Pancreatic Cancer

Aka: Pancreatic Cancer, Pancreatic Adenocarcinoma, Courvoisier's Sign

1. Epidemiology
   1. Third leading cause of cancer deaths in United States
   2. Incidence: 2% of new cancers in United States
      1. New cases: 56,770 cases in 2019 (US)
      2. Mortality: 45,750 deaths in 2019 (US)
   3. Age
      1. Typically over age 50 years old
2. Risk Factors
   1. Mild Risk Factors (<5 fold increased risk)
      1. Alcohol use >4 drinks/day
      2. Obesity with Body Mass Index (BMI) >30 kg/m2
      3. BRCA1 gene carrier
      4. Polycyclic or chlorinated hydrocarbon exposure
      5. Diabetes Mellitus Type II (for 5 years or more)
      6. Familial Adenomatous Polyposis
      7. Familial nonpolyposis Colorectal Cancer
      8. Family History: 1 first degree relative with Pancreatic Cancer
      9. Tobacco Abuse or exposure
         1. Responsible for 25-30% of Pancreatic Cancer
   2. Moderate Risk Factors (5-10 fold increased risk)
      1. BRCA2 gene carrier
      2. Chronic Pancreatitis
      3. Cystic Fibrosis
      4. Family History: 2 first degree relatives with Pancreatic Cancer
   3. Severe Risk Factors (>10 fold increased risk)
      1. Familial atypical multiple mole Melanoma
      2. Family History: 3 or more first, second or third degree relatives with Pancreatic Cancer
      3. Hereditary Pancreatitis
      4. Peutz-Jeghers Syndrome
   4. References
      1. Brand (2007) Gut 56(10): 1460-9
3. Pathophysiology
   1. Adenocarcinoma of pancreatic ductal epithelium (90% of cases)
   2. Onset usually in head of Pancreas
4. Symptoms: General
   1. Common
      1. Unexplained weight loss (>5 pounds per month)
      2. Epigastric Abdominal Pain radiating to back
   2. Nonspecific associated symptoms
      1. Nausea or Vomiting
      2. Anorexia
      3. Early satiety
      4. Weakness
   3. Other presentations
      1. New onset Type II Diabetes Mellitus in a thin patient over age 50 years old
      2. Recurring Superficial Thrombophlebitis
5. Symptoms: Head of Pancreas involved
   1. Head of Pancreas involved in two thirds of Pancreatic Cancers
   2. Biliary duct obstruction related symptoms
      1. Jaundice
      2. Dark Urine
      3. Acholic stool (Light colored stool)
6. Signs
   1. Non-specific findings
      1. Cachectic patient
      2. Bruising
      3. Jaundice (if biliary duct obstruction)
   2. Courvoisier's Sign
      1. Non-tender, but distended, palpable Gall Bladder
      2. Associated with Jaundice
      3. Test Sensitivity only <56%, but Test Specificity >82%
   3. Other findings
      1. Left Supraclavicular Lymphadenopathy involving Virchow's Node
      2. Subcutaneous Nodules of fat or pancreatitic Panniculitis (rare)
7. Differential Diagnosis
   1. Gall Bladder Disorders (e.g. Cholecystitis, Cholelithiasis or Choledocholithiasis)
   2. Peptic Ulcer Disease or Gastritis
   3. Pancreatitis
   4. Abdominal Aortic Aneurysm
   5. Other abdominal cancer
      1. Liver cancer (or liver metastases)
      2. Lymphoma
      3. Stomach Cancer
      4. Colon Cancer
8. Labs
   1. General markers (if biliary duct obstruction)
      1. Alkaline Phosphatase increased
      2. Conjugated Serum Bilirubin increased
   2. Tumor Markers
      1. CA 19-9 (use for diagnosis/prognosis, NOT screening)
      2. bHCG (better prognostic indicator than CA 19-9)
      3. CA 72-4 (better prognostic indicator than CA 19-9)
9. Imaging
   1. Routine screening not recommended in general
      1. Consider endoscopic Ultrasound if Family History or other high risk factors listed above
   2. Initial testing
      1. Standard CT Abdomen
      2. Transabdominal Ultrasound
         1. Reflex to CT Abdomen if non-diagnostic
   3. Most accurate testing
      1. Triple-phase helical CT with Pancreas protocol (preferred)
         1. Includes imaging during arterial, late and venous phases
      2. Endoscopic Ultrasound
         1. Indicated if helical CT not diagnostic or for biposy
         2. Guides FNA in non-operable cancer
   4. Other testing
      1. MRI Abdomen with contrast (and MR cholangiopancreatography)
         1. Indicated if CT contrast is contraindicated or to define extrapancreatic disease
         2. MRI is less sensitive than CT Abdomen (with Pancreas protocol) in initial evaluation
10. Evaluation: Suspected Pancreatic Cancer
    1. Metastatic cancer
       1. Endoscopic Ultrasound with fine needle aspirate
    2. No metastatic disease
       1. Multidisciplinary review (oncology, surgery, radiology, pathology)
       2. Liver Function Tests
       3. Chest imaging
       4. Consider endoscopic Ultrasound with fine needle aspirate
       5. Consider other imaging (e.g. MRI)
          1. Indicated if Pancreatic Cancer suspected but non-diagnostic triple-phase helical CT with Pancreas protocol
       6. Consider diagnostic staging laparoscopy
          1. Exclude occult peritoneal metastases
11. Evaluation: Pancreatic Cyst evaluation
    1. Endoscopic Ultrasound with fine needle aspirate
    2. Concerning Pancreatic Cystic lesions
       1. Pancreatic serous cystadenoma
       2. Pancreatic mucinous cystic neoplasm
       3. Pancreatic intraductal papillary mucinous neoplasm (and other pancreatic duct dilitations)
       4. Pancreatic Cystic endocrine tumor
       5. Pancreatic ductal adenocarcinoma
12. Staging
    1. Protocol
       1. Based on evaluation including imaging and biopsy as described above
       2. Multidisciplinary Consultation
    2. Stages
       1. Localized within Pancreas, resectable (Stage 0, IA and IB)
          1. Classification: Tis-T2, N0, M0
          2. Found this early in only 8% of patients
          3. Five year survival: 21.5% for Stage 0 and 12% for Stage Ib
       2. Locally invasive, resectable (Stage IIA, IIB)
          1. Classification: T1-3 N0-1, M0
          2. Found at this stage in only 27% of patients
          3. Five year survival: 5-7%
       3. Locally advanced, NOT-resectable (Stage III)
          1. Classification: T4 N0-1 M0
          2. Five year survival: 3%
       4. Metastatic disease, NOT resectable (Stage IV)
          1. Classification: T1-4, N0-1, M1
          2. Found at this stage in only 53% of patients
          3. Five year survival: 1.9%
    3. Stages: Summary
       1. Resectable (15% five year survival)
          1. Accounts for 15-20% of Pancreatic Cancer cases
          2. Resectability is defined by degree of SMA, SMV or Portal Vein involvement
          3. Invasion of aorta, inferior vena cava or distant metastases excludes resection
          4. Body or tail Pancreatic Cancer more advanced at presentation
             1. Less commonly resectable at presentation than cancer involving the pancreatic head
       2. Locally advanced (3% five year survival)
       3. Metastatic (1.9% five year survival)
13. Management: General
    1. See Cachexia in Cancer
    2. See Mood Disorders in Cancer
    3. Treat Cancer Pain
       1. See Cancer Pain Management
       2. Celiac plexus neurolysis (via endoscopic Ultrasound)
          1. Alcohol injected into celiac plexus
          2. Significantly reduces pain
    4. Pancreatic Cancer specific concerns
       1. Malabsorption from exocrine pancreatic insufficiency
       2. Pancrealipase 30,000 IU
          1. Taken before, during and after meal
       3. Jaundice secondary to biliary obstruction
          1. Biliary decompression via surgery or endoscopy
14. Management: Resectable Pancreatic Cancer
    1. Criteria for resectable cancer
       1. No distant metastatic cancer
       2. No vascular invasion
          1. No superior Mesenteric Artery involvement
          2. No aorta or inferior vena cava involvement
          3. No celiac involvement
    2. Surgery
       1. Performed at high volume center (>15 pancreatic resections annually)
       2. Cancer involving head of Pancreas: Whipple Procedure
          1. Classic pancreaticoduodenectomy
             1. Resection of pancreatic head as well as Gall Bladder, common bile duct and second part of duodenum AND
             2. Distal Stomach
          2. Pylorus-Preserving Pancreaticoduodenostomy
             1. Resection of pancreatic head as well as Gall Bladder, common bile duct and second part of duodenum AND
             2. Postpyloric duodenum
       3. Cancer involing body and tail of Pancreas
          1. Distal pancreatectomy with or without splenectomy
          2. Resection is rarely possible due to delayed presentation with advanced disease
    3. Adjuvant Chemotherapy
       1. Leucovorin and fluorouracil apper to be effective
       2. Gemcitabine (Gemzar) also appears effective
       3. Radiation associated with worse prognosis
    4. Post-resection surveillance
       1. History and physical exam every 3-6 months for 2 years, then yearly
       2. Diagnostic options every 3-6 months
          1. Cancer Antigen 19-9
          2. Triple-Phase CT Abdomen - Pancreas protocol
          3. Endoscopic Ultrasound
15. Management: Locally advanced Pancreatic Cancer
    1. Combination protocol: Chemoradiotherapy
       1. Radiation Therapy and
       2. Fluorouracil or Gemcitabine
    2. Efficacy
       1. One year survival: 40% (versus 10% with no treatment)
16. Management: Metastatic Pancreatic Cancer - Chemotherapy and radiation options
    1. Precaution
       1. Chemotherapy and/or radiation only prolong median survival to 10.`5 months over 6.9 months
    2. Consider Gemcitabine
       1. Improves 1 year survival
       2. May be used in combination with fluorouracil, cisplatin and oxaliplatin
    3. Consider Irinotecan (Camptosar)
       1. Improves progression free and overall survival, but toxicity may limit tolerability
    4. Consider intensity-modulated Radiotherapy or stereotactic body Radiotherapy
       1. Localized radiation to the Pancreatic Cancer
17. Management: Metastatic Pancreatic Cancer - Palliative Care
    1. General measures
       1. Involve Hospice early
       2. Palliative pain management
       3. Depression Management
    2. Biliary obstruction (65-75% of patients)
       1. Endoscopic metal biliary stent placement
    3. Gastric outlet obstruction (10-25% of patients)
       1. Enteral stent (if Life Expectancy <3 months) or
       2. Gastrojejunostomy tube
    4. Exocrine pancreatic insufficiency
       1. Oral pancreatic enzyme replacement
       2. Adjust dosing based on body weight change
    5. Recurrent Venous Thromboembolism Prevention
       1. Low Molecular Weight Heparin (instead of Warfarin)
18. Prevention
    1. Fruit and vegetables in diet
    2. Exercise
    3. NSAIDs (possible)
    4. Screening indications
       1. Moderate to high risk of Pancreatic Cancer may prompt screening with CT Abdomen or endoscopic Ultrasound
19. Prognosis
    1. At diagnosis, only 15-20% of cancers are localized
    2. Five year survival
       1. Localized Pancreatic Cancer: 37.4%
       2. Regional Pancreatic Cancer: 12.4%
       3. Metastatic Pancreatic Cancer: 2.9%
    3. Best prognostic findings post-resection
       1. Negative margins
       2. Tumor DNA content
       3. Smaller pancreatic tumor size
       4. No lymph node metastases
20. Resources
    1. Pancreatic Cancer Statistics (NCI)
       1. https://seer.cancer.gov/statfacts/html/pancreas.html
21. References
    1. (2019) Am Fam Physician 100(12): 770A-C [PubMed]
    2. De La Cruz (2014) Am Fam Physician 89(8): 626-32 [PubMed]
    3. Freelove (2006) Am Fam Physician 73(3):485-92 [PubMed]
    4. Li (2004) Lancet 363:1049-57 [PubMed]