5/24/06 Brent White Richard Barth Pancreatic Neoplasm 5/24/06 Brent White Richard Barth

Facts About Brent & Georgia Born in Durham, NC 4/8/74 My family moved to Columbus, Georgia when I was 6 weeks old Georgia is known as “The Goober State” Goober=Peanut Georgia produces quite a few peanuts, growing 42% of peanuts grown in the US

Overview During 2006, estimated 32,300 people will die in the US of pancreatic cancer Fourth and fifth most common cause of cancer deaths in men and women in the US respectively Peak incidence in age 60-80 African Americans with slightly higher incidence compared with Caucasians

Types of Pancreatic Neoplasms Broadly speaking, there are three basic types: Ductal adenocarcinoma >90% of pancreatic cancers with a 4% 5-year survival (worst of any cancer) Neuroendocrine tumors aka islet-cell tumors, rare Cystic neoplasms account for <1% of pancreatic cancers

Clinical Scenario #1 – Adenocarcinoma of the Pancreas 70yo female with PMH of HTN who developed jaundice without significant abdominal pain, no fever Bilirubin 12 No significant complaints of abdominal pain

Clinical Scenario #1 – Adenocarcinoma of the Pancreas What are typical symptoms of pancreatic CA? Abdominal pain->pain can suggest neural plexus, tail lesion, unresectability, poor prognosis Anorexia Weight loss Jaundice Pruritis ->biliary obstruction Steatorrhea->pancreatic duct obstruction

Risk Factors for Pancreatic Cancer? Firmly linked to cigarette smoking No clear dietary factors Increased BMI associated with increased risk Occupational exposures to amines (chemistry, hairdressing, rubber work) associated with increased risk

Risk Factors for Pancreatic Cancer Previous epidemiology identified chronic pancreatitis as a risk factor May actually be EtOH, smoking, and a degree of selection bias instead of pancreatitis Familial excess of pancreatic cancer, hereditary cancer syndromes, hereditary pancreatitis, BRCA-2 mutations all associated with increased risk of pancreatic cancer

Adenocarcinoma of the Pancreas: Workup 70yo female with painless jaundice... What would widely be regarded as the single most useful imaging study in this patient’s workup? CT

Adenocarcinoma of the Pancreas: CT scan CT can confirm pancreatic cancer with a sensitivity of 85-95% (sensitivity is limited by smaller tumor size) Other than the presence of a pancreatic mass, what else can you determine from CT scan? PRESENCE of METASTASES (along with CXR) RESECTABILITY

Adenocarcinoma of the Pancreas: CT scan What makes a pancreatic mass likely resectable? No evidence of extrapancreatic disease Evidence of nonobstructive superior mesenteric-portal vein confluence No evidence of direct tumor extension to the celiac axis and SMA EUS, laparoscopy are universally regarded as useful adjuncts to CT, not as essential however

Adenocarcinoma of the Pancreas: CT scan “Borderline” Resectable lesions include: SMV occlusion of a short segment (open vein proximally and distally) Body and tail lesions with + celiac, para-aortic nodes in the vicity Tumors briefly involving the IVC may be borderline

Adenocarcinoma of the Pancreas: CT scan

Adenocarcinoma of the Pancreas: Workup The mass appears “borderline” resectable per these criteria Now what? GI consultation for ERCP and EUS!

Pancreatic Cancer: Endoscopic Adjuncts ERCP can be utilized to: detecting small tumors not visualized on CT (irregular solitary duct stenoses >1cm long, abrupt cutoff of main pancreatic duct, or panc and bile duct obstruction) palliating biliary obstruction brush cytology of the pancreatic duct has fair sensitivity (70%) but excellent specificity EUS can be utilized to: aid in diagnosis and characterization of lesion obtain tissue biopsy; may be associated with lower risk of peritoneal seeding c/w percutaneous approach

Pancreatic Cancer: Endoscopic Adjuncts ERCP picture

Pancreatic Cancer: Serum Markers Is there a role for serum markers? If so, what? CA 19-9 is a sialylated Lewis A blood group antigen commonly expressed and shed in pancreatic and hepatobiliary disease, not tumor specific This antigen, when significantly increased, can assist in differentiating between pancreatic adenocarcinoma and inflammatory pancreatic disease decrease in serial CA 19-9 correlates with survival of pancreatic patients after surgery or chemotherapy Debatable as to whether this is useful as early treatment of recurrences have not been shown to improve outcomes

Pancreatic Cancer Staging Though TNM staging exists, we can roughly simplify to: local/resectable, median survival 17 months locally advanced and unresectable, median survival 8-9 months metastatic disease, median survival of 4-6 months

Pancreatic AdenoCA Algorithm

Pancreatic Cancer: Neoadjuvant Therapy This 70yo female has “borderline” resectable features, has been stented to answer obstructive jaundice via ERCP with EUS demonstrating a positive adenocarcinoma Is there any role for neoadjuvant therapy for this patient? If so, what sort of regimen and with what objectives?

Pipas, Barth et al. 24 patients with pancreatic adenocarcinoma Inclusion criteria: biopsy-proven adenocarcinoma of pancreas (Stage I-III), age>18yo, Karnofsky of >70%, Creatinine<2, WBC >3000, Hgb >10g/dL, Plts >100,000 No history of chemo/XRT or malignancy Treatment consisted of docetaxel 65mg/m2 IV over 1 hour and gemcitabine 4000mg/m2 IV over 30 minutes on days 1, 15, 29. On Day 43, XRT at 50.4 Gray with gemcitabine 50mg/m2 IV over 30 minutes biweekly for 12 doses

Pipas, Barth et al. All but one of 24 patients completed 12 week course of therapy Grade 3 and 4 toxicities common, but manageable No tumor progression, 12 responded to therapy with one radiographic CR 50% of patients had radiographic response, 17/24 patients underwent resection after therapy Of 17 resection patients, 13 (76%) with negative margins

Pipas, Barth et al.

Adenocarcinoma 70yo female undergoes docetaxel/gemcitabine followed by gemcitabine with XRT and appreciable response is seen on repeat CT Whipple Operation Utility to pylorus preservation? Extended lymphadenectomy? Does type of pancreatic anastamosis matter? Do stents decrease pancreatic fistulas?

Case #2 28yo surgical resident was golfing, badly. Suddenly, according to his partners, he began acting “crazy” and drove the golf cart wildly around the green, through a sandtrap and into a small creek. He was incoherent when he was brought to the ER and found to have a serum glucose of 32.

How is insulinoma diagnosed? Whipple’s Triad: symptoms of hypoglycemia during fasting or exercise serum glucose <45mg/dL during symptoms relief of symptoms with administration of glucose Definitive test is 72-hour fast with measurement of insulin and glucose 75% of patients develop symptoms and GB<40 within 24 hours insulin:glucose ratio >0.4 is indicative of insulinoma Elevated c-peptide proinsulin levels are confirmatory along with screening for antiinsulin antibodies, sulfonylureas

What percent are malignant? 10% are malignant, indicated by metastases Metastases usually to regional peripancreatic lymph nodes, liver generally sporadic, solitary, benign, <2cm occurring in equal distribution throughout the pancreas

How are insulinomas localized? Non-invasive preoperative imaging studies fail to localize 30-35% of insulinomas CT/MRI, etc. generally reserved by most endocrine surgeons to r/o hepatic metastases Intraoperative U/S and palpation are the GOLD standard for finding an insulinoma, 96-100% sensitivity

What is proper operation for insulinoma? Generally wide Kocher maneuver, superior and inferior pancreatic border mobilization, medial reflection of the spleen Bimanual palpation with U/S Enucleation of the lesion Secretin can assist in identifying pancreatic duct leak after enucleation completed What about lesion in pancreatic head? Need to monitor glucose levels q15 minutes until lesion out

Case #3 A patient has a gastric ulcer diagnosed endoscopically and is treated with Cimetidine. One month later, the ulcer is still present despite treatment.

How is ZE diagnosis made? Elevated serum gastrin level, elevated basal acid secretory rate both only suggest possible gastrinoma Secretin stimulation test discontinue acid-inhibitory medication basal serum gastrin levels 2 U/kg of secretin IV bolus, then serum gastrin measured at 2, 5, 10, and 20 minutes later Positive response is gastrin >200pg/mL above basal level

How would you control gastric acid secretion? Proton pump inhibitor titrated to achieve non-acidic gastric pH

Where are gastrinomas? How would you localize it? Most are found in the duodenum, pancreas, or lymph nodes near the head of the pancreas, 10% of the time they are heart, liver, bile ducts, ovary, etc. Localization with somatostatin receptor scintigraphy (SRS) (only 30% of gastrinomas <1.1cm) SRS and EUS can, in tandem, improve detection of small gastrinomas within the wall of the duodenum

At operation, what is the likelihood of finding metastatic tumor? Metastatic tumor to liver is found in 5-14% of cases, nodal metastases in 50% of patients

Where are most gastrinomas found? Gastrinoma triangle is where most tumors are found (70-90%) Tumor detection can be improved via palpation, IOUS, extended Kocher maneuver, transillumination of the duodenum, and duodenotomy

Hypercalcemia and Gastrinoma If patient has MEN-1 (hyperparathyroidism, pituitary adenoma, islet-cell tumor), can they be cured with surgery for gastrinoma? Seldom can biochemical cure be achieved due to multicentric nature of disease in MEN-1 93% of patient with MEN-1 alive 15 years after diagnosis, if they are on PPI’s and have no liver mets some advocate surgical treatment only in sporadic form of disease; others propose operating on MEN-1 gastrinomas only when 2.5-3cm in size in order to reduce possibility of metastases