Treatment of Gastroenteropancreatic Neuroendocrine Tumors GEPET

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Treatment of Gastroenteropancreatic
Neuroendocrine Tumors(GEPET)

• Michael Gu, M.D
• 11/21/03

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Case 1

• 58 y.o. AAF.
• Abdominal bloating, weight loss(gt50 Ib) x 12
  months.
• CT scan
• Bone scan ()T8 and left hip.
• Liver bx
• Tumor cells () of synaptophysin, chromogranin,
  neuron-specific enolase.
• Metastatic pancreatic islet cell carcinoma.

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Case 2

• 63 y.o. WF.
• LUQ pain and 25 Ib Wt. Loss in 1 year. Diagnosis
  of diverticulitis.
• Acute onset of right side headache ptosis, and
  CN III/VI palsy.
• MRI of head 1.1 cm sella mass with cavernous
  extension.
• CXR right hilar mass
• CT of the abdomen
• Liver bx
• Tumor cells ()chromogranin, (-)synatophysin
• Metastatic carcinoid tumor

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Case 2

• 63 y.o. WF.
• LUQ pain and 25 Ib Wt. Loss in 1 year. Diagnosis
  of diverticulitis.
• Acute onset of right side headache ptosis, and
  CN III/VI palsy.
• MRI of head 1.1 cm sella mass with cavernous
  extension.
• CXR right hilar mass
• CT of the abdomen
• Liver bx
• Tumor cells ()chromogranin, (-)synaptophysin
• Metastatic carcinoid tumor

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Gastroenteropancreatic (GEP) Neuroendocrine Tumor

• Incidence 1-2/100,000
• Classification
• Functionality - Functional
• - Non-functional
• Sporadic or association with MEN1
• Localized or metastatic no TNM stage
• State of differentiation well differentiated
  -anaplatic .
• Etiology
• Sporadic Unknown
• MEN 1 associate menin gene defect

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Type, Distribution and Frequency of
GEPNET
Relative frequency
Function
Histology
Foregut 30 Functional Islet
cell
Midgut 60 Functional
Carcinoid
Hindgut lt10 Non-functional Carcinoid
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Neuroendocrine Tumors of Pancreas(Islet Cell
Tumors, ICT)

• Neuroendocrine Tumors of Pancreas Islet cell
  tumor(gt95) Carcinoid (lt5)
• Endocrine pancreas
• Islets of Langerhans contains 5 cell types
• Incidence
• Random autopsies 1-1.5
• Clinical 1/100,000
• 250 new cases / year in US
• Age group 40-60

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Carcinoid Tumors(serotoninomas)

• Incidence
• 1/100,000 of autopsy
• appendix gt small bowel gt rectum
• 2/10, 000 clinical incidence
• 95 arise from GI
• MF 11.5
• Age 70
• Share many histology, ultrastructure and
  biochemical features with Islet cell tumors.
• Release
• neurotransmitters (serotonin, histamine)
• neuropeptides(tachykinins, VIP, bradykinin,
  prostagladins)

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• Clinical presentation
• Carcinoid syndrome
• Cutaneous flushing upper part of the body (80)
• Watery diarrhea and abdominal cramp (80)
• Bronchospasm
• Endocardial fibrosis( 30-40 ) arrhythmia. Right
  heart insufficiency.
• Bowel obstruction
• GI bleeding (rare)

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• Behavior is related to site of origin
• Midgut locations are most common
• Ileal lesions have the greatest metastatic
  potential
• Hingut tumors non-functional.
• Foregut tumors functional
• Midgut tumors
• 80 become functional when the liver metastasis
  established.
• Slow growing and has better prognosis than other
  neuroendocrine tumors.

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Non-functional neuroendocrine tumors

• Consists of -50 of the neuroendocrine tumor
  (Pathology ICT or Carcinoid).
• Most common primaries rectum and pancreas.
• Hypersecreation products are hormone-inactive
  or non-functional.
• Asymptotic until causing obstruction or
  metastasis
• Fatigue and weight loss
• Liver metastasis- protrusion and pain
• Obstruction GI or Biliary

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• Histology
• Small round cell
• Low proliferation index (Ki67)
• Commonly well differentiated.
• Some time the diagnosis of malignancy can only be
  made by the determination of metastasis or local
  invasion.
• Immunohistochemistory marker
• Chromogranin A
• Synaptophysin
• Neuron-specific enolase (less specificity)

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• Laboratory
• Blood chromogranin A level
• Islet cell
• Carcinoid
• 24 hour urine 5-hydroxyindlasecetic Acid level
  (5-HIAA)
• Carcinoid
• Specific hormone level
• In selected functional islet cell cases
• Imaging Studies
• Non-specific CT/MRI/US(EUS,IOUS)
• Specific Somatostatin-receptor scintigraphy
  (SRS). (Useful for both Islet cell and Carcinoid)

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Treatment

• Localized disease
• Curative resection
• Unresectable and Metastatic disease
• most symptomatic carcinoid tumor
• gt 60 non-insulinoma islet cell tumors
• Symptom control.
• Cytotoxic systemic chemotherapy.
• (Chemo)embolization of the liver lesions.
• Bioagent
• interefon
• New treatment options
• Antiangigensis
• Radiotherapy

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Symptomatic Treatment

• Medications
• PPI gastrinoma
• H2-blockade gastrinoma
• Somatostatin analogues most of the GEPNE
• Surgical Debulking
• Embolization or Chemoembolization

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Somatostatin Analogues
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Somatostatin Analogues

• Somatostatin receptor(SR) expresssed in 80-90 of
  the neuroendocrine tumors.
• Somastostatin analogues
• Octreotide and Ostreotide LAR
• Vapreotide(RC-160)
• Lanreotide
• Effect on GEPNET
• Symptomatic control
• Diarrhea/Flush 35-45 cases (200ug tid)
• Hormonal inhibition 30 cases
• Antiproliferation

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• As first choice
• Carcinoid Syndrome
• Glucagonoma Syndrome
• Verner-Morrison Syndrome
• Etopic functional tumor
• As second choice
• Gastrinoma
• Unpredictable effect
• Insulinoma
• only 50 SR ().
• less responsive in atypical granules or agranular
  tumors
• suppress glucagon and aggravate hypoglycemia.

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• Antiproliferative effect
• Study I
• 47 patients
• 3-6 months pretreatment observation shown
  CT-documented tumor progression
• octreotide 200ug tid
• results
• 40 stable disease for mediam 18 m
• no imaging tumor regression
• Study II(B Eriksson, Annal Oncology. 1997)
• 19 Pts (13 carcinoid and 6 ICT)
• 17/18 had () SRS
• 750-12,000 ug /day for 12 months
• 58 biochemical response
• 12 Pts(70) stable disease for 12 M
• 1 Pt (5) reduced tumor size

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• Side Effects
• Gallstone up to 60
• Diarrhea and steatorrhea
• inhibits fat absorption
• pancreatic enzyme supplement
• Alopecia
• Water intoxication
• N/V
• Pain at injection site
• Conclusion
• good symptomatic control.
• ? Anti- proliferation activity.

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Systemic Cytotoxic Therapy
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Streptozocin

• A broad spectrum antibiotic isolated from
  Streptomyces achromogenes.
• Nitrosourea analogy
• Mechanism intrastrand cross-links of DNA
• Effect on animal model (1960s)
• Antitumor effect mouse leukemia L1210
• Diabetogenic effect

1. Diabrtes 2. ? pancreas insulin level by 90 3.
Pancreatic ß- cell narcosis
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Streptozocin alone - Islet cell tumor

• First case report (A. L. Eddleston, et al,
  Lancet. 1968)
• NCI phase II study(1973)
• 52 patients with metastatic islet cell carcinoma
• Streptozotocin 0.6-1.0 gm/m2 weekly IV or IA
• Results
• Biochemical response 64
• Measurable disease response 50
• Toxicity
• N/V 98
• Renal 65 ( 5 Pts died of renal failure)
• Hepatic 67
• hematologic 20

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Streptozotocin 5FU
N Engl J Med. 1980 303 1189-94

• ECOG randomized study(12/72-12/78, 28
  institutions).
• 103 patients with advanced islet cell carcinoma.
• Regimens
• Streptozotocin alone 500mg/m2 IV QD x 5
• Streptozotocin alone 500mg/m2 IV QD x 5
• 5-FU 400 mg/m2 IVP QD x 5
• Repeat Q 6 weeks
• Result
• ? RR(64 vs. 12). ? CR(33 vs. 12)
• No significant survival benefit.

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Streptozocin Doxorubicin
N Engl J Med 1992 362 519-23

• ECOG randomize study(11/78-06/85)
• 105 Pts with advanced islet cell carcinoma
• Study arms
• Chlorazotocin 150mg/m2 x 1, Q7 weeks
• Streptozocin 500mg/m2 QD x 5, Q6 weeks
• 5-FU 400 mg/m2
• Streptozocin 500 mg/ m2 Q.D x 5
• Doxorubicin 50 mg/m2 day 1 and day22
• Results

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Response
Toxicity
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Progress Free survival
Overall Survival
MS 2.2 vs.. 1.2 years
PFS 20 vs. 6.9 months
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• Streptozocin based regimens are less effective in
  carcinoid than islet cell carcinoma (33 vs.66)

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Failure to Confirm Major Objective Antitumor
Activity for Streptozocin and Doxorubicin in the
Treatment of Patients with Advanced Islet Cell
Carcinoma
Cancer 199986944-948

• MSKCC. 2/92-2/98
• 16 patients with ICC treated with STZ Doxo.
• Results
• 1/16(6) with imaging PR.
• 9/16(56) with stable disease.
• 6/16(38) progressed during treatment.

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Etoposide Cisplatin
Cancer 68 227-232, 1991

• 57 patients with NET (well-differentiated
  Carcinoid, well-differentiated ICC and anaplastic
  neuroendocrine tumor).
• Etop 130mg/m2/d x 3. Cis 45mg/m2/d x 2 days.

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Other combination chemotherapy trials
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Interferon Based Regimen

• Well tolerated regimen with minimum toxicity
• As effective as streptozocin-based therapy in
  carcinoid(RR - 20) with less toxicity
• Less effective in inducing objective response in
  non-carcinoid neuroendocrine tumor.
• Interferon alone is as effective as interferon
  5-FU.

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Anti-Angiogenesis

• Expression of VEGF in GEPNET

• IHC with anti-N terminal peptide Ab of VEGF165

In ICT 16/20 80
In Carcinoid 25/28 89
B.Terris et al, Histopathology 1998, 32, 133-138
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Effect of angiogenesis inhibitors in mice model
G Bergers et al, science 1999, 284 808

• RIP1-Tag2 transgenic mouse model

Prevention
Intervention
Regression
5 W
10 W
15 W
Born
Death
Normal islets (-400/pancreas)
Hyperplastic islet (?50) B-cell
hyperproliferation and dysplasia Carcinoma in situ
Angiogenic islet Small adenoma Large
adenoma Invasive carcinoma
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Human Study

• SU011248
• Tyrosine kinase inhibitor of VEGFR and PDGFR
• Phase II trail

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Liver Embolization/chemoembolization

• Principle
• liver tumor derive gt80 of their blood supply
  from hepatic artery. Normal liver parenchyma is
  supplied mostly by portal vein.
• Occlusion of hepatic artery will accomplish
  relatively selective tumor ischemia
• Intra-arterially deliver chemo agents will have
  10 fold greater concentration in the tumor then
  given through the portal vein.

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Hepatic Artery Chemoembolization for Management
of Petients with Advanced Metastatic Cacinoid
Tumors
JG Drougas et al, Am J Surg 1998, 175408-412

• 15 patients progressing in symptom or tumor size
  while on somtostatin.
• IA 5-FU x 5 day HACE (adriamycin
  cisplatinmitomycine Cpolyvinly alcohol).
• Results
• ? markers 100
• ? diarrhea 67
• ? flushing 58
• ? abdominal pain 75
• tumor liquefaction 77
• ? PS from 66/-2 to 84/-2.

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• HAE/HACE regional therapy is safe and has good
  symptom palliative effect.
• It benefit more in carcinoid in terns of symptom
  palliation.(liver involvement is the source of
  hormone and the many of the symptoms)
• ?Survival benefit?
• Time to employ? Early or later in the disease
  cause?

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Radiotherapy

• Yttrium-90-labeled somatostatin analogue.
• 10 SRS () patients.
• 4 Pts received single dose
• 2 partial response
• 2 stable disease
• 6 Pts received multiple dose
• 3 partial response
• 3 stable disease

A Otte et al, Lancet 1998
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Summary

• GEPNET are rare and slow growing tumors.
• The efficacy of systemic cytotoxic treatment is
  still controversy.
• Somatostatin and chemoembolization of liver
  lesions provide good palliative symptom control.
• Antiangiogenesis is a new direction.