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					Current Oncologic Considerations in
    the Treatment of Pancreatic
      Neuroendocrine Tumors




                   Barbra S. Miller, M.D.
                          Assistant Professor
Endocrine Surgery – Division of General and Laparoendoscopic Surgery
              University of Texas Health Science Center
                           San Antonio, TX
                  Introduction
• Neuroendocrine Tumors
  – Extremely rare.

  – Many types with different specific hormone
    production.

  – Functioning and Nonfunctioning counterparts.

  – Benign and Malignant counterparts.

  – Originate from multiple sites in the body.
            Neuroendocrine Tumor
                Epidemiology

• Epidemiology not well studied.
• Account for only 0.5% of all malignancies.
• Incidence of 2/100,000.
• Female predominance under age 50 due to
  appendiceal location (carcinoids).
• Family history is extremely important (MEN/VHL).
• Main primary sites are:
    – GI tract (62-67%)
    – Lung (22-27%)
Types of Neuroendocrine Tumors

•   Pituitary adenomas         •   Insulinoma
•   Medullary Thyroid Cancer   •   Gastrinoma
•   Small cell carcinomas      •   VIPoma
•   Bronchial carcinoid        •   Glucagonoma
•   ACTHomas                   •   Somatostatinoma
•   Pheochromocytoma           •   Nonfunctioning tumors
•   Paraganglioma
•   GI Carcinoid
•   Others
Types of Neuroendocrine Tumors

•   Pituitary adenomas         •   Insulinoma
•   Medullary Thyroid Cancer   •   Gastrinoma
•   Small cell carcinomas      •   VIPoma
•   Bronchial carcinoid        •   Glucagonoma
•   ACTHomas                   •   Somatostatinoma
•   Pheochromocytoma           •   Nonfunctioning tumors
•   Paraganglioma
•   GI Carcinoid
•   Others
                     Goals
• Neuroendocrine tumors in general.

• Specific pancreatic neuroendocrine tumors.

• Familial syndromes.

• Follow-up and management.

• Recurrent and metastatic disease.

• For the future.
         Neuroendocrine Tumors
• Benign vs. Malignant
   – Presentation with metastatic disease accounts for 12-
     22% of patients.

• Functional vs. Nonfunctional
   – Although tumor may stain for a certain hormone, it is
     not considered a “functional” tumor unless patient has
     an associated clinical syndrome.

   – Many tumors stain for multiple hormones
      • never release it
      • don’t release it in great enough quantities
      • release it in an inactive form.
         Tumor markers for NETs
• Chromogranin A
•   Synaptophysin
•   Cytokeratin
•   Neuron-specific enolase
•   Pancreatic polypeptide
•   Tumor-specific stains
    –   Gastrin
    –   Insulin
    –   VIP
    –   Somatostatin
    –   Calcitonin
    –   Others (5-HIAA, serotonin, metanephrines)
             Plasma Chromogranin A
• 49 kDa monomeric hydrophilic, acidic glycoprotein widely
  expressed in NETs.

• Important for circulating levels and immunohistochemistry.

• Correlates well with tumor burden.

• Functioning PNETs have significantly higher levels of CgA
  than non-functioning PNETs.
                            Caution…
• Abnormally high CgA levels occur in renal insufficiency.
   – Serum creatinine levels should be checked in patients with high CgA levels.

• Slightly elevated CgA levels can occur in patients with:
   – severe liver failure
   – in some patients with inflammatory bowel disease
   – some non-endocrine tumors

• Treatment with Somatostatin analogs spuriously decreases CgA
  levels.

• In MEN 1 patients, the finding of very high CgA levels is usually
  indicative of the presence of a PNET.

   – Moderately high values should prompt other biochemical and imaging
     studies and serial CgA levels.
    Imaging of Pancreatic Neuroendocrine
                  Tumors
• CT – sensitivity of 25-70%
     – Generally appear hypervascular, but have
       many appearances.
     – With spiral CT, sensitivity may improve.

•   Abdominal US – 0-60%
•   MRI – 15-50%
•   Selective Arteriography - 35-91%
•   SVS – 80-100% (tumor region)
•   Arterial Stimulated Venous Sampling – 88-100%

• EUS –
     – Head – 80%
     – Distal – 37%

• Intra-operative localization with palpation and intra-op ultrasound
     – 93-100%
                     Octreoscan
• Nuclear medicine study using
  111In-pentetreotide (Octreoscan).



• Specific for neuroendocrine
  tumors.

• Binds to receptor subtypes 2 and
  5 of target cell.
  – Many Insulinomas lack sufficient
    numbers of these receptor subtypes
    explaining poor imaging with
    Octreoscan.
           To FNA or not to FNA
• If not going to operate on someone due to comorbidities,
  can do FNA to document what the lesion is.

• Imaging, tumor location, patient history, exam, tumor
  markers and intraoperative findings dictate procedure to
  perform without need for FNA and possibly seeding tract.

• If functioning, already know what it is and no biopsy
  necessary.

• If non-functioning PNET, have high chance of malignancy
  and needs to be removed.
                      Cytologic findings
• If FNA has already been
  done…
   – Aspirates richly cellular
   – Predominantly single cell
     population
   – Relatively small cells,
     indistinct cell borders.
   – Usually appear uniform and
     monotonous.
   – Moderate cytoplasm.
   – Nuclei round to oval.
   – Finely granular chromatin.
   – Eccentric nuclear location.
   – Mitoses rare.
           Cytomorphologic/Histologic
                   Features
• Well Differentiated           • Poorly Differentiated
   – Organoid strucure             – Solid architecture
   – Solid, trabecular, or         – Central necrosis
     glandular patterns.           – Markedly atypical cytologic
   – Monomorphic patterns            features.
   – Clear to eosinophilic         – Numerous mitoses.
     cytoplasm.                    – Prominent lymphovascular
   – Little cellular atypia.         invasion.
   – Low mitotic index.            – Usually present with distant
   – Tumor necrosis absent or        mets to liver and extra-
     only focal.                     abdominal sites.
       WHO Classification of Pancreatic
            Endocrine Tumors




Presence of metastasis is only absolute criterion for malignancy.
    Islet Cell Tumors of Pancreas

• Endocrine Pancreas contains at least 6 types of
  cells that produce characteristic polypeptides.



• Peak incidence is between ages 40 and 60 years.
  Pancreatic Neuroendocrine Tumors
• Of functioning tumors, up to 50% are insulinomas.

   – Insulinomas are most common functional PNET in
     patients with sporadic disease.
   – Gastrinoma is the most common functional PNET in
     patients with MEN 1.


• Most non-functioning tumors are malignant (60-
  90%).

• Islet cell tumors in MEN patients are typically
  multiple, and require different treatment strategies
  than for those with sporadic PNETs that are
  usually solitary.
                             Insulinomas

• Usually a single tumor (10% multiple – think MEN 1).
   – Equally distributed throughout pancreas.
   – 10% malignant.
   – 90% less than 2 cm


• Whipple’s triad
   – Glucose <45
   – Symptoms of hypoglycemia during fasting or exertion
   – Resolution with glucose/eating.

• Confirm with 72 hour fast
   – Glucose <45
   – Plasma insulin to glucose ratio >0.3
   – Elevated levels of c-peptide
                    Insulinomas
• EUS – localizes 80% in body and head of pancreas. Also
  can show proximity of duct to insulinoma.
• CT/MRI
• Selective Venous Sampling -step-up in insulin levels.
• Octreoscan? – limited SRS 2 and 5.


• Imamura/Doppman procedure
   – Intra-arterial stimulation with calcium and
     measurement of insulin in the right hepatic vein, or is
     some cases the left hepatic vein.
   – Most recommend this test only in patients with
     persistent or recurrent insulinoma or when other
     localization tests are negative.
                   Surgical Treatment
• Surgery - Open vs. Laparoscopic

• Measure glucose levels in O.R. at short intervals.

• Intra-operative US very useful as well as full pancreatic
  mobilization and palpation to identify tumor.

• Enucleation possible if benign.
   – Sometimes distal pancreatectomy.
   – Enucleation if in head of pancreas.
   – Whipple is rare, but indicated if malignant or too large for enucleation.


• If cannot find tumor, blind distal pancreatectomy not advised.
   – Can do intra-op SVS and send for insulin levels to localize.
   – Can biopsy small segment to look for nesidioblastosis.
   – Re-evaluate with arterial stimulated venous sampling if not already done.
                 Diazoxide
• A nondiuretic benzothiadiazine.

• Reduces insulin secretion and raises glucose levels
  by acting directly on beta cells as well as by other
  extrapancreatic mechanisms.

• Efficacy is ~60% in pts with insulinomas.

• Can also be used in metastatic unresectable
  insulinomas.

• Rarely used prior to surgery as it interferes with
  intra-op glucose monitoring.
                        Gastrinoma
• Second most common sporadic
  functional NET.

• 50-60% of tumors are malignant
  at time of diagnosis.

• 60% located within pancreas,
  30% within duodenum.

• Cells stain for multiple
  hormones. Differentiation
  between the types of NET is
  based on evidence of
  hypergastrinemia.
         Evaluation - Gastrinoma
• Fasting serum gastrin level off of acid suppression.
   – Gastrin levels also not reliable in those with
     hypercalcemia/hyperparathyroidism.


• Diagnosis:
   – Fasting gastrin > 1000pg/mL with gastric pH< 5.
   – Indeterminate/equivocal levels:
      • Secretin stimulation test – rise in gastrin by >200pg/mL (sens. 90%)
      • Calcium infusion test with Ca Gluconate ( rise >50%) (sens. 74%)
      • Standard meal test.


• Imaging studies (CT/MRI, EUS, Octreoscan)
             Operative Technique
• Sporadic
  – Pre-operative localization

  – Usually a single tumor

  – If not found in pancreas, explore periduodenal region,
    then perform duodenotomy.

  – Can use intraoperative endoscopy to aid in finding
    duodenal lesions, but palpation of duodenal mucosa is
    best.
        Operative Technique
• Familial
  – Multiple tumors (gastrinoma and other NETs)
  – Explore pancreas and duodenum.

     • Thompson procedure
        – Enucleate pancreatic head tumors (Whipple rare), distal
          pancreatectomy (propensity for multiple tumors in tail),
          duodenotomy, periduodenal lymph node dissection.


     • All patients with MEN syndrome should undergo
       duodenotomy.
                 Gastrinoma staging
• Ellison at OSU
• 3 determinants of survival:
   – Primary tumor size
   – Presence of liver metastases
   – Complete resection of tumor

   – 10 yr survival:
      • Stage I – (primary <2cm, no liver mets) 94-96%
      • Stage II – (primary >2cm, no liver mets) 86-91%
      • Stage III – (liver mets) 65-90%

      • When tumor not resected:
          – Stage I – 68-82%
          – Stage II – 40-55%
          – Stage III - 7-50%
Gastrinoma Assessment of Cure and
           Follow-up
• Check serum gastrin prior to discharge and
  at 3 month intervals for first year.
• Secretin stimulation test at 3 months may
  unmask some as not cured.
• CT scan at 1 to 2 yr intervals in selected
  patients if gastrin levels rising.
         Metastatic gastrinoma
• Survival is greater than 90% at 10 years for
  those with continuing hypergastrinemia or
  regional metastases.

• With liver and more distant metastases,
  20% 5 yr survival.

• Chemotherapy is not recommended for
  regional disease, but is recommended for
  liver metastases.
          Metastatic Gastrinoma

• Liver metastases occur more often with pancreatic
  gastrinomas than duodenal ones.

• Gastrinomas found only in lymph nodes or duodenum had
  10 yr survival rate of 100% and 94%.

• Those with pancreatic gastrinomas had 10 year survival
  rate of 59%.

• Surgical biochemical cures can be difficult to attain long
  term (eugastrinemia), but surgery delays spread to liver.
        NIH Gastrinoma Study
   “Assessment and prediction of long-term cure in
       patients with ZES: The best approach.”
        (Annals Intl. Med. 119:199, 1993.)

• 3% patients undergoing surgery developed hepatic
  metastases. (Mean follow-up 6 years)

• 23% medically managed developed hepatic
  metastases.

• 5 year survival with hepatic metastases (w/out
  liver resection) as low as 20%.
                     Glucagonoma
• “4D Syndrome”
   –   Diabetes – mean Hgb A1C – 9.8
   –   Dermatitis
   –   DVT – up to 30%
   –   Depression

• Usually rather large at diagnosis (>4cm).
   – Blood for glucagon level.
   – CT/MRI, EUS and Octreoscan.


• Usually in body/tail of pancreas.

• Hepatic metastases in >50% at time of diagnosis.
   – Tumors >5cm at diagnosis have 60-80% rate of metastases.
   – Can metastasize to LN, bones, adrenals, kidneys, lungs.
                    Glucagonoma
• Characterized by
  diabetes, anemia,
  weight loss, glossitis,
  necrolytic migratory
  erythema.
               VIPoma
       Verner-Morrison Syndrome
• Characterized by “WDHA”
   – Watery diarrhea
       • 70% >3 liters per day. (<700 cc/d excludes)
       • High sodium, low stool osmolal gap
   – Hypokalemia
   – Achlorhydria/Hypochlorhydria
   – Also flushing, hypercalcemia, hyperglycemia.

• VIP binds with receptor in intestinal lumen, activating
  adenylate cyclase and cAMP.
   – Leads to secretion of fluids/electrolytes into lumen and
     inhibits absorption of others.
   – Increases bowel motility.
                  VIPoma
• Measure fasting VIP level.
  – Mean level 958 pg/mL (225-1850).

• CT scan, Octreoscan.

• Aggressively treat diarrhea, rehydrate
  patient.
  – Somatostatin very helpful.

• Surgical exploration.
  – Debulking can be helpful.
           Somatostatinomas
• Somatostatin acts in paracrine manner to
  inhibit secretion of insulin, glucagon,
  gastrin, and growth hormone.

• Inhibits CCK-mediated secretion of
  pancreatic enzymes, intestinal absorption,
  and gastric acid secretion.

• Diabetes, cholelithiasis*, diarrhea,
  steatorrhea.
                       Somatostatinoma
• Most are solitary.                • Measure fasting plasma
                                      somatostatin level.
                                        – Level >14 mol/L is
• 60-70% located in pancreas
                                          suggestive.
  (2/3 in head).
   – Extrapancreatic locations in
     duodenum, ampulla, small       •    CT (MRI, EUS, Octreoscan
     bowel, colon and rectum            less important b/c of large
                                        size)
• Metastatic in 75% of cases.

                                    • Surgery for
• Most > 5cm.
                                      resection/debulking.
         Non-functioning PNET
• Not associated with clinical syndrome related to hormone
  hypersecretion, though may secrete elevated levels of
  various hormones.

• Account for 10-25% of all PNETs.

• Generally large by time of diagnosis related to
  compressive symptoms.

• 60-80% metastatic at diagnosis.

• Serum chromogranin A

• CT/MRI usually sufficient for diagnosis.

• Aggressive surgical resection.
         “Malignant Non-functioning Endocrine Tumors of the
         Pancreas: Predictive Factors for Survival after Surgical
                               Treatment”
                            Chung, Choi, Choi, Jo, Heo, Kim
                            Dept. Surgery, Samsung Medical Center, Seoul, Korea



• 22 pts with malignant non-functioning PNET over 10 years.
• 78% with liver metastases.
• Tumor recurrence in 40%.

• Overall 1, 2, and 5-year survival rates were 84%, 73%, and 53%.

• Factor with most prognostic significance was negative resection
  margin.
   – Negative vs. positive resection margin 5-year survival = 73% vs. 33% (p=0.045)

• Involvement of lymph nodes, tumor size, differentiation did not
  influence survival.
              General Treatment of PNETs
• Surgical resection is the optimal treatment for pancreatic
  endocrine tumors and only potential for cure.

• Before excision, any symptoms of hormonal excess must be
  treated.
   – Insulinomas
       • stabilize glucose levels with diet and/or octreotide and/or diazoxide, when
         possible.


   – Gastrinomas
       • Acid suppression.


   – Glucagonoma/VIPoma
       •   Treat electrolyte imbalance, give IV fluids, and octreotide if needed.
       •   Zinc supplementation for patients with glucagonoma skin rash.
       •   Also consider TPN if have had significant weight loss.
       •   Consider pre-op anticoagulation/vena cava filter (increased risk for DVT/PE)
             Surgical Approaches
• Differ for:
   – Occult gastrinomas/insulinomas
   – Sporadic vs. Hereditary disease
   – Metastatic disease


• For unresectable disease, prophylactic
  cholecystectomy should be performed at time of
  initial surgery.

• Cholecystectomy should be considered for all patients
  with a high risk for recurrent disease and thus need for
  somatostatin therapy.
Genetic Syndromes Associated
with Pancreatic Neuroendocrine
           Tumors
    MEN 1 - Wermer’s Syndrome
• Pituitary
• Parathyroid
• Pancreas – 75% with MEN 1 and islet cell tumor in
  pancreas have a functioning tumor. Frequently have
  multiple tumors.

• Menin gene (tumor suppressor) - Chromosome 11q13
• Autosomal Dominant

• May also be associated with carcinoid tumors of the
  lung and thymus, and with multiple lipomas.
         MEN 1- Gastrinoma
• Thompson procedure
  – Tumor enucleation and duodenotomy with
    periduodenal node dissection with or without
    spleen-preserving distal pancreatectomy.
  – 70% will have other extrapancreatic
    gastrinomas necessitating routine
    duodenotomy.

• Invasive tumors or those >5cm in head of
  pancreas should undergo
  pancreaticoduodenectomy with
  periduodenal node dissection.
          MEN 1 Surveillance
• H and P, calcium and other specific hormone
  related markers 3 months after resection, then
  every 6 months x 3 years, then annually.

• CT/MRI at 3 months and in long term as clinically
  indicated.

• Octreoscan every 2 years and specific hormone
  testing based on pre-operative abnormal hormone
  levels.

• Genetic counseling/testing.
         Von Hipple Lindau
• Autosomal dominant.

• Chromosome region 3p25-26.

• Tumor suppressor gene.

• Function of protein not precisely known.

• Median life expectancy of 49.
VHL
  Pancreatic Manifestations of VHL
• Simple cysts, diffuse cystosis, cystadenomas, rare
  adenocarcinomas, islet cell tumors.

• Incidence of pancreatic involvement 0-56%.

• Replacement of pancreas with cysts can cause
  diabetes, steatorrhea, overall insufficiency.

• Can US for screening, but CT or MRI superior for
  finding small lesions.

• Solid islet cell tumors may occur in 5-17% of
  patients.
                   VHL
• VHL associated islet cell tumors are mostly
  hormone inactive.

• Can be detected during screening
  evaluations.

• No specific predictors for malignancy in
  VHL-associated islet cell neoplasias, but
  solid tumors smaller than 3 cm in diameter
  are believed to always be benign.
  Follow-up and Management of
Pancreatic Neuroendocrine Tumors
 Follow-up of Patients with No
      Evidence of Disease

– Asymptomatic patients

  • Observation and follow up with tumor
    markers and scans every 3 to 6 months.

  • Clinical trial.
    Management of NET Locoregional
     Recurrent or Metastatic Disease
• Resectable locoregional disease
   – Surgical resection is recommended.

• For liver metastases, surgical excision if possible,
  including debulking (>90% resection).

• Also, consider RFA, cryoablation, targeted
  chemotherapy and arterial embolization.

• For unresectable disease, consider XRT for symptom
  control or clinical trial.
• Symptomatic or progressive distant metastases:
  – Functional tumors.
  – Nonfunctional tumors evident on Octreoscan.
  – Those with elevated biomarkers.

     • Octreotide 150mcg SQ tid.

     • If tolerated, initial monthly dose of 20mg LAR
       Octreotide IM, then increase based on tolerance and
       result.

     • Inhibits secretion of hormone, improves symptom
       control, can slow tumor growth and can cause
       regression in some tumors.
Options for painful bone metastases


• Radiotherapy with or w/out bisphosphonates.



• Clinical trial.
      Chemotherapeutic options
• 5-FU, doxorubicin, streptozocin, dacarbazine used alone or
  in combination.

                              OR

• Combination chemotherapy using other agents such as
  cisplatin/etoposide.

• Response rates range from 20%-50%.

• Although therapy is palliative, long survival times are
  possible.

• Clinical trials.
ECOG Unresectable/Metastatic NET
             Trial
• Published in 1992.

• 105 patients with unresectable or metastatic islet
  cell carcinoma enrolled.

• Surgical resection not required in study.

• Chemotherapy trial using combinations of:
   –   Streptozocin
   –   Doxorubicin
   –   5-Fluorouracil
   –   Chlorozotocin.

                                Moertel, Lefkopoulo, Lopsitz, et al. NEJM 326:519-523.
    ECOG Unresectable/Metastatic NET
                 Trial
• Streptozocin + Doxorubicin superior to Streptozocin
  + Fluorouracil for rate of tumor progression.

  – Evidence of progression - 69% vs. 45%, p=0.05.

  – Length of time to tumor progression - median, 20 vs. 6.9
    months, p=0.001.

  – Survival advantage - median 2.2 vs. 1.4 years, p=0.04.
                                      Moertel, Lefkopoulo, Lopsitz, et al.
                                      NEJM 326:519-523.
             Chemoembolization
• Liver tumors tend to derive 80% of blood supply from
  hepatic artery.
   – Normal liver parenchyma derives ~ 70% of blood supply
     from portal vein.

• Intratumoral drug concentration is much greater when
  given intra-arterially compared with administration via
  the portal vein.

• Combined with embolization (to slow blood flow
  through the hepatic tumor bed) intra-arterial
  chemotherapy may achieve an even greater
  concentration of drug and time of exposure.
Surgical Resection of Metastatic
            Disease
• NET features that lend themselves to aggressive
  resection:
  – Cancer growth rate is indolent
  – Primary tumor growth characterized by expansion
    against other structures rather than invasion of
    nearby vessels/organs.
  – Growth characteristics of hepatic metastases are
    similar.
  – Control of the primary cancer is imperative before
    resection/ablation of hepatic metastases.
  – ? Concurrent vs. staged resections ?
• Natural history of unresected pancreatic islet cell
  tumors with hepatic metastases is poor.
  – 5 year survival rate ~ 30%.
  – Intra-abdominal complications have accounted for
    majority of rest of deaths.



• Current outcomes for nonsurgical approaches do
  not warrant categoric exclusion of surgical
  approaches.
• 23 Patients underwent distal
  pancreatectomy/splenectomy.
   – 17 minor (<3 segments) partial hepatectomies.

   – 6 major (> 3 segments) hepatectomies.

   – RO/R1 resection in 9 patients

   – R2 resection in 14 patients (<10% remaining after
     resection)

   – No perioperative deaths. Major complications in 18%.
• 5 year results:
   – 71% Overall survival (median 76 months)
   – 5% Progression Free (median 21 months)
   – 24% Symptom Free (median 26 months)
• Resection, though not often curative, may delay
  other treatments and does not prevent their
  eventual implementation.

• Despite recurrence of disease in all patients, all
  experienced significant reduction of antisecretory
  medications and their symptoms.

• A previous study reported a 28% 5-year survival
  without debulking, but 79% 5-year survival with
  debulking.
• Resection of Pancreatic islet cell cancer is
  contraindicated in the presence of undebulkable
  hepatic or distant metastases if patients are
  asymptomatic.
   – Treat with chemotherapy/somatostatin analogues.


• Conclusion:
   – Data supports aggressive concurrent resection
     of pancreatic islet cell cancers and synchronous
     hepatic metastases when technically feasible.
                          Arch Surg. 2006;141:1000-1004.


• 48 pts with liver-only neuroendocrine metastases.
   – 75% carcinoid, 25% islet cell
   – 1996-2004


• 13 treated with surgical resection of liver metastases.

• 17 treated conservatively (octreotide, observation, or systemic
  chemotherapy).

• 18 underwent hepatic artery embolization.

• No difference in percentage of liver involvement between groups
                  Survival




Selection bias of those able to undergo surgery?
  Summary of Recent Series for
Survival after Hepatic Resection for
         Metastatic NETs
• Indications for pancreaticoduodenectomy:
   –   Large tumor size
   –   Deep intraparenchymal position adjacent to pancreatic duct
   –   Tumors with malignant characteristics (presence of metastases).
   –   Multifocality (rarely)


• Tumors rarely involve SMA/SMV – push rather than invade.
   – Can replace SMV or portal vein in some cases if necessary.

• 29 patients between 1980-1995:
   – 20/29 tumors non-functioning
   – 2/29 underwent total pancreatectomy
   – Major morbidity – 31%
• Is Pancreaticoduodenectomy justified?

   – Of 20 patients with unresectable locally advanced
     disease, 9 died of complications directly related to
     primary tumor in median time of 1.7 years.
      • Median number of hospitalizations – 4 (1-11).

• No patient in this study undergoing PD developed
  recurrence of their endocrinopathy.
• Results:
• Mean follow-up: 8.8 years

• 5-year survival – PD 82% vs. Enucleation 50-60%
   – Greater for node-negative patients (100% vs. 67%,
     p=0.04)

• 10-year survival – 70%

• Recurrence free survival – 76% at 5 and 10 years.
  – Trend towards greater recurrence-free survival for node-
    negative patients (88% vs. 65% at 5 years, p=0.13)
              Conclusion
Pancreaticoduodenectomy is an appropriate
strategy for selected malignant islet cell tumors
of the pancreas, which offers extended survival
with a low recurrence rate and control of
endocrine symptoms.
          Liver transplantation for NET




• 19 patients (mean f/u 15months, range 0-84 months).

• Overall 1 year survival 87%.

• 1 year recurrence free survival 77%.

• 3/11 with GEP had recurrence.

• All 8 with carcinoid remain disease free.
              Liver transplantation for NET




• 15 patients with metastases to liver only (all >50% of liver volume).

• 5-year overall survival 90% (mean f/u 53 months, range 2-88 months).

• Good symptom relief, potential cure (6/15 NED).

• Recurrence free survival 70% at 1 year.
• Recurrence free survival 20% at 5 years.
      What’s on the Horizon?

• Radiolabelled Octreotide therapy.

• Transfection of tumor cells with specific
  receptors for targeted therapy.

• New chemotherapeutic agents.
  – VEGF Inhibitors
       Radiolabelled Octreotide Therapy




• Currently being used in Europe. Not available in U.S.

• Somatostatin analogues bind specific receptors on tumor
  cells.

• Act as vehicle to deliver radioactivity to tissues expressing
  somatostatin receptors.
      Radiolabelled Octreotide Therapy
•   111In-DTPA   led to symptomatic improvement, but short
    lived objective tumor responses.

•   90Y-DOTATOC     (OctreoTher) was associated with 10-
    30% response rate, effective in larger tumors.

•   177Lu-DOTATATE       has higher affinity for subtype 2
    receptor. Resulted in 30% complete of partial tumor
    responses. Effective in smaller tumors.

• Better responses in gastroenteropancreatic tumors than
  other NETs.
• Study evaluated transfection of PNET cells
  with thyroid sodium iodide symporter, then
  treated with radioactive iodine (I 131).

• Appears to be a promising novel approach
  in the therapy of NETs if its in vitro
  effectiveness can be transferred to the in
  vivo situation.
     List of ongoing clinical trials
• http://www.nccn.org/clinical_trials/default.asp

• A review of the current clinical trials for
  gastroenteropancreatic neuroendocrine tumours.
  Expert Opin Investig Drugs. 2007
  Feb;16(2):219-24.

• CTRC Trials
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