly differentiated neuroendocrine carcinomas with high grade (G3, Ki67>20%) malignant behaviour.
Diagnostic algorithm for p NETs History clinical examination Chromogranin-A Fasting gut hormones FDG-PET scan High-grade tumours Suspected second malignancy Triple phase CT c/a/p Somatostatin Receptor Scintigraphy (Octreoscan / Ga-68 PET) MRI liver MRI spine Tc-Bone scan EUS Tissue diagnosis Commencement of treatment Clinical, biochemical & radiological follow-up
Treatment of p NETs A) Medical control of patient s symptoms. B) Resection of tumor primary and if possible, metastatic lesions. C) Control of tumor growth in cases of advanced disease. D) Improvement and maintenance of patient s quality of life.
Somatostatin Analogues Octreotide LAR Lanreotide Autogel
Somatostatin analogues in functional pancreatic NETs VIPomas Glucagonomas GRFomas Insulinomas Patients treated 31 32 9 55 Symptomatic Improvement % Biochemical response % 87 75 100 36 87 78 100 45 4 weeks after first injection of Somatostatin analogues Wermers, Fatourechi et al, Medicine (Baltimore) 1996 Nikou, Toumpanakis et al, Hepatogastroenterology 2005 Vezzosi, Bennet et al, Eur J Endocrinol 2005
Control of tumour growth for advanced p NET Locoregional therapy Medical therapy Somatostatin analogues (SSAs) Interferon-α Molecular Targeted therapies mtor inhibitors VEGFR inhibitors other TKIs Systemic Chemotherapy MIBG, meta iodobenzylguanidine; mtor, mammalian target of rapamycin; PRRT, peptide-receptor radiotherapy; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Radiofrequency ablation (RFA) Embolization / chemoembolization / radioembolization Nuclear medicine and Radiation Tumor-targeted, radioactive therapy: PRRT using e.g. 90 Y-DOTATOC 177 Lu DOTATATE External Radiation (for bone, brainmetastases) Brachytherapy (for liver metastases) ENETS consensus guidelines for the management of NET. Neuroendocrinology. 2012;95:71-176. NCCN guidelines: Neuroendocrine tumors. V2.2013.
Patients alive and with no progression (%) Progression-free survival and tumor growth with Lanreotide Autogel in patients with enteropancreatic NETs: Results from CLARINET, a randomized, double-blind, placebo-controlled study 100 90 80 Primary endpoint: PFS (ITT, N=204) Lanreotide Autogel vs. placebo p=0.0002 HR=0.47 [95% CI: 0.30, 0.73] 70 60 50 40 30 20 10 Lanreotide Autogel 120 mg 32 events / 101 patients median, not reached Placebo 60 events / 103 patients median, 18.0 months [95% CI: 12.1, 24.0] 0 0 3 6 9 12 18 24 27 Time (months) P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model. HR, hazard ratio; ITT, intention-to-treat. 62% 22% Caplin et al, NEJM 2014
PFS: therapeutic effect in pre-defined subgroups generally consistent with overall population PFS in p NETs Lanreotide : not reached Placebo: 12.1 months Caplin M, et al. New Engl J Med 2014
Streptozocin for pancreatic NETs Randomised Controlled trials (did not use RECIST criteria, nor did they report PFS) Author Date Regimen Number Patients Response % Survival months P value Moertel 1980 STZ 42 36 16.4 NSD 5FU/STZ 42 63 26 Moertel 1992 CZT 33 30 18 P<0.03 5FU/STZ 34 45 17 P<0.004 DOX/STZ 38 69 26 Case Series Author Date Regimen Number Patients Response % Survival months Cheng 1999 STZ/DOX 16 6 - McCollum 2004 STZ/DOX 16 6 20 Delaunoit 2004 DOX/STZ 45 36 24 Kouvaraki 2004 5FU/DOX/STZ 84 39 37 Turner 2010 5FU/CIS/STZ 49 38 32
Temozolomide for pnets Author Date Number Patients PNET Regimen Response Rate (PNET) Kulke 2006 29 11 TMZ/thalidomide 25 (45) Chan 2012 34 15 TMZ/Bevacizumab 15 (33) Ekeblad 2007 36 12 TMZ 14 (8) Chan 2013 40 40 TMZ/Everolimus (40) Strosberg 2011 30 30 TMZ/Capecitabine (70) Welin 2011 25 10 (PDEC) TMZ/Capecitabine (+Bev 5pts) 33 Koumarianou 2012 15 7 mtmz/bevacizumab/lar 64
1 Chemotherapy to downstage NETs 1. Pancreatic NET + PV Tumour 2. STZ + 5FU+ ADR (5 cycles) 3. Surgery 2 3
Systemic Chemotherapy 1. Platinum-based chemotherapy is the treatment of first choice in GEP-NECs with good RR but short PFS. 2. A 55% cut-off level of Ki67 seems promising predictive factor of response in NECs. 3. Streptozocin-based regimens induce responses in 30-40% well-differentiated pnets. 4. Temozolomide combinations are promising but direct comparison with streptozocin is required. 5. More studies are needed to assess the response in functional NETs. 6. Ki67 by itself cannot predict response in welldiff NETs. 7. Chemotherapy seems to be the preferred option in pnets with rapid symptomatic and radiological progression, however prospective studies are needed. Kouvaraki, M. A. et al. J Clin Oncol 2004 Toumpanakis et al, Best Pract Res Clin End Metab 2007 Sorbye et al: the NORDIC NEC study, Ann Oncol 2013
Sunitinib Everolimus D.Metz & R.Jensen, Gastroenterology 2008
Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors Eric Raymond, M.D et al, N ENGL J MED 2011; 364:501-513 Double blind randomized study 171 patients Progression within 12 months Ki67 < 20% 69% had chemotherapy before Sunitinib 37.5mg vs placebo Adverse effects : 30% : diarrhoea, nausea, vomiting, fatigue 10-20% : Hypertension, neutropenia Sunitinib 11.4 months PFS OR Deaths Learning point from Sunitinib trial Oral Sunitinib can Placebo control tumour 5.5 growth months in G1/G2 advanced & progressive pancreatic NETs with potential favorable implications to OS 9.3% 9 (10%) 0% 21 (25%) With the exception of diarrhea, sunitinib had no impact on global HRQoL Vinik A et al, Target Oncol 2016 Five years after study closure, median OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (P = 0.094), with 69% of placebo patients having crossed over to sunitinib Faivre et al, Ann Oncol 2016
Everolimus for Advanced Pancreatic Neuroendocrine Tumours (RADIANT-3) James C. Yao et al, N ENGL J MED 2011; 364:514-523 Double blind randomized trial 410 patients 50% chemo-naive Ki67 < 20% Progression within 12 months Everolimus 10 mg vs placebo PFS Learning point from RADIANT-3 trial OR Everolimus 11 months 5% Placebo 4.6 months 2% Oral Everolimus can control tumour growth in G1/G2 advanced & progressive pancreatic NETs Adverse effects : 30% : aphthous ulcers,rash, diarrhoea, fatigue 10 30% : lower respiratory infections, interstitial pneumonitis < 10% : cytopenias, hyperglycaemia Everolimus prolonged PFS regardless of prior chemotherapy Lombard-Bohas C et al, Pancreas 2015
Peptide Receptor Radionuclide Therapy (PRRT) Mechanism of Action Somatostatin receptor Isotope + Sst analogue Tumour cell Tumour cell The -emitter labelled somatostatin analogue delivers a lethal radiation dose to the tumour cell.
Radiolabelled Somatostatin Analogue LU-177-DOTA,Tyr3 Octreotate in patients with endocrine gastroenteropancreatic tumours Kwekkeboom et al JCO 2005;23:2754-2762 131 pts CR 2%; PR 26%; MR 19%; SD 35%; PD 18% Computed tomography scans in a patient with a metastasized nonfunctioning endocrine pancreatic tumor before treatment (left) and 3 months after the last treatment (right)
Recent results of PRRT in p NETs Isotope No Patients Stable Disease Lu-177 DOTATATE Lu-177 DOTATATE Y-90 DOTATATE Partial Response Median PFS OS 33 36% 54.5% 26 months 55 months 68 25% 60% 34 months 53 months 29 - - 25 months 42 months Ezziddin et al, Eur J Nucl Med Mol Imaging. 2014 Ezziddin et al, J Nucl Med, 2014 Rogowski et al, Future Oncol 2016
Salvage Treatment with Peptide Receptor Radionuclide Therapy (PRRT) in patients with advanced VIPomas and severe Werner- Morrison syndrome 2 patients with severe syndrome and progressive disease, despite previous SSTAs, chemotherapy and molecular targeted treatment had significant symptomatic, radiological and metabolic response post PRRT. Yalchin et al, ENETS 2015
Neoadjuvant Treatment of Nonfunctioning Pancreatic Neuroendocrine Tumors with [177Lu-DOTA0,Tyr3]Octreotate 29 pts included 9 had surgery post PRRT. 5 patients had a local recurrence or developed liver metastases 8, 14, 22, 48, and 56 mo after surgery. Median PFS was 69 mo for patients with successful surgery (yellow line) and 49 mo for the other patients (red line). 4 / 9 (44%) patients remained disease-free with a median followup of 59 mo (range, 7 96 mo) after surgery. Esther I. van Vliet et al. J Nucl Med 2015
Do combination treatments improve the outcome of p NETs? Study Drugs Pts ORR (%) COOPERATE-2 EVE vs EVE + PAS CALGB 80701 EVE vs EVE + BEV 160 6.2 20.3 150 12 31 PFS (m) 16.8 16.4 14.0 16.7 OS (m) > 34 > 34 35.0 36.7 EVE : everolimus PAS : pasireotide BEV : bevacizumab Kulke et al, ENETS 2015 Kulke et al, ASCO 2015 More adverse effects with EVE + BEV (hypertension 41 vs 12% G3/G4 : 81 vs 49%)
Transarterial Hepatic Embolization and Chemoembolization Symptomatic benefit (40-80%) Partial response : ~ 50%? Survival benefit Brown et al J Vasc Interv Radiol 1999;10(4):397-403 Chamberlain et al J Am Coll Surg 2000;190:432-445 Morbidity (fever, pain, hepatic failure, intestinal ischaemia) Mortality Careful selection of patients Toumpanakis et al, Best Pract Res Clin End Metab 2007
New Clinical Trials with cold and hot somatostatin analogues CLARINET FORTE Administration of Lanreotide Autogel 120 mg every 2 weeks in patients with progressing p NETs, being on Lanreotide 120 mg every 4 weeks REMINET Lanreotide Autogel vs placebo in p NETs who responded to chemotherapy or molecular targeted therapy COMPETE (PRRT vs everolimus) In patients with p NETs who progressed despite cold somatostatin analogues or chemotherapy
New trials (2) Name SEQTOR Phase III (crossover design) OCLURANDOM Phase II (progressive despite SSAs, Everolimus or Chemotherapy) Design Arm 1 Everolimus and then 5-FU + STZ Arm 2 5-FU + STZ and then Everolimus Arm 1 Lu-177 DOTATATE Arm 2 Oral Sunitinib
Which treatment and for Whom Patient s clinical status, comorbidities and preferences Tumour Histology Positive uptake in Octreoscan or Ga-68 PET Tumour burden Tumour status Predictive molecular markers? Cost??
G3 GEP-NETs Patient s performance status 0-2 Systemic Chemotherapy Ki67 > 55% Ki67 < 55% Platinum-based chemotherapy Temozolomide-based chemotherapy Disease progression Well differentiated G3 GEP-NETs? PRRT? Molecular targeted 2 nd Line Systemic Chemotherapy Sorbye at al, CANCER 2014
G1 & G2 pancreatic NETs SA or supportive care PS 3-4 PS 0-2 Resectable disease Non-resectable Predominantly Hepatic Disease TACE RFA HPB Surgery (primary +/- hepatic metastases) asymptomatic G 1 symptomatic or PD G 2 Somatostatin Analogues PD Systemic chemotherapy or Everolimus / Sunitinib PS : performance status PD : progressive disease PD PRRT
Treatment sequence in specific,advanced (G1/G2) p NET, clinical scenarios Non-functional p NETs High tumour volume, Ki67 > 10% Symptomatic +/- radiological progression Systemic chemotherapy (everolimus / sunitinib) Malignant insulinomas Everolimus (Ki67<10%) Systemic chemotherapy (Ki67> 10%) PRRT Advanced Gastrinomas Systemic chemotherapy: limited efficacy? PRRT Faivre et al, Cancer Met Rev 2014 Valle et al, Cancer Treat Rev 2014 Kulke et al NEJM 2009 Kwekkeboom et al JCO 2005 Kouvaraki M A et al. JCO 2004 Advanced VIPomas / Glucagonomas Very limited data
Dieticians Hepatobiliary & GI surgery Specialist NET Nurses Endocrinology NET patient Pathology Genetics Cardiology Oncology Radiology & Nuclear Medicine Gastroenterology Palliative care & Pain control
Multi-Disciplinary Team (MDT) approach for NETs Accurate diagnosis & staging Evaluation of performance status & quality of life Consensus agreement on treatment plan Continuous reassessment, discussion and peer review of the individualized treatment plan
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