GI CARCINOID Dr Mussawar Iqbal Consultant Oncologist Hull and East Yorkshire Hospitals NHS Trust

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1 GI CARCINOID Dr Mussawar Iqbal Consultant Oncologist Hull and East Yorkshire Hospitals NHS Trust

2 Introduction Carcinoid was old term, introduced in 1906 by German pathologist Cancinoma like More recent nomenclature is Gastroenteropancreatic Neuroendocrine Tumours (GEP-NET) 80% in small and large bowel, 20% in stomach and Pancreas.

3 Classification Various classification used to describe them Embryological (Fore gut, mid gut and hind gut) Behaviour (Carcinoid, Atypical carcinoid and neuroendocrine carcinoma) Histological (Well differentiated, moderately well differentiated and poorly differentiated)

4 CLASSIFICATION

5 Presentation Primary often small and asymptamatic Symptoms more often when metastasis occurs Can secrete variety of Hormones like Histamine, Gastrin, Somatostatin, Serotonin When symptomatic, symptoms depends upon location of tumour and anatomy of organ involved, like obstruction, perforation, bleeding etc.

6 Incidence of NETs Increasing Incidence per 100,000 - NETs All malignant neoplasms Neuroendocrine tumors Incidence per 100,000 All malignant neoplasm Yao JC et al. J Clin Oncol. 2008;26:

7 Investigation Identify the primary Depends upon symptoms Upper and lower GI endoscopy CT scan Fasting Gut hormones Extent of disease CT/MR scan MIBG scan Octreotide scan PET scan (Gallium) ECHO cardiography

8 Investigation Tumour markers Help in diagnosis Monitoring treatment Two commonly used markers are: Serum chromogranin A Urine 5 HIAA false +ve tryptophan/ serotonin-rich foods (bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, and walnuts)

9 Behavior of GI Carcinoids by Site

10 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential

11 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant

12 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant

13 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant Appendiceal (40%). 1% malignant

14 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant Appendiceal (40%). 1% malignant

15 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant Appendiceal (40%). 1% malignant Hindgut carcinoids Rectal (20%), 15% malignant

16 Gastric Carcinoids

17 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis

18 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm)

19 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent

20 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent!! Sporadic

21 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent!! Sporadic!! Account for 20% of gastric carcinoids

22 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent!! Sporadic!! Account for 20% of gastric carcinoids!! Most aggressive

23 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent!! Sporadic!! Account for 20% of gastric carcinoids!! Most aggressive!! Metastatic in 60% at resection

24 Gastric Carcinoids Type I! Atrophic Gastritis, Autoimmune Gastritis Type II! ZE, MEN (type 1) Clinical course is usually indolent (if <1 cm) Type III. Gastrin-independent!! Sporadic!! Account for 20% of gastric carcinoids!! Most aggressive!! Metastatic in 60% at resection!! May produce 5-HT and cause carcinoid! syndrome

25 Small Bowel Carcinoids

26 Small Bowel Carcinoids Most aggressive

27 Small Bowel Carcinoids Most aggressive May present with obstruction or abdominal pain due to intussusception, mechanical effect of the tumor, or mesenteric ischemia due to local fibrosis or angiopathy

28 Small Bowel Carcinoids Most aggressive May present with obstruction or abdominal pain due to intussusception, mechanical effect of the tumor, or mesenteric ischemia due to local fibrosis or angiopathy Carcinoid syndrome present in up to 10% patients

29 Small Bowel Carcinoids Most aggressive May present with obstruction or abdominal pain due to intussusception, mechanical effect of the tumor, or mesenteric ischemia due to local fibrosis or angiopathy Carcinoid syndrome present in up to 10% patients Multiple tumors in up to 30% of patients (worse prognosis)

30 Small Bowel Carcinoids Most aggressive May present with obstruction or abdominal pain due to intussusception, mechanical effect of the tumor, or mesenteric ischemia due to local fibrosis or angiopathy Carcinoid syndrome present in up to 10% patients Multiple tumors in up to 30% of patients (worse prognosis)!!

31

32 Appendiceal Carcinoids Typically benign course 1/300 appendices contains a carcinoid tumor Often found incidentally Goblet cell carcinoid variety makes serotonin and is more aggressive!!

33 Colon/Rectal Carcinoids Colon Usually right colon, particularly caecum Carcinoid syndrome is rare Rectal Carcinoids!! Size correlates with metastases: <1 cm - rare; > 2 cm (>70%) Carcinoid syndrome is rare Local excision of small carcinoids Extensive excision of larger (similar to adenocarcinoma) Controversial between 1cm and 2cm

34 Carcinoid Syndrome Manifests in the form of diarrhoea and flushing Occurs primarily with liver metastasis. Liver inactivates bioactive products; thus carcinoid syndrome does not happen in absence of liver mets (or non-gi carcinoids) Diversion of tryptophan to serotonin can result in tryptophan and nicotinic acid deficiency (pellagra) Serotonin causes diarrhea, stimulates fibroblast growth and fibrogenesis Serotonin does NOT cause flushing Flushing may be caused by histamine and kallikrein Most useful initial test is 24-hour urine 5-HIAA

35 Treatment General measure replacement of electrolytes and fluid lost in the course of diarrhoea; anti-ulcer medicines; avoiding food that precipitates symptoms etc. Surgery Resection of: Primary Appendectomy, right hemicolectomy, lobectomy Metastasis Ablation

36 Treatment Drug treatment Somatostatin receptor antagonist Short acting Long acting (Sandostatin LAR, Somatuline Autogel) Biologics Alpha interferone Chemotherapy Sunitinib Everolimus Cisplatin/Carboplatin + Etoposide. Streptozocin Adriamycin 5FU PRRT (Peptide Receptor Radionuclide Treatment)

37 Octreotide: Side effects Abdominal discomfort (29%) Flatulence (25%) Constipation (19%) Nausea (10%) Gall stones, biliary sludge, jaundice (62% over 18 months therapy) Hypoglycemia/Hyperglycemia Hypothyroid

38 PROMID: Octreotide LAR Slows Progression in Midgut NETs Proportion without progression TTP in Midgut NET Octreotide LAR vs placebo P = HR = 0.34 [95% CI: ] Time (months) Octreotide LAR (n = 42) Median 14.3 months Placebo: (n = 43) Median 6.0 months Based on conservative ITT analysis HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP = time to progression Rinke A et al. J Clin Oncol. 2009;27:

39 Other Trials CLARINET Study Assessing the effect of lanreotide autogel on tumour progression-free survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumours. >200 pts Awaiting analysis RADIANT 4 Double-blind, phase III study of Everolimus plus best supportive care Vs placebo + BSC in advanced NET GI/Lung origin

40 Cytotoxic Chemotherapy Streptozocin/Doxorubicin: 6-wk cycle Streptozocin 500 mg/m2 IV daily for 5 days Doxorubicin 50 mg/m2 IV days 1 and 22 (cumulative max dose of 500 mg/m2) 5FU/Doxorubicin/Streptozocin: 28 day cycle Streptozocin 400 mg/m2 IV days 1-5 5FU 400 mg/m2 IV bolus days 1-5 Doxorubicin 40 mg/m2 IV day 1 Temozolomide/Capecitabine: 28 day cycle Capecitabine 750 mg/m2 per dose PO BID, days 1-14 Temozolomide 200 mg/m 2 PO QD, days 10-14

41 PRRT Peptide Receptor Radionuclide Therapy (PRRT) Systemic radiotherapy Radiolabeled Somatostatin analogs Two potent agents 177 Lu-octreotate 90 Y-octreotide Available only in Few centre in UK

42 PRRT: Why to give? Study N Radiolabeled somatostatin analog Response (PR+CR) Symptom relief or reduction Median overall survival (Months) Bushnell, 2010 USA 90 90Y-edotreotide 4% >50% 26.9 Delpassand, 2008 USA 18 In-111 pentetreotide 11% N/A 13.3 Kwekkeboom 2008 Netherlands Forrer 2006 Switzerland 310 Lu-177-octreotate 30% N/A Y-DOTATOC 27% 83% N/A Anthony 2002 USA 26 In-111 pentetreotide 8% 62% 18 Schmidt et al, Oncogene, 2011

43 Any Questions?

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