Treatment algorithm Neuroendocrine tumours. Gregory Kaltsas Endocrine Unit, Department of Pathophysiology, University of Athens, Greece

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1 Treatment algorithm Neuroendocrine tumours Gregory Kaltsas Endocrine Unit, Department of Pathophysiology, University of Athens, Greece

2 Outline Presenting a meaningful algorithm Means used to develop algorithm Treatment algorithm for limited disease Treatment algorithm for extensive disease Treatment algorithm of PDNEC Personal view

3 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

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

5 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 ECOG: Eastern Cooperative Oncology Group; PS: performance status

6 Survival according to differentiation 1.0 Chance of survival G1 G1 vs G2 G1 vs G3 G2 vs G3 G2 P = P < P < Grade Grading NET* Mitotic count Ki67 index (10 HPF) (%) G1 2 2 G G3 > 20 > G Time (months) * ENET and AJCC grading system Rindi G, et al. Virchows Arch. 2006;449: Rindi G, et al. Virchows Arch. 2007;451: Pape UF, et al. Cancer. 2008;113:

7 TNM classification for GEP-NETs Stage 0* Τis N0 M0 Stage I T1** N0 M0 Stage IIa T2 N0 M0 IIb T3 N0 M0 Stage IIIa T4 N0 M0 IIIb Any Τ Ν1 Μ0 Stage IV Any Τ Any Ν Μ1 Classification according to the anatomic origin ENETS 2009

8 Survival according to TNM stage 1.0 Stage I Probability of survival Stage III Stage IV Stage II I vs II P = I vs III P = I vs IV P < II vs III P = II vs IV P < III vs IV P = ENET TNM Staging Months N = 202 cases: gastric (48), duodenum (23), pancreatic (131); n = 193. Pape UF, et al. Cancer. 2008;113:

9 Growth pattern GEP-NETs Poorly differentiated G3 Well differentiated G1/2

10 Guides management Biology of tumor (WHO classification, grading) Extent of disease (TNM, stage)

11 The GEP-NET Patient May Suffer From Flushing Sweating Cardiorespiratory failure Hypotension Rash Diabetes Muscle wasting Weight loss Severe diarrhea Dehydration Hypokalemia Hypochlorhydria Hypoglycemia Peptic Ulcer

12 Non functioning tumours, atypical symptoms delayed diagnosis Localized Regional Flushing Distant Diarrhea Mainly nocturnal 27% Bronchospasm IBS 50% 24% Functioning tumours Non functioning tumours

13 GEP-NETs Incidence /10 5 % patients with metastases % with ΜΕΝ 1 Carcinoid Tumours % Rare Non functioning pancreatic neuroendocrine tumours (pnet) % 20% Ιnsulinoma % 5-7% Gastrinoma % 18-25% Glucagonoma 0.1 >70% 10% VIPoma % 10-15% Somatostatinoma? >70% 10% Rare tumours??????

14 Familial syndromes associated with GEP-NETs ΜΕΝ-1 Von Hippel Lindau Von Recklinghausen Tuberous sclerosis Carneys complex

15 Treatment Goals in GEP-NETs Total eradication by surgery Control of tumor growth Alleviation of clinical symptoms Improving and preserving quality of life

16 Treatment Options in GEP-NETs Surgery Cytoreduction Embolization (± chemotherapy) & radiofrequency ablation Medical treatment Somatostatin analogues Alpha interferon therapy Chemotherapy PRRT Biological targeted agents PRRT: peptide receptor radionuclide therapy

17 Surgical Options in GEP-NETs Radical surgery Complete resection of entire tumour even in presence of liver metastases (R0/1) Debulking surgery Always employed in functional neoplasms, when medical therapies do not control symptoms Resection of at least the primary tumour and liver metastases (suitable procedure when at least 90% of the tumour is resectable) Palliative surgery No resection Biliary, gastric, or digestive bypasses in case of obstruction when tumour is unresectable

18 Radical resection vs. other therapies Radical resection (n= 90) Other therapies (n= 83) p = Median: 40.4 months

19 Treatment algorithm for limited disease NET Gastric 1,2 Duodenal Appendiceal Rectal Ileal,pancreatic and colon

20 Management of gastric NEN 23% ERC 2010; 17:909

21 Gastric Neoroendocrine Neoplasms GNEN type 1 GNEN type 2 GNEN type 3 % GNET Characteristics neoplasms Single or multiple, polypoid small sized lesions (1-2 cm) Multiple, polypoid small sized lesions (1-2 cm) Mostly single polypoid, ulcerated lesions, size >2cm, Concomitant pathologies Chronic atrophic gastritis Gastrinoma/MEN1 - Histopathological features Well differentiated neoplasms Well differentiated neoplasms Well/moderate differentiated neoplasms Serum gastric Ν Gastric PH Ν Metastases % Deaths 0 <

22 Management of Gastroduodenal Neoplasms Gastric tumors One or more lesions < 1cm Endoscopic resection Gastric carcinoid type 1 One or more lesions > 1cm YES EUS to access wall invasion and lymph node invasion NO Polypectomy EMR Invasion beyond submucosa or positive margins EMR Surgery Local resection Antrectomy Gastrectomy Histology Invasion Localization ENETS Neuroendocrinology 2012;95:74-87

23 Treatment of GCs type 1 with long acting somatostatin analogues ERC 2008, 15,

24 Αntrectomy Gastrin Chromogranin A

25 Management of Gastroduodenal Neoplasms Gastric NET Type 1 As per algorithm Gastric NET Gastric NET Type 2 Local excision Gastric NET Type 3 Treat as adenocarcinoma Partial/total gastrectomy LMN dissection Chemotherapy ENETS Neuroendocrinology 2012;95:74-87

26 Management of Duodenal Neoplasms d-nen (diagnosis on endoscopic biopsies) ᴓ < 1 cm 1 cm < ᴓ < 2 cm ᴓ > 2cm Periampullary Surgical resection Not periampullary Endoscopic resection Endoscopic vs. surgical resection (not standardized) EUS + CT scan for staging N+: surgical excision M+: SRS & medical therapy based on G ENETS Neuroendocrinology 2012;95:74-87

27 Neuroendocrine neoplasms of appendix ENETS UICC/AJCC T X primary tumor can not be assessed 0 no evidence of primary tumor 1 Tumor 1 cm invading submucosa and muscularis propria 1a 1b 2 Tumor 2cm invading submucosa, muscularis propria and/or minimally (up to 3 mm) subserosa/mesoappendix 3 Tumor > 2cm and/or extensive (>3mm) invasion or subserosa/mesoappendix Tumor 1 cm in greatest diameter Tumor > 1cm but 2 cm in greatest diameter Tumor > 2 cm but 4 cm or with extension to the caecum Tumor > 4 cm or with extension to the ileum 4 Tumor invades peritoneum/other organs Tumor perforates peritoneum or invades other adjacent organs or structures (abdominal wall and skeletal muscles)

28 Management of Appendiceal NEN T1/T1a (<1cm) Simple appendicectomy (?Base/3mm) Appendiceal NEN T2/T1b (1-2cm) Base >3mm Ki67>3% angionvasion R hemicolectomy Goblet cell tumors T3/T2 (>2cm) R hemicolectomy Neuroendocrinology 2012, 95:146

29 Management NEN of the rectum Rectal NEN at endoscopy < 1cm 1-2 cm > 2cm Without Muscularis invasion Muscularis invasion MRI/CT MRI/SRS/PET Endoscopic resection Transanal resection Without muscularis invasion, N- Transanal Muscularis invasion, N+ Anterior resection Without mets Obstruction With mets No Obstruction Transanal resection Incomplete resection Anterior resection Adjuvant therapy if LMN Surgery & Medical therapy Medical therapy

30 Radical Surgery in GEP-NETs: Consider Likelihood of Malignancy (Location & size) Site Low malignant potential Malignant Jejunoileal* Same as in carcinoma irrespective size Pancreas Atypical resection: Enucleation Middle pancreatectomy 2 cm cut-off Typical resection, same as in carcinoma: Pancreatic duodenectomy Left pancreatectomy In absence of liver metastases or nearby structure invasion * NEN Colon: Same as carcinomas (? Size < 2cm polypectomy or EMR)

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32 Treatment algorithm for symptom control of functioning tumors Top up doses of SS Carcinoid syndrome Somatostatin analogs (SS) SS & INFa Functioning tumors* Gastrinomas PPi SS Investigational drugs Pasireotide Telotristat Insulinomas SS (SRS) diazoxide Everolimus Other functioning tumors SS * Cytoreductive techniques

33 Treatment algorithm for extensive disease

34 Debulking Procedures in GEP-NETs Aims Means Reduce mechanical symptoms Preserve one target organ (the liver) for further therapies Improve survival Surgery TACE RFTA Radioembolization Combination of these procedures RFTA: radiofrequency thermal ablation; TACE: transarterial (chemo) embolization

35 Prognosis and Clinical Course of Patients With Liver Metastatic Midgut NETs: A Retrospective European Study Survival of patients with bowel bypass vs. failed resection, no resection, or resection 1.0 Log rank (Mantel-Cox) P <.000 Cumulative Survival Primary removed Bowel bypass (n = 12) Failed resection (n = 17) No resection (n = 80) Resected (n = 210) Yrs 5 Yrs 10 Yrs 15 Yrs 20 Yrs 25 Yrs 30 Yrs Duration of follow up from date of diagnosis Ahmed A, et al. Endocr Relat Cancer. 2009;16:

36 Stage IV NETs liver mets only

37 Elias D et al. Ann Surg 2010;251:

38 Discrepancy between imaging, intra-operative, histological findings Lack of evidence based data whether surgical is superior to other cytoreductive techniques Elias D et al. Ann Surg 2010;251:

39 Stage IV GEP-NETs : Results on chemotherapy Clinical Evidence based mostly on Ph II & retrospective studies Tumor types DTIC FU+STZ Dox+STZ Temoz. Temoz+Bev CDDP+Eto Carcinoid 16% 16% % - - Pancreatic 34% 45% 69% (40%)** PD carcinoma 70%* 24% % DTIC: dacarbazine; FU+STZ: fluorouracil+streptozotocin; Dox: dorubicin; Temoz: temozolomide; Bev: bevacizumab; CDDP+Eto: cisplatin+etoposide Temozolomide + Capecitabine (Strosberg et al. Cancer 2011, 117:268) ** Retrospective studies Costa et al, Best Practice&Research Clinical Gastroenterology 2013 (in press)

40 Outcome of GEP-NET on currently existing evidence N Overall survival RADIANT 3 (phase III)1 Everolimus Placebo Sunitinib (phase III)2 Sunitinib Placebo Streptozocin based chemotherapy 3* Streptozocin fluorouracil Streptozocin doxorubicin PRRT 4** PRRT with 177Lutetium PRRT with 90Yttrium (821) Not reached 36.6 months 30.5 months 24.4 months 16.8 months 26.4 months 46 months 30 months 1. Yao et al, NEJM 2011, 364(6): , 2. Raymond et al, NEJM 2011, 364 (6); , 3. Moertel et al, NEJM 1992, 326(8): , 4.Kwekkeboom et al, JCO 2008, 26; , 5. Imhof et al, JCO 2011, 29: * Prospective but not randomized, **Single center studies

41 Drug ENETS: Therapeutic options and conditions for preferential use as first line therapy Functional status Grading Primary site SSTR status Special considerations Octreotide + G1 midgut + Low tumor burden Lanreotide + G1 + Placebo control data on antiproliferative activity pending STZ+5FU ± G1-2 pancreas Progressive in short term, high tumor burden or symptomatic TEM/CAP ± G2 pancreas Progressive in short term, high tumor burden or symptomatic, or contraindication for STZ based CTX Everolimus ± G1-2 pancreas Insulinoma, contraindication CTX Sunitinib ± G1-2 pancreas Contraindication CTX PRRT ± G1-2 any + Extended disease, extrahepatic disease (bone metastases), down-staging Cisplatin & etoposide ± G3* any ± Poorly differentiated NEC CTX: chemotherapy, STZ: streptozotocin, SSRT: somatostatin receptors, G3*:heterogeneity

42 An Oncol 2013, 24:

43 Therapeutic algorithm for PDNEC

44 Algorithm for sequential non-surgical treatment in patients with well differentiated (G1,2) advanced (stage IV) GEP-NETs

45 Functioning SS analogs Investigational drugs ** (Pasireotide) High volume* Slow growth SS analogs GI NET Non-functioning High volume* Rapid growth Low volume Rapid growth Everolimus? PRRT Investigational drugs Chemotherapy PRRT GEP NET Functioning Low volume Slow growth SS analogs, PPi, everolimus SS analogs pnet High volume Slow growth* MT** Non-functioning High volume* Rapid growth Low volume Rapid growth Chemotherapy PRRT Investigational drugs Second line chemotherapy *Cytoreductive techniques **MT=Molecular targeted therapy Low volume Slow growth MT**

46 Concluding remarks Patients with GEP-NETs should be managed by multidisciplinary team preferably in experienced centers (Centers Excellence) Factors to consider include: Where is primary site? Progressive or stable disease? Stage and grade of disease? Central registration patients, regular auditing & early involvement in multicenter (phase III or non-inferiority) trials Consider tumor molecular profile & potential combination of treatments

47 Future Directions Biomarkers and molecular imaging for evaluation of therapeutic response Personalized treatment based on molecular genetics and tumor biology WHO and TNM classification Molecularly targeted treatment will be the future: Targeted agents PRRT Combinations of traditional cytotoxics with targeted agents Combinations of targeted agents

48 Ευχαριστώ