Pancreatic Cancer Epidemiology

• Eighth most common malignancy
• Fifth leading cause of adult cancer death (following lung, colon, breast, and prostate)
• Incidence is 28,000 new cases per year
• Mortality is 28,000 deaths per year
• Risk increases after 5th decad
• Incidence has been stable over the past 20 years
• Male to female ratio 1.3 :1

Pancreatic Cancer Etiology

• Primary etiology unknown
• Cigarette smoking increases risk threefold
• Coffee, alcohol, organic solvents have been linked
• Long-standing diabetes and chronic pancreatitis have been implicated
• 10% have a familial predisposition

Pancreatic Cancer Familial

• Difficult to recognize since the presentation is similar and the penetrance is low

• Minority of familial pancreatic cancers are associated known genetic syndromes such as BRCA2, p16/CDKN2, Hereditary Non-polyposis colon cancer (Lynch II), Gardner’s syndrome.

Pancreatic Cancer

• Genetic discoveries from familial cases have contributed to the understanding of sporadic cancers

• Genetic alterations accumulate as the lesion progresses from normal duct to severe atypia

Pancreatic Cancer Mutuation Frequency

• 90% for K-ras and p16
• 50% for HER2/neu, p53, and DPC4
• 10% for BRCA2

Screening

• K-ras mutation in codon 12 are present in 90% of invasive cancers
• Numerous studies have attempted to correlate K-ras mutation assays in serum, stool, duodenal juice, pancreatic juice, and brushings.
• Progression model suggests that later mutations such as p16 may be more valuable

Pathology

• 90% of pancreatic exocrine tumors arise from pancreatic ductules
• 70% of theses tumors arise in the head and uncinate process
• Adenocarcinoma most commonly seen
• Desmoplastic reaction with perineural invasion is common

Natural History of Pancreatic Cancer

• Early spread to regional lymph nodes
• Hematogenous spread to liver and lungs
• Locally advanced cancers have a median survival of 6-10 months
• Metastatic cancers have a median survival of 3-6 months

Helical CT Scan Criteria for Resectability

• Absence of extra-pancreatic disease
• Patent SMPV confluence
• Normal plane between tumor and SMPV confluence
• No direct tumor extension to the celiac axis or SMA

Endoscopic Ultrasound (EUS)

• Provides superior visualization of small tumors missed by CT scan (2cm)
• Allows visualization of regional lymph nodes
• Less effective in showing portal vein involvement
• Allows for FNA of tumor when tissue diagnosis is necessary

EUS with FNA

• Provides superior visualization of small tumors missed by CT scan (2cm)
• Allows visualization of regional lymph nodes
• Less effective in showing portal vein involvement
• Allows for FNA of tumor when tissue diagnosis is necessary

Endoscopic Ultrasound (EUS)

• Provides superior visualization of small tumors missed by CT scan (2cm)
• Allows visualization of regional lymph nodes
• Less effective in showing portal vein involvement
• Allows for FNA of tumor when tissue diagnosis is necessary

Endoscopic Retrograde Cholangiopancreatography

• ERCP plays an important role in the work-up of the jaundiced patient
• Double-duct sign 80% specific for malignancy
• Pancreatic duct brushings are an insensitive method
• Helps differentiate choledocholithiasis and chronic pancreatitis from malignancy

Nonoperative Management

• Surgery is avoided in patients who are discovered to have distant metastases or unresectable local disease by staging studies
• Patients too high risk for surgery
• Palliation of biliary obstruction can be performed endoscopically. Plastic as well as metallic endoprostheses available

Operative Therapy

• Surgical resection is the only potentially curative treatment modality
• Palliative surgery is appropriate in patients with unresectable disease discovered at the time of exploration for potential cure

Palliative Surgery

• Retrocolic hepatojejunostomy
• Avoid use of gallbladder
• Performance of retrocolic gastrojejunostomy is controvertial.
• 19% of patients will eventually obstruct duodenum (randomized trial published in 1999 JHU)
• Chemical celiac nerve block (50% alcohol)

Palliative Surgery

• Retrocolic hepatojejunostomy
• Avoid use of gallbladder
• Performance of retrocolic gastrojejunostomy is controvertial.
• 19% of patients will eventually obstruct duodenum (randomized trial published in 1999 JHU)
• Chemical celiac nerve block (50% alcohol)

Preparation for Operative Intervention

• Assessment of medical condition
• Assessment of nutritional status
• Assessment of coagulation status
• Consideration of biliary catheter drainage

Preoperative Biliary Drainage

• 1999 retrospective study from Sloan –Kettering -- 240 consecutive PD where 53% underwent preoperative decompression

• Study found a statistical relationship between the use of preoperative drainage and post-operative complications, namely infectious

• Advocate selective use of pre-operative drainage in symptomatic or septic patients

Pancreaticoduodenectomy

• Whipple first performed this procedure in 2 stages in 1935 in 3 patients
• First stage was the biliary decompression
• Second stage was the resection
• 1937 the first one stage PD was reported.
• 37 cases were reported in the 1940’s

Controversies Regarding Pancreaticoduodenectomy

• Classic versus pylorus preservation
• Options for pancreatic reconstruction
• Standard versus radical resection

Pylorus Preservation

• First described in 1978 by Longmire
• Popularized by Lahey clinic and JHU
• No difference in survival
• Early delayed gastric emptying seen
• Better postoperative nutritional status, lower incidence of dumping syndrome
• 85% of cases at JHU

Pancreatic Anastomosis

• A leak from the pancreatic anastomosis remains the leading cause of morbidity
• JHU published results of a randomized trial in 1995 comparing pancreaticogastrostomy versus pancreaticojejunostomy
• Fistula rate was identical at 12%
• Octreotide has not been show effective in decreasing fistula rates in 2 prospective, randomized trials

Standard vs Radical Resection

• Radical resection includes a 40% gastrectomy
• Retroperitoneal lymph node dissection
• Complete uncinate process removal flush from the SMA was performed in all cases

Factors Influencing Survival Postresection

• Presence of positive resection margin
• Presence of positive resected lymph nodes
• Tumor diameter greater than 3 cm
• Diploid vs. aneuploid tumors

When Should Portal Vein Reconstruction be Performed?

• After pancreas has been transected and there is adherence of the uncinate process to the portal vein.
• No tumor extension into SMA

Adjuvant Therapy Rationale

• 5-year survival is poor in resected patients
• 85% of patients recur in the field of resection
• 70% of patients develop liver metastasis

Adjuvant Therapy

• Most chemotherapeutic agents have limited activity against pancreatic cancer
• 5-Fluorouracil (5-FU) and Gemcitabine are the only active agents
• 15%-28% response rates have been reported
• 5-FU and gemcitabine act as a radiosensitizer
• The Gastrointestinal Tumor Study Group was the first study to demonstrate a survival advantage with postoperative chemoradiation
• Prospective, randomized trial
• 500 mg/m2/day 5-FU for 6 days plus 40 Gy of radiation vs resection alone
• 20 months median survival vs 11 months

Neoadjuvant Therapy

• Rationale- 25% of patients do not receive intended postoperative chemoradiation
• Because chemoradiation is given first, delay in postoperative therapy is not an issue
• Patients who progress rapidly are not subjected to surgery

M.D. Anderson Protocol

• Biliary stent and EUS biopsy required
• 50.4Gy over 5.5 weeks
• 5-FU at 300 mg/m2/day
• Restaging performed 4 weeks after completion
• Gemcitabine as a radiosensitizer currently being evaluated