CARCINOID and PANCREATIC NEUROENDOCRINE TUMORS

PRESENTED BY: ALOK GUPTA

History

1890- Ranson, first description of a carcinoid(Ileum).

1907- Oberndorfer, used the term ‘karzinoide’.

1928- Masson stated that carcinoids should be considered as endocrine tumors.

1953- Lembech demonstrated the presence of serotonin in carcinoid tumors.

1955- Page et al. described increased urinary 5-HIAA in patients with carcinoid syndrome.

Modlin IM, Oberg K, Chung DC et al. Gastroenteropancreatic neuroendocrinetumours. Lancet Oncol 2008; 9: 61–72

Epidemiology

SEER- the estimated annual incidence of carcinoid tumors in 2004 was 5.25 per 100,000 population and slightly more common in females (55% of all cases).

The incidence in England, Scotland, Spain, Italy, and Japan is 0.7 per 100 000 people.

In autopsies, however, the rate tends to be much higher. (0.65%- 1.2%)

Nomenclature and Classification of Neuroendocrine Tumors

Evolving process:

• 1907- Oberndorfer, used the term ‘karzinoide’.

• 1963- Williams & Sandler(location)

• 1980- The first WHO classification of NETs

• 2000–2004- WHO updated classification based on histopathology.

• 2006 and 2007- ENETs TNM system based on the WHO system. ENETS also proposed three tumor grades based on mitotic count and proliferative index (Ki-67).

• 2009- International Union Against Cancer/ American Joint Committee on Cancer published a new TNM classification system

Carcinoid Incidence by Location

Location % of Patients

Foregut Thymus 0.4%

Lung, bronchi, trachea 29.8%

Stomach 4.9%

Midgut Small intestine 30.4%

Gallbladder, pancreas 1%

Appendix 5.1%

Hindgut Colon 9.2%

Rectum 14.5%

Adapted from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934-959.

Pathology

The neuroendocrine cell system:

1. Glands

2. DNES(lung, gastrointestinal tract, skin, thyroid, thymus, pancreas, biliary, and urogenital tracts)

Carcinoid tumors are characterized by monotonous sheets of small round cells with uniform nuclei and cytoplasm.

(a) Microscopic section from a well-differentiated neuroendocrine carcinoma demonstrating low mitotic rate and low-grade bland histology.

(b) Microscopic section from a poorly differentiated neuroendocrine carcinoma demonstrating high mitotic rate and high-grade histology similar in appearance to small cell carcinomas.

Well differentiated NET

A. Carcinoids:1. Gastrointestinal carcinoids(75%)2. Non-Gastrointestinal carcinoids(25%)

B. Pancreatic NET1. Gastrinoma, 60% malignant, 90% multiple, 30%-

MENI, majority in duodenum2. Insulinoma, 10% malignant, 80% active3. Glucagonoma, usually malignant, 4D4. VIPoma, Somatostatinoma, Ppoma.

Gastrointestinal carcinoids

A. Gastric carcinoids:

• 75% a/w chronic atrophic gastritis type A

• 5-10% a/w gastrinoma and the familial MEN1

• 15-25% sporadic cases

B. Intestinal carcinoids:

• Midgut carcinoid- mc type of carcinoid, frequently presents with intestinal obstruction, abdominal pain, diarrhea, and gastrointestinal bleeding. 90% cases of carcinoid syndrome.

Symptoms

• Endocrinologically inactive(50-70%) Appendicitis, bowel obstruction, painful hepatomegaly. Bronchial carcinoids produce cough, hemoptysis, frequent pulmonary infection.

• Endocrinologically active(30-50%)- carcinoidsyndrome- Attacks of flushing, diarrhea, hypotension, light-headedness, bronchospasmeither spontaneous or precipitated by emotional or physical stress, alcohol, vigorous liver palpation.Heart failure, chronic skin changes

neuron-specific enolase, 5-hydroxytryptophan(5-HTP), synaptophysin, chromogranin-A and C, growth hormone, neurotensin, pancreatic polypeptide,calcitonin, tachykinins, growth hormone-releasing hormone,bombesin, adrenocorticotropic hormone

(ACTH),kallikrein, glucagon,

histamine, catecholamines, prostaglandins,substance P, gastrin, insulin, pancreastatin, And various growth factors such as transforming growth factor(TGF-), platelet-derived growth factor (PDGF), and bfibroblast growth factor

Carcinoid tumors produce and secrete a number ofsubstances, including

Carcinoid Syndrome

99% 1%

Niacin

5-HIAA

5-HT

DietaryTryptophan

99% 1%

Pellegra- Triad: dermatitis, diarrhea, dementia

Symptoms cont..

• Specific to the type of pancreatic neuroendocrine tumor:

1. Gastrinoma- severe peptic ulcer disease with diarrhea.

2. Insulinoma- fasting hypoglycemia

3. Glucagonoma- dermatosis, diarrhea, depression and deep vein thrombosis.

4. VIPoma- Watery diarrhea, hypokalemia, achlorhydria.

Diagnosis

• Routine blood- CBC, RFT, LFT, FBS, SE• Abdominal USG/CT scan• Chest CT• Upper GI endoscopy• Nuclear imaging using radiolabelled somatostatin analog-

Octreoscan(80-90% sensitive), Lu177 DOTATOC• Biopsy• Symptomatic pts- 5-HIAA( 24 hours urinary level>9mg),

CgA(non-specific)• Others- Fasting serum gastrin level(>500 pg/ml),

insulin(>6µU/ml + hypoglycemia), C peptide.• Individuals with sporadic or familial bronchial or gastric

carcinoid should have a family history evaluation and consideration of testing for germline MEN1 mutations.

Radiopharmaceuticals used in imaging NETs

(68)Ga-DOTATOC PET is superior to (111)In-DTPAOC SPECT in the detection of NET manifestations in the lung and skeleton and similar for the detection of NET manifestations in the liver and brain-Buchmann I et al, Eur J Nucl Med Mol Imaging. 2007 Oct;34(10):1617-26. Epub2007 May 23.

Sensitivities (%) of various imaging techniques

Ramage JK, Davies AH, Ardill J et al. Guidelines for the management ofgastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005; 54 (Suppl 4): iv1–iv16.

Prognostic factors for NET

• A primary tumour of >2.5 cm

• Presence of clinical symptoms

• Ki67 index

• Any oncological surgical procedure was associated with a decreased risk of death.

• Presence of metastasis at initial diagnosis is a risk factor for firsttumour progression.

-Ulrich-Frank Pape et al,Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer (2008) 15 1083–1097

In patients with midgut carcinoids:

• multiple liver metastases,

• presence of carcinoid syndrome,

• advanced age and

• plasma chromogranin A >5000 μg/l were independent predictors of overall survival.

- Janson ET et al,Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center. Annals of Oncology.1997, vol. 8, no7, pp. 685-690.

Treatment

• Principle- Therapeutic restraint

• Octreotide- ameliorates symptoms in 90%.

• Hypotension- Methoxamine, norepinephrine

• Flushing- H1 and H2 blockers, prednisolone

• Bronchospasm- aminophylline

• Diarrhea- loperamide, diphenoxylate, methysergide, ondansetron

Treatment

Locoregional disease: Resection of the primary tumor and local lymph nodes is the treatment of choice. Adjuvant therapy for carcinoid tumors is not recommended.

• Localized pulmonary carcinoid tumors, a wedge or segmental resection is preferred.

• Gastric carcinoids- <1cm local excision,>2cm subtotal gastrectomy.

• S I carcinoid- resection that includes lymphadenectomyand removal of the mesentery.

• Carcinoids of the appendix-< 2 cm appendectomy, >2cm right hemicolectomy.

Treatment of Advanced Disease

1. Treatment of Patients with Hepatic-predominant Metastatic Disease

2. Somatostatin Analogs

3. Peptide receptor radionuclide therapy (PRRT)

4. Interferon Alpha

5. Cytotoxic Chemotherapy

6. Molecular Targeted Therapy

Treatment of Patients with Hepatic-predominant Metastatic Disease

• In selected cases, metastatic liver disease can be surgically resected.

• The role of transplantation in this setting remains uncertain.

• Hepatic arterial embolization

1. Bland (gelatin powder, polyvinyl alcohol)

2. Chemo (fluorouracil/doxorubicin/CDDP/mitomycin C)

3. Radioembolization- yttrium (90Y) microspheres

Tumor response rate:

For Bland and chemo embolization: 33% to 60%

For Radioembolization: 63%

Somatostatin Analogs

• SSTRs are highly expressed on NETs(5 subtypes- SSTR1–5)• Somatostatin inhibits the release of pituitary hormones and

GI hormones (e.g., insulin, gastrin, and serotonin), inhibits flushing, diarrhea, and other symptoms of carcinoidsyndrome.

• It also has antiproliferative, proapoptotic, and anti-angiogenic activity.

• Analogs:1. Octreotide: 2 forms, an aquaeous, immediate-release product

and long-acting release (LAR) form.2. Lanreotide and Lanreotide Autogel(new).3. Pasireotide is a panreceptor agonist that binds SSTR1–3 and

SSTR5 with high affinity

Response Rate to somatostatin analogs

A randomized study of lanreotide sustained release compared with octreotide in 33 patients with carcinoid syndrome demonstrated similar rates of symptom control. O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of

carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotidein terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88:770- 776.

• Octreotide LAR significantly lengthened time to tumor progression compared with placebo (14.3 and 6 months, respectively; p 0.000072) in midgut carcinoids.(independent of functionality, CgA level, PS or age).

• Rinke A, Mu¨ ller H, Schade-Brittinger C, et al. Placebo-controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27:4656-4663.

‘Escape from response’ phenomenon: Role of pasireotide

• After 6–18 months, mechanism unknown

• Pasireotide -high affinity for sst1–3 and sst5

• In a phase II trial of patients with refractory carcinoid syndrome treated with pasireotide, symptom control was achieved in 12 (27%) of 44 patients. Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of

pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study. J Clin Oncol 2006;24:18s (suppl; abstr 4082).

• A phase III study of pasireotide LAR versus octreotide LAR is ongoing

Peptide receptor radionuclide therapy (PRRT)

• The most frequently used radionuclides for targeted radiotherapy include 90Y and 177Lu.

• Complete and partial tumor remissions with [177Lu-DOTA0,Tyr3]Octreotate: occurred in 2% and 28% of 310 GEPNET patients.Median time to progression was 40 months and median OS was 46 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis.

- Dik J. Kwekkeboom et al. Treatment With the Radiolabeled Somatostatin Analog

[177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival. J Clin Oncol 26:2124-2130.

• 90Y-edotreotide was evaluated in a prospective, phase II study of 90 patients with metastatic carcinoid tumors. The objective tumor response rate was 4%, although more than 50% of patients experienced improvement in symptom control.

Interferon Alpha

• Mechanism: IFN-alpha 2a and IFN-alpha 2b bind to specific IFN receptors on NET cells, potentially leading to changes in gene transcription, inhibition of protein synthesis, and degradation of peptide hormones.

• Have a biochemical response in at least 30% to 35% of patients. Oberg KE. Gastrointestinal neuroendocrine tumors. Ann Oncol. 2010; 21:vii72-vii80 (suppl 7).

• One prospective randomized trial of octreotide with or without IFN-alpha in patients with progressive metastatic foregut and midgut NETs has reported no substantial differences in time to treatment failure and long-term survival between treatment arms. Arnold R, RinkeA, Klose K, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3:761-771

• The role of IFN in the treatment of carcinoidremains controversial. When used, it is typically after a trial of SSTAs, in the setting of unresectable, progressive metastases, alone or in combination with octreotide.

• Currently, IFN is being compared with bevacizumab in a large randomized study performed by the Southwest Oncology Group (SWOG) and the North American Intergroup (S0518).

Cytotoxic ChemotherapyCarcinoid1. Streptozocin/fluorouracil (FU)2. Doxorubicin/FU• The radiographic response rate was similar for the two

regimens (16% each), and there was a slight but statistically significant median survival benefit associated with streptozocin/FU (24 vs. 16 months).Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23:4897-4904.

3. Temozolomide-based regimens, only one patient (2%) experienced a tumor response. Kulke M, Hornick J, Frauenhoffer C, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009;15:338-345.

With relatively modest response rates they are currently rarely used in this setting.

Pancreatic NETs

• In contrast to carcinoid tumors, pancreatic NETs are clearly responsive to cytotoxic chemotherapy.

STREPTOZOCIN BASED:

• Treatment with streptozocin and doxorubicin was associated with combined biochemical and radiologic response rate of 69% and a median survival duration of 2.2 years. Moertel CG,

Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced isletcell carcinoma. N Engl J Med. 1992;326:519-523

TEMOZOLOMIDE BASED:In phase II studies in pancreatic NET, temozolomide has been combined with thalidomide, bevacizumab, or everolimus, with overall response rates ranging from 24% to 45%.•Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401-406.•Kulke M, Stuart K, Earle C, et al. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:18s (suppl; abstr 4044).•Kulke M, Blaszkowsky L, Zhu A, et al. Phase I/II study of everolimus (RAD001) in combination with temozolomide (TMZ) in patients (pts) with advanced pancreatic neuroendocrine tumors(NET). 2010 Gastrointestinal Cancers Symposium:Abstract 2010;127.

Temozolomide combined with capecitabine- objective response rate was 70%.Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomidein patients with metastatic pancreatic endocrine carcinomas. Cancer. 2010;117:268-275.

Molecular Targeted Therapy

• Inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway and the mammalian target of rapamycin (mTOR) have demonstrated activity in patients with NETs.

• These agents appear to be more active in pancreatic than in carcinoid NETs.

Vascular Endothelial Growth Factor Pathway Inhibitors

• VEGF expression correlates with angiogenesis, metastases, and decreased PFS among patients with low-grade NET.

• Agents under investigation/approved:

– the anti-VEGF antibody bevacizumab,

– VEGFR tyrosine kinase inhibitors (TKIs), including sunitinib, sorafenib, and pazopanib.

TKI in Carcinoid NETs.

• Sunitinib, sorafenib, and pazopanib have been evaluated in the phase II setting.– low radiographic response rates (2.4%)

– relatively high rate of disease stabilization(83%)

– encouraging PFS duration (6-months PFS, 40% to 73% across studies).

• Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitnib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403-3410.

• Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol. 2007;25:18s (suppl; abstr 4505).

• Phan A, Yao J, Fogelman D, et al. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol, 2010;28:18s (suppl; abstr 4044).

Bevacizumab in Carcinoid NETs.

• Phase II study of 44 patients, patients were randomly assigned to 18 weeks of bevacizumab or pegylated IFN alpha 2b, followed by treatment with both drugs.

• Results: During the first 18 weeks of therapy, – four (18%) of the bevacizumab-treated patients

experienced radiographic partial responses,

– 95% of patients treated with octreotide plus bevacizumabremained progression free, compared with only 68% of those receiving octreotide plus IFN alpha 2b.

• On the basis of these results, SWOG is leading a large, randomized study of bevacizumab compared with interferon in patients with advanced carcinoid tumors(S0518).

TKI in Pancreatic NETs.

• In an initial phase II trial, sunitinib (50 mg daily for 4 of every 6 weeks) was administered to 109 patients with advanced NETs.

• Result: Of 61 patients with pancreatic NETs, 11 (18%) had a partial response.– Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitnib in patients with advanced

neuroendocrine tumors. J Clin Oncol. 2008;26:3403-3410.

171 patients were randomly assigned to receive sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was PFS.

Agent No. ofPatients

TumorResponseRate (%)

Median TTPor PFS(Months)

Sunitinib 86 9 11.4

Placebo 85 0 5.5

(hazard ratio [HR] 0.42; p 0.001).

• Two other tyrosine kinase inhibitors, sorafeniband pazopanib, have been evaluated in phase II study.

Sorafenib -responses were observed in 11% Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol. 2007;25:18s (suppl; abstr 4505).

Pazopanib-The response rate among patients with pancreatic NETs was 17%.Phan A, Yao J, Fogelman D, et al. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol, 2010;28:18s (suppl; abstr 4044).

mTOR Pathway Inhibitors

CARCINOID• Phase II study of Everolimus+octreotide- Partial

responses were observed 17% patients.• Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in

advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311-4318.

• Phase III study- 429 patients were randomly assigned to receive everolimus plus octreotide LAR, or placebo plus octreotide LAR. Although this analysis also favoredthe everolimus arm over placebo (PFS- 16.4 vs. 11.3 months; HR 0.77, p 0.026), the predefined threshold for statistical significance (p 0.0246) was not met.

• Yao JC, Hainsworth JD, Baulin E., et al. Everolimus plus octreotide LAR (EO) versus placebo plus octreotide LAR (P) in patients with advanced neuroendocrine tumors (NET): updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2). J Clin Oncol. 2011;29:4 (suppl; abstr 159).

mTOR Pathway Inhibitors in Pancreatic NETs.

• Phase II study- octreotide + everolimus, 27% of patients experienced partial responses.

• Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotideLAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311-4318.

Agent No. ofPatients

TumorResponseRate (%)

Median TTPor PFS(Months)

Everolimus 207 NR 11

Placebo 203 NR 4.6

Everolimus was associated with a significant prolongation in median PFS (11.6 vs. 4.6 months; HR 0.35, log-rank p 0.0001).

James C. Yao,et al(RADIANT-3)

Combination Regimens with Molecularly Targeted Therapies

• Everolimus and bevacizumab was recently shown to be well tolerated and associated with an overall response rate of 26% in a phase II single-arm study enrolling patients with low- or intermediate-grade NETs.

• Combination of temozolomide and everolimus in patients with pancreatic NET reported objective response rate of 35%.

• The combination of everolimus with pasireotideis also well-tolerated and potentially active.

Studies from India

• Amarapurkar DN, et al. A retrospective clinico-pathological analysis of neuroendocrine tumorsof the gastrointestinal tract. Trop Gastroenterol2010 Apr-Jun;31(2):101-4.

• Results:74 patients, male preponderance(2.5:1), stomach 22 (30.2%), followed by pancreas 17 (23.3%) and duodenum 14 (18.9%), 3 (4.1%) patients presented with carcinoid syndrome, disease was localized in 46.

Summary

• The clinical course of patients with metastatic NETs is highly variable.

• Patients with symptoms of hormone hypersecretion will, in most cases, achieve symptomatic improvement with somatostatin analogs.

• Advanced Carcinoid- Treatment with SSTAs has been shown to improve PFS. IFN or cytotoxic agents are sometimes used in the second-line setting. mTOR and VEGF pathway inhibitors have shown activity in carcinoid but the precise role of these agents has not yet been established.

• Advanced pancreatic NETs- Treatment with either everolimus or sunitinib has recently been shown to prolong PFS. Treatment with streptozocin- or temozolomide-based regimens will likely also continue to play a role particularly in those with a high tumor burden.

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