GASTROENTEROPANCREATIGASTROENTEROPANCREATIC NEUROENDOCRINE C NEUROENDOCRINE

TUMORSTUMORSBy Dr Nagaraja.V.TBy Dr Nagaraja.V.T

Moderator-Dr Bindumati.P.LModerator-Dr Bindumati.P.L

BACKGROUNDBACKGROUND Incidence 1-2 in 100,000 (true Incidence 1-2 in 100,000 (true

incidence is underestimated due to incidence is underestimated due to vague presentations and misdiagnosis) vague presentations and misdiagnosis)

Account for <2% of GI malignanciesAccount for <2% of GI malignancies Neuroendocrine tumors of the lung, GI Neuroendocrine tumors of the lung, GI

tract and mediastinum have a higher tract and mediastinum have a higher incidence in patients >50 (exception: incidence in patients >50 (exception: carcinoid of the appendix have a higher carcinoid of the appendix have a higher incidence in patients age <30)incidence in patients age <30)

NEUROENDOCRINE CELLSNEUROENDOCRINE CELLS 1969 (Pearse) described APUD cells (amine 1969 (Pearse) described APUD cells (amine

precursor uptake and decarboxylation) cells precursor uptake and decarboxylation) cells that make polypeptides and biogenic aminesthat make polypeptides and biogenic amines

These cells have dense core secretory These cells have dense core secretory granules which store and release hormones granules which store and release hormones in response to external stimuliin response to external stimuli

Do not have axons/synapsesDo not have axons/synapses Are part of the diffuse endocrine system Are part of the diffuse endocrine system

(DES)(DES) Endocrine tumors of the gut and pancreas Endocrine tumors of the gut and pancreas

originate from DES cellsoriginate from DES cells

CLASSIFICATIONCLASSIFICATION WHO CLASSIFICATION WHO CLASSIFICATION

– Well differentiated NET (non-invasive, Well differentiated NET (non-invasive, benign behaving or uncertain malignant benign behaving or uncertain malignant potential)potential)

– Well-differentiated NE carcinomas (low Well-differentiated NE carcinomas (low grade malignant and has invasion or grade malignant and has invasion or muscularis propria or metastasis)muscularis propria or metastasis)

– Poorly differentiated endocrine Poorly differentiated endocrine carcinomas (high grade, malignant)carcinomas (high grade, malignant)

CLASSIFICATIONCLASSIFICATION GENERAL CLASSIFICATION of GENERAL CLASSIFICATION of

Neuroendocrine gastroenteropancreatic Neuroendocrine gastroenteropancreatic tumorstumors– Carcinoid tumorsCarcinoid tumors

25% foregut (lung, thymus, gastric mucosa, duodenum)25% foregut (lung, thymus, gastric mucosa, duodenum) 40-60% midgut (distal ileum and jejunum) (includes 40-60% midgut (distal ileum and jejunum) (includes

carcinoid syndrome)carcinoid syndrome) Hindgut (colon, rectum)Hindgut (colon, rectum)

– Endocrine Pancreatic TumorsEndocrine Pancreatic Tumors 60% Functioning (Zollinger Ellison, glucagonomas, 60% Functioning (Zollinger Ellison, glucagonomas,

VIPomas, etc)VIPomas, etc) Non-functioning (usually large and metastatic at the Non-functioning (usually large and metastatic at the

time of diagnosistime of diagnosis

Gastrointestinal Gastrointestinal Neuroendocrine Tumor Neuroendocrine Tumor

Syndrome Syndrome

General Characteristics of General Characteristics of Gastrointestinal Gastrointestinal

Neuroendocrine Tumors Neuroendocrine Tumors [Carcinoids, Pancreatic [Carcinoids, Pancreatic

Endocrine Tumors (Pets)]Endocrine Tumors (Pets)] A. Share general neuroendocrine cell markers A. Share general neuroendocrine cell markers (identification used for diagnosis)(identification used for diagnosis)

1. Chromogranins (A, B, C) are acidic monomeric 1. Chromogranins (A, B, C) are acidic monomeric soluble proteins found in the large secretory soluble proteins found in the large secretory granules. Chromogranin A is the most widely used.granules. Chromogranin A is the most widely used.

2. Neuron-specific enolase (NSE) is the - dimer of 2. Neuron-specific enolase (NSE) is the - dimer of the enzyme enolase and is a cytosolic marker of the enzyme enolase and is a cytosolic marker of neuroendocrine differentiation.neuroendocrine differentiation.

3. Synaptophysin is an integral membrane 3. Synaptophysin is an integral membrane glycoprotein of 38,000 molecular weight found in glycoprotein of 38,000 molecular weight found in small vesicles of neurons and neuroendocrine small vesicles of neurons and neuroendocrine tumors.tumors.

B. Pathologic similaritiesB. Pathologic similarities 1. All are APUDomas showing amine precursor 1. All are APUDomas showing amine precursor

uptake and decarboxylation.uptake and decarboxylation. 2. Ultrastructurally they have dense-core secretory 2. Ultrastructurally they have dense-core secretory

granules (>80 nm).granules (>80 nm). 3. Histologically, generally appear similar with few 3. Histologically, generally appear similar with few

mitoses and uniform nuclei.mitoses and uniform nuclei. 4. Frequently synthesize multiple peptides/amines, 4. Frequently synthesize multiple peptides/amines,

which can be detected immunocytochemically but which can be detected immunocytochemically but may not be secreted.may not be secreted.

5. Presence or absence of clinical syndrome or 5. Presence or absence of clinical syndrome or type cannot be predicted by immunocytochemical type cannot be predicted by immunocytochemical studies.studies.

6. Histologic classifications increasingly predictive 6. Histologic classifications increasingly predictive of biologic behavior. Only invasion or metastases of biologic behavior. Only invasion or metastases establish malignancyestablish malignancy

C. Similarities of biologic behaviorC. Similarities of biologic behavior 1. Generally slow growing, but a 1. Generally slow growing, but a

proportion are aggressive.proportion are aggressive. 2. Secrete biologically active 2. Secrete biologically active

peptides/amines, which can cause peptides/amines, which can cause clinical symptoms.clinical symptoms.

3. Generally have high densities of 3. Generally have high densities of somatostatin receptors, which are somatostatin receptors, which are used for both localization and used for both localization and treatment.treatment.

D. Similarities/differences in molecular D. Similarities/differences in molecular abnormalitiesabnormalities

1. Similarities1. Similarities a. Uncommon—alterations in common oncogenes a. Uncommon—alterations in common oncogenes

(ras, jun, fos, etc)(ras, jun, fos, etc) b. Uncommon—alterations in common tumor-b. Uncommon—alterations in common tumor-

suppressor genes (p53, retinoblastoma)suppressor genes (p53, retinoblastoma) c. Alterations at MEN 1 locus (11q13) and c. Alterations at MEN 1 locus (11q13) and

p16INK4a (9p21) occur in a proportion (10–45%).p16INK4a (9p21) occur in a proportion (10–45%). d. Methylation of various genes occurs in 40–87%d. Methylation of various genes occurs in 40–87% 2. Differences2. Differences a. PETs—loss of 1p , 3p , 3q , 11q , 6q . Gains at a. PETs—loss of 1p , 3p , 3q , 11q , 6q . Gains at

17q , 7q , 4q .17q , 7q , 4q . b. Carcinoids—loss of 18q >18p > 9p, 16q21. b. Carcinoids—loss of 18q >18p > 9p, 16q21.

Gains at 17q, 19p , 4q, 14q .Gains at 17q, 19p , 4q, 14q .

CARCINOIDCARCINOID 1.5 per 100,0001.5 per 100,000 Symptoms depend on location and size Symptoms depend on location and size

of tumor and presence of metastasisof tumor and presence of metastasis Can secrete a number of hormonal, Can secrete a number of hormonal,

growth, and other factorsgrowth, and other factors Symptoms include flushing of the face, Symptoms include flushing of the face,

severe diarrhea, and can have severe diarrhea, and can have “asthma” symptoms“asthma” symptoms

Synthesis, secretion, and Synthesis, secretion, and metabolism of serotoninmetabolism of serotonin (5- (5-

HT) HT)

Genetic Syndromes Associated Genetic Syndromes Associated with an Increased Incidence of with an Increased Incidence of Neuroendocrine Tumors (Nets) Neuroendocrine Tumors (Nets)

[Carcinoids or Pancreatic [Carcinoids or Pancreatic Endocrine Tumors (PetsEndocrine Tumors (Pets

1. Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 (MEN 1) .1 (MEN 1) .

2. von Hippel–Lindau disease 2. von Hippel–Lindau disease 3. von Recklinghausen's disease 3. von Recklinghausen's disease

[neurofibromatosis 1 (NF-1)] [neurofibromatosis 1 (NF-1)] 4. Tuberous sclerosis 4. Tuberous sclerosis

Clinical Characteristics in Clinical Characteristics in Patients with Carcinoid Patients with Carcinoid

Syndrome Syndrome

Cardiac manifestations Cardiac manifestations The cardiac disease is due to the formation The cardiac disease is due to the formation

of fibrotic plaques (composed of smooth-of fibrotic plaques (composed of smooth-muscle cells, myofibroblasts, and elastic muscle cells, myofibroblasts, and elastic tissue) involving the endocardium, tissue) involving the endocardium, primarily on the right side, although lesions primarily on the right side, although lesions on the left side also occur occasionally, on the left side also occur occasionally, especially if a patent foramen ovale exists. especially if a patent foramen ovale exists.

The dense fibrous deposits are most The dense fibrous deposits are most commonly on the ventricular aspect of the commonly on the ventricular aspect of the tricuspid valve and less commonly on the tricuspid valve and less commonly on the pulmonary valve cusps. pulmonary valve cusps.

They can result in constriction of the They can result in constriction of the valves, and pulmonic stenosis is usually valves, and pulmonic stenosis is usually predominant, whereas the tricuspid predominant, whereas the tricuspid valve is often fixed open, resulting in valve is often fixed open, resulting in regurgitation predominating. regurgitation predominating.

Overall, in patients with carcinoid heart Overall, in patients with carcinoid heart disease, 97% have tricuspid disease, 97% have tricuspid insufficiency, 59% tricuspid stenosis, insufficiency, 59% tricuspid stenosis, 50% pulmonary insufficiency, 25% 50% pulmonary insufficiency, 25% pulmonary stenosis, and 11% (0–25%) pulmonary stenosis, and 11% (0–25%) left-side lesions. left-side lesions.

Diagnosis of the Carcinoid Diagnosis of the Carcinoid Syndrome and Carcinoid Syndrome and Carcinoid

Tumors Tumors The diagnosis of carcinoid syndrome relies The diagnosis of carcinoid syndrome relies

on measurement of urinary or plasma on measurement of urinary or plasma serotonin or its metabolites in the urine. serotonin or its metabolites in the urine.

The measurement of 5-HIAA is used most The measurement of 5-HIAA is used most frequently. frequently.

False-positive elevations may occur if the False-positive elevations may occur if the patient is eating serotonin-rich foods such patient is eating serotonin-rich foods such as bananas, pineapples, walnuts,etc. as bananas, pineapples, walnuts,etc.

Serum chromogranin A levels are Serum chromogranin A levels are elevated in 56–100% of patients with elevated in 56–100% of patients with carcinoid tumors, and the level carcinoid tumors, and the level correlates with tumor bulk. correlates with tumor bulk.

Serum chromogranin A levels are not Serum chromogranin A levels are not specific for carcinoid tumors because specific for carcinoid tumors because they are also elevated in patients they are also elevated in patients with PETs and other neuroendocrine with PETs and other neuroendocrine tumors. tumors.

TreatmentTreatment Treatment includes avoiding conditions that Treatment includes avoiding conditions that

precipitate flushing, dietary precipitate flushing, dietary supplementation with nicotinamide, supplementation with nicotinamide, treatment of heart failure with diuretics, treatment of heart failure with diuretics, treatment of wheezing with oral treatment of wheezing with oral bronchodilators, and control of the diarrhea bronchodilators, and control of the diarrhea with antidiarrheal agents such as with antidiarrheal agents such as loperamide and diphenoxylate. loperamide and diphenoxylate.

If patients still have symptoms, serotonin If patients still have symptoms, serotonin receptor antagonists like receptor antagonists like methylsergide,cyproheptadine and methylsergide,cyproheptadine and ketanserin,ondansetron,etc or somatostatin ketanserin,ondansetron,etc or somatostatin analogues are the drugs of choice.analogues are the drugs of choice.

Patients with mild to moderate Patients with mild to moderate symptoms usually are treated initially symptoms usually are treated initially with octreotide 100 g SC every 8 h and with octreotide 100 g SC every 8 h and begun on long-acting monthly depot begun on long-acting monthly depot forms (octreotide-LAR or lanreotide-forms (octreotide-LAR or lanreotide-autogel).autogel).

Forty percent of patients escape Forty percent of patients escape control after a median time of 4 control after a median time of 4 months, and the depot dosage may months, and the depot dosage may have to be increased as well as have to be increased as well as supplemented with the shorter-acting supplemented with the shorter-acting formulation, SC octreotide. formulation, SC octreotide.

Other modalitiesOther modalities Interferon is reported to be effective Interferon is reported to be effective

in controlling symptoms of the in controlling symptoms of the carcinoid syndrome either alone or carcinoid syndrome either alone or combined with hepatic artery combined with hepatic artery embolization. embolization.

chemoembolization (5-fluorouracil, chemoembolization (5-fluorouracil, doxorubicin, cisplatin, mitomycin).doxorubicin, cisplatin, mitomycin).

Parachlorophenylanine can inhibit Parachlorophenylanine can inhibit tryptophan hydroxylase and therefore tryptophan hydroxylase and therefore the conversion of tryptophan to 5-HTP the conversion of tryptophan to 5-HTP

Carcinoid Tumors Carcinoid Tumors (Nonmetastatic) (Nonmetastatic)

Surgery is the only potentially Surgery is the only potentially curative therapy curative therapy

Depends on site of involvement and Depends on site of involvement and tumor size.tumor size.

GASTRINOMASGASTRINOMAS Over secretion of gastrinOver secretion of gastrin Zollinger-Ellison Syndrome: atypical peptic Zollinger-Ellison Syndrome: atypical peptic

ulcer disease, gastric hyperacidity and ulcer disease, gastric hyperacidity and hypersecretion, associated with islet cell hypersecretion, associated with islet cell pancreatic tumorspancreatic tumors

Age at diagnosis ~50Age at diagnosis ~50 More common in males (~60%)More common in males (~60%) Metastasis in 60% of patientsMetastasis in 60% of patients Complete resection results in 10 year survival Complete resection results in 10 year survival

of 90%; less likely if large primaryof 90%; less likely if large primary

DiagnosisDiagnosis The diagnosis of ZES requires the The diagnosis of ZES requires the

demonstration of inappropriate fasting demonstration of inappropriate fasting hypergastrinemia, usually by demonstrating hypergastrinemia, usually by demonstrating hypergastrinemia occurring with an increased hypergastrinemia occurring with an increased basal gastric acid output (BAO) basal gastric acid output (BAO) (hyperchlorhydria).(hyperchlorhydria).

If the fasting gastrin is >1000 pg/mL If the fasting gastrin is >1000 pg/mL (increased tenfold) and the pH is 2.0, which (increased tenfold) and the pH is 2.0, which occurs in 40–60% of patients with gastrinoma, occurs in 40–60% of patients with gastrinoma, the diagnosis of ZES is established after the the diagnosis of ZES is established after the possibility of retained antrum syndrome has possibility of retained antrum syndrome has been ruled out by history been ruled out by history

Treatment Treatment oral gastric antisecretory drugs.oral gastric antisecretory drugs. PPIs (H+,K+-ATPase inhibitors) are PPIs (H+,K+-ATPase inhibitors) are

the drugs of choice .the drugs of choice . Surgical resection.Surgical resection.

INSULINOMASINSULINOMAS Islet cell tumorsIslet cell tumors Secrete excess of predominantly insulinSecrete excess of predominantly insulin Usually present at age 40-50Usually present at age 40-50 More common in womenMore common in women Clinical symptoms include sweating, Clinical symptoms include sweating,

tremors, tachycardia, confusion, weaknesstremors, tachycardia, confusion, weakness 10% of patients develop metastasis10% of patients develop metastasis Complete resection cures most patientsComplete resection cures most patients

In insulinomas, in addition to In insulinomas, in addition to elevated plasma insulin levels, elevated plasma insulin levels, elevated plasma proinsulin levels are elevated plasma proinsulin levels are found, and C-peptide levels can be found, and C-peptide levels can be elevated. elevated.

Diagnosis Diagnosis The diagnosis of insulinoma requires the The diagnosis of insulinoma requires the

demonstration of an elevated plasma demonstration of an elevated plasma insulin level at the time of hypoglycemia. insulin level at the time of hypoglycemia.

In addition to having an insulin level >6 In addition to having an insulin level >6 U/mL when blood glucose is <40 mg/dL, U/mL when blood glucose is <40 mg/dL, some investigators also require an some investigators also require an elevated C-peptide and serum proinsulin elevated C-peptide and serum proinsulin level, an insulin/glucose ratio >0.3, and a level, an insulin/glucose ratio >0.3, and a decreased plasma -hydroxybutyrate level decreased plasma -hydroxybutyrate level for the diagnosis of insulinomas.for the diagnosis of insulinomas.

Treatment Treatment Only 5–15% of insulinomas are Only 5–15% of insulinomas are

malignant; therefore, after appropriate malignant; therefore, after appropriate imaging (see below), surgery should be imaging (see below), surgery should be performed. performed.

Before surgery, the hypoglycemia can be Before surgery, the hypoglycemia can be controlled by frequent small meals and controlled by frequent small meals and the use of diazoxide (150–800 mg/d). the use of diazoxide (150–800 mg/d). Diazoxide is a benzothiadiazide whose Diazoxide is a benzothiadiazide whose hyperglycemic effect is attributed to hyperglycemic effect is attributed to inhibition of insulin release. inhibition of insulin release.

For the 5–15% of patients with malignant For the 5–15% of patients with malignant insulinomas, these drugs or somatostatin insulinomas, these drugs or somatostatin analogues are used initially. analogues are used initially.

In a small number of patients with In a small number of patients with insulinomas, some with malignant insulinomas, some with malignant tumors, mammalian target of rapamycin tumors, mammalian target of rapamycin (mTor) inhibitors (everolimus, (mTor) inhibitors (everolimus, rapamycin) are reported to control the rapamycin) are reported to control the hypoglycemia. hypoglycemia.

If they are not effective, various If they are not effective, various antitumor treatments such as hepatic antitumor treatments such as hepatic arterial embolization, arterial embolization, chemoembolization, chemotherapy, and chemoembolization, chemotherapy, and peptide receptor radiotherapy have been peptide receptor radiotherapy have been used used

GLUCAGONOMASGLUCAGONOMAS Presents with mild DM and severe Presents with mild DM and severe

dermatitis (necrolytic migratory dermatitis (necrolytic migratory erythema), stomatitis, diarrheaerythema), stomatitis, diarrhea

~70% are malignant~70% are malignant Metastasis in >60% patientsMetastasis in >60% patients

Diagnosis Diagnosis The diagnosis is confirmed by The diagnosis is confirmed by

demonstrating an increased plasma demonstrating an increased plasma glucagon level. glucagon level.

Characteristically, plasma glucagon Characteristically, plasma glucagon levels exceed 1000 pg/mL (normal is levels exceed 1000 pg/mL (normal is <150 pg/mL) in 90%; 7% are <150 pg/mL) in 90%; 7% are between 500 and 1000 pg/mL, and between 500 and 1000 pg/mL, and 3% are <500 pg/mL. 3% are <500 pg/mL.

Treatment Treatment In 50–80% of patients, hepatic In 50–80% of patients, hepatic

metastases are present, and so metastases are present, and so curative surgical resection is not curative surgical resection is not possible. possible.

Long-acting somatostatin analogues Long-acting somatostatin analogues such as octreotide and lanreotide such as octreotide and lanreotide improve the skin rash in 75% of improve the skin rash in 75% of patients and may improve the weight patients and may improve the weight loss, pain, and diarrhea but usually do loss, pain, and diarrhea but usually do not improve the glucose intolerance. not improve the glucose intolerance.

SOMATOSTATINOMASSOMATOSTATINOMAS Cholelithiasis, DM, diarrhea, weight Cholelithiasis, DM, diarrhea, weight

loss, steatorrhealoss, steatorrhea Metastasis in ~50% patientsMetastasis in ~50% patients Complete resection with 5 year Complete resection with 5 year

survival of 95% and if has metastasis survival of 95% and if has metastasis the 5 year survival decreases to the 5 year survival decreases to 60%60%

VIPOMASVIPOMAS Over secretion of VIPOver secretion of VIP Causes watery diarrhea, marked hypokalemiaCauses watery diarrhea, marked hypokalemia 80% are associated with the pancreas80% are associated with the pancreas Metastasis occurs in ~70% of patients Metastasis occurs in ~70% of patients This syndrome also is called Verner-Morrison This syndrome also is called Verner-Morrison

syndrome, pancreatic cholera, and WDHA syndrome, pancreatic cholera, and WDHA syndrome for syndrome for wwatery atery ddiarrhea, iarrhea, hhypokalemia, ypokalemia, and and aachlorhydria, which some patients chlorhydria, which some patients develop.develop.

The mean age of patients with this syndrome The mean age of patients with this syndrome is 49 years is 49 years

Diagnosis Diagnosis The diagnosis requires the The diagnosis requires the

demonstration of an elevated plasma demonstration of an elevated plasma VIP level and the presence of large-VIP level and the presence of large-volume diarrhea. volume diarrhea.

A stool volume <700 mL/d is A stool volume <700 mL/d is proposed to exclude the diagnosis of proposed to exclude the diagnosis of VIPoma. VIPoma.

Treatment Treatment The most important initial treatment The most important initial treatment

in these patients is to correct their in these patients is to correct their dehydration, hypokalemia, and dehydration, hypokalemia, and electrolyte losses with fluid and electrolyte losses with fluid and electrolyte replacement.electrolyte replacement.

These patients may require 5 L/d of These patients may require 5 L/d of fluid and >350 meq/d of potassium.fluid and >350 meq/d of potassium.

In nonresponsive patients the combination In nonresponsive patients the combination of glucocorticoids and octreotide/lanreotide of glucocorticoids and octreotide/lanreotide has proved helpful in a small number of has proved helpful in a small number of patients. patients.

Other drugs reported to be helpful in small Other drugs reported to be helpful in small numbers of patients include prednisone numbers of patients include prednisone (60–100 mg/d), clonidine, indomethacin, (60–100 mg/d), clonidine, indomethacin, phenothiazines, loperamide, lidamidine, phenothiazines, loperamide, lidamidine, lithium, propranolol, and metoclopramide. lithium, propranolol, and metoclopramide.

Treatment of advanced disease with Treatment of advanced disease with embolization, chemoembolization, embolization, chemoembolization, chemotherapy, radiotherapy, chemotherapy, radiotherapy, radiofrequency ablation, and peptide radiofrequency ablation, and peptide receptor radiotherapy may be helpful.receptor radiotherapy may be helpful.

DIAGNOSTIC PROCEDUREDIAGNOSTIC PROCEDURE Biopsy Biopsy Immunohistochemistry Immunohistochemistry

– Antibodies to chromogranin AAntibodies to chromogranin A– Neuron specific endolaseNeuron specific endolase– SynapthophysisSynapthophysis– Stain for serotonin if suspect carcinoidStain for serotonin if suspect carcinoid– Stain for gastrin if suspect Zollinger – Stain for gastrin if suspect Zollinger –

EllisonEllison

RADIOLOGIC DIAGNOSISRADIOLOGIC DIAGNOSIS CTCT MRIMRI USUS Somatostatin Receptor Scintigraphy (SRS) – Somatostatin Receptor Scintigraphy (SRS) –

based on presence of somatostatin receptors based on presence of somatostatin receptors in 80-90% of NETin 80-90% of NET

PET to evaluate tumor metastasisPET to evaluate tumor metastasis Endoscopic ultrasound – sensitivity/specificity Endoscopic ultrasound – sensitivity/specificity

appx 80% for tumors in pancreas and appx 80% for tumors in pancreas and duodenum and can allow for FNAduodenum and can allow for FNA

CTCT

SRSSRS

Treatment: Advanced Disease Treatment: Advanced Disease (Diffuse Metastatic Disease) (Diffuse Metastatic Disease)

Specific Antitumor Specific Antitumor TreatmentsTreatments

Radio frequency thermal ablation can Radio frequency thermal ablation can be applied to GI NET liver metastases be applied to GI NET liver metastases if they are limited in number (usually if they are limited in number (usually <5) and size (usually <3.5 cm in <5) and size (usually <3.5 cm in diameter).diameter).

Chemotherapy Chemotherapy The current regimen of choice is The current regimen of choice is

streptozotocin and doxorubicin. streptozotocin and doxorubicin. In poorly differentiated PETs, In poorly differentiated PETs,

chemotherapy with cisplatin, chemotherapy with cisplatin, etoposide, or their derivatives is the etoposide, or their derivatives is the recommended treatment, with recommended treatment, with response rates of 40–70%; however, response rates of 40–70%; however, responses are generally short-lived. responses are generally short-lived.

Some newer combinations of Some newer combinations of chemotherapeutic agents show chemotherapeutic agents show promise in small numbers of patients, promise in small numbers of patients, including temozolomide (TMZ ).including temozolomide (TMZ ).

Hepatic embolization and Hepatic embolization and chemoembolization (with chemoembolization (with dacarbazine, cisplatin, doxorubicin, 5-dacarbazine, cisplatin, doxorubicin, 5-fluorouracil, or streptozotocin) have fluorouracil, or streptozotocin) have been reported to decrease tumor bulk been reported to decrease tumor bulk and help control the symptoms of the and help control the symptoms of the hormone-excess state.hormone-excess state.

Radiotherapy with radiolabeled Radiotherapy with radiolabeled somatostatin analogues that are somatostatin analogues that are internalized by the tumors is being internalized by the tumors is being investigated. investigated.

Selective internal radiation therapy Selective internal radiation therapy (SIRT) using 90yttrium glass or resin (SIRT) using 90yttrium glass or resin microspheres is being evaluated in microspheres is being evaluated in patients with unresectable NET liver patients with unresectable NET liver metastases. metastases.

The use of liver transplantation has The use of liver transplantation has been abandoned for treatment of been abandoned for treatment of most metastatic tumors to the liver. most metastatic tumors to the liver. However, for metastatic NETs, it is However, for metastatic NETs, it is still a consideration. still a consideration.

For younger patients with metastatic For younger patients with metastatic NETs limited to the liver, liver NETs limited to the liver, liver transplantation may be justified. transplantation may be justified.

Newer approaches show some promise Newer approaches show some promise in the treatment of advanced GI NETs. in the treatment of advanced GI NETs.

They include the use of growth factor They include the use of growth factor inhibitors or inhibitors of their receptors inhibitors or inhibitors of their receptors (using tyrosine kinase inhibitors, (using tyrosine kinase inhibitors, monoclonal antibodies), inhibitors of monoclonal antibodies), inhibitors of mTor signaling (everolimus, mTor signaling (everolimus, temsirolimus), angiogenesis inhibitors, temsirolimus), angiogenesis inhibitors, and VEGF or vascular endothelial and VEGF or vascular endothelial growth factor receptor (VEGFR) growth factor receptor (VEGFR) tyrosine kinase inhibitors. tyrosine kinase inhibitors.

A number of these agents, A number of these agents, particularly sunitinib (tyrosine kinase particularly sunitinib (tyrosine kinase inhibitor), various mTor inhibitors, inhibitor), various mTor inhibitors, and bevacizumub (monoclonal and bevacizumub (monoclonal antibody against VEGF), show antibody against VEGF), show impressive activity. Additional value impressive activity. Additional value may result from selected may result from selected combinations of agents.combinations of agents.

Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 200425(3): 458-511, 2004

OutcomesOutcomes

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Lancet Oncology. Volume 9: pages 61-72, 2008.Lancet Oncology. Volume 9: pages 61-72, 2008. Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: Recent Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: Recent

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Gastroenteropancreatic Neuroendocrine (including Carcinoid) Gastroenteropancreatic Neuroendocrine (including Carcinoid) Tumours. Gut. Volume 54: pages 1-16, 2004Tumours. Gut. Volume 54: pages 1-16, 2004

Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 2004Reviews. 25(3): 458-511, 2004

Kasper, Dennis, and Eugene Braunwald, New York: McGraw-Hill, Kasper, Dennis, and Eugene Braunwald, New York: McGraw-Hill, 2005.2005.

Tierney Jr, Lawrence, and Stephen McPhee, 45th edition, eds. Current Tierney Jr, Lawrence, and Stephen McPhee, 45th edition, eds. Current Medical Diagnosis and Treatment. New York: McGraw-Hill, 2006.Medical Diagnosis and Treatment. New York: McGraw-Hill, 2006.

Uptodate: Management of Metastatic Gastroenteropancreatic Uptodate: Management of Metastatic Gastroenteropancreatic Neuroendocrine TumorsNeuroendocrine Tumors

Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell tumors)tumors)

Uptodate: Neuroendocrine Carcinoma of Unknown Primary SiteUptodate: Neuroendocrine Carcinoma of Unknown Primary Site

THANK UTHANK U