Pancreatic Cancer

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

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II. Epidemiology

  1. Third leading cause of cancer deaths in United States
  2. Lifetime Risk (U.S.): 1.7%
  3. Incidence: 2-3% of new cancers in United States (7% of cancer related deaths)
    1. New cases: 64,050 cases in 2023 (US)
    2. Mortality: 50,550 deaths in 2023 (US)
  4. Age
    1. Typically over age 55 years old (90%)
    2. Median age of diagnosis: 70 years old
  5. Family History
    1. Sporadic cases in 85% of cases
    2. Familial in 10% of cases
    3. Genetic Syndrome in 5%

III. Risk Factors

  1. Mild Risk Factors (<3 fold increased risk
    1. General
      1. Routine screening not recommended
    2. Alcohol use >4 to 6 drinks/day (adjusted Odds Ratio 1.6)
    3. Obesity with Body Mass Index (BMI) >30 kg/m2 (adjusted Odds Ratio 1.3)
    4. BRCA1 gene carrier (RR 2.26)
    5. Polycyclic or chlorinated Hydrocarbon exposure
    6. Diabetes Mellitus Type II (for 5 years or more, or onset in the last year)
    7. Hepatitis B Infection (adjusted Odds Ratio 1.4)
    8. Familial Adenomatous Polyposis
    9. Familial nonpolyposis Colorectal Cancer
    10. Family History: 1 first degree relative with Pancreatic Cancer
    11. Tobacco Abuse or exposure (adjusted Odds Ratio 1.6)
      1. Responsible for 25-30% of Pancreatic Cancer
  2. Moderate Risk Factors (3-10 fold increased risk)
    1. General
      1. Start screening at age 50 years (or 10 years younger than affected relative)
    2. ATM gene mutation (RR 3.9)
    3. BRCA2 or PALB2 gene carrier (RR 3.5 to 6.2)
    4. Li Fraumeni Syndrome (RR 7.3)
    5. Chronic Pancreatitis for more than 2 years (adjusted Odds Ratio 4.3)
    6. Cystic Fibrosis
    7. Family History: 2 first degree relatives with Pancreatic Cancer (RR 6.4)
  3. Severe Risk Factors (>10 fold increased risk)
    1. General
      1. Start screening after age specific for risk factor
    2. Family History: 3 or more first, second or third degree relatives with Pancreatic Cancer
      1. Three first degree relatives confers RR 32
    3. Familial atypical multiple mole Melanoma (RR 13 to 39)
      1. Start screening at age 40 years
    4. Lynch Syndrome (RR 8 to 11)
      1. Start screening at age 50 years (or 10 years younger than youngest relative)
    5. Hereditary Pancreatitis (Standardized Incidence ratio 53)
      1. Start screening at age 40 years
    6. Peutz-Jeghers Syndrome (RR 132)
      1. Start screening at age 25 years
  4. References
    1. Brand (2007) Gut 56(10): 1460-9

IV. Pathophysiology

  1. Onset usually in head of Pancreas
  2. Pancreatic ductal adenocarcinoma (90% of cases)
    1. Adenocarcinoma of pancreatic ductal epithelium

V. 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

VI. 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 or pale stool)

VII. 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)

VIII. Differential Diagnosis

  1. Gall Bladder Disorders (e.g. Cholecystitis, Cholelithiasis or Choledocholithiasis)
  2. Peptic Ulcer Disease or Gastritis
  3. Acute Pancreatitis or Chronic Pancreatitis
  4. Abdominal Aortic Aneurysm
  5. Constipation
  6. Other abdominal cancer
    1. Liver cancer (or liver metastases)
    2. Lymphoma
    3. Stomach Cancer
    4. Colon Cancer

IX. Labs

  1. Initial labs on presentation of suspected pancreatic lesion
    1. Complete Blood Count
    2. Comprehensive metabolic panel
      1. Alkaline Phosphatase and Direct Bilirubin increased in bile duct obstruction
    3. Serum Lipase
    4. Hemoglobin A1C
  2. Tumor Markers
    1. CA 19-9
      1. Indicated for diagnosis and prognosis (Do NOT use for screening)
      2. Level >37 U/ml have 72% Test Sensitivity (LR- 0.32) and 86% Test Specificity (LR+ 5.1)
      3. False Negatives in 10% of population that fails to synthesize CA 19-9
    2. Other markers with better prognostic efficacy than CA 19-9
      1. bHCG
      2. CA 72-4

X. Imaging: Diagnosis

  1. Initial testing
    1. CT Abdomen with contrast
      1. Triple phase CT (see below) is preferred first-line study for diagnosis and staging
    2. Transabdominal Ultrasound
      1. Alternative option, and preferred in undifferentiated PAINFUL Jaundice (obtain CT in PAINLESS Jaundice)
      2. Decreased Test Sensitivity for small pancreatic lesions <3 cm
      3. Reflex to CT Abdomen if non-diagnostic
  2. 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. Most accurate detection of Pancreatic Cancer (esp. lesions <3 cm)
      2. Indications
        1. Helical CT not diagnostic
        2. Biopsy or FNA in non-operable cancer
        3. Intervention for obstructive cholestasis (ERCP)
  3. 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
      3. MRI visualizes entire Pancreas and identifies 84% of cystic and obstructive pancreatic lesions
      4. MRI is frequently used for screening high risk patients (see below)

XI. Imaging: Screening

  1. Indications
    1. Routine screening not recommended in low risk, asymptomatic patients
    2. Consider screening in Moderate to High risk patients (e.g. Genetic Syndromes, see above)
  2. Imaging
    1. MRI/MRCP Abdomen (contrast enhanced 1.5 Tesla MRI)
      1. First-line screening with reflex abnormal imaging to endoscopic Ultrasound
    2. Endoscopic Ultrasound
  3. Protocols: Screening Options (per American Society of Gastrointestinal Endoscopy)
    1. Endoscopic Ultrasound yearly OR
    2. MRI/MRCP Abdomen yearly OR
    3. Alternating yearly between MRI/MRCP one year and Endoscopic Ultrasound the next year
  4. Precautions
    1. Avoid blood test screening (e.g. Galleri, ImmRay PanCan-d Tests)
      1. No prospective, independent validation efficacy studies available as of 2024

XII. 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

XIII. 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

XIV. 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)

XV. Management: General

  1. See Cachexia in Cancer
  2. See Mood Disorders in Cancer
  3. Treat Cancer Pain
    1. See Cancer Pain Management
    2. Involve Palliative Care
    3. 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. Consider Biliary decompression via surgery or endoscopy
  5. Anticipate Chemotherapy adverse effects
    1. Neutropenia
    2. Diarrhea
    3. Thrombocytopenia
    4. Peripheral Neuropathy
  6. Other measures
    1. Nutritional Supplementation
      1. May reduce Fatigue and weight loss
    2. Psychosocial support

XVI. Management: Resectable Pancreatic Cancer

  1. Criteria for resectable cancer (met by only 20% of Pancreatic Cancer patients)
    1. Patients with good functional status and without significant comorbidities AND
    2. No distant metastatic cancer AND
    3. 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, Gall Bladder, common bile duct and second part duodenum AND
        2. Distal Stomach
      2. Pylorus-Preserving Pancreaticoduodenostomy
        1. Resection of pancreatic head, Gall Bladder, common bile duct and second part 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 (in combination with surgery)
    1. Folfirinox (Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan) is preferred in 2024
    2. Gemcitabine (Gemzar) also appears effective as monotherapy or in combination in low functional status patients
    3. Radiation associated with worse prognosis
  4. Other measures
    1. Preoperative Biliary drainage for Obstructive Jaundice
      1. Increases morbidity without additional benefit
      2. Van Der Gaag (2010) N Engl J Med 362(2): 129-37 [PubMed]
  5. 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

XVII. 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)
    2. Radiation Therapy has not added significant survival benefit when added to standard therapy
      1. [PubMed]

XVIII. 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 is used only for palliative therapy of symptoms in metastatic Pancreatic Cancer

XIX. 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)

XX. Prevention

  1. Fruit and vegetables in diet
  2. Exercise
  3. Reduce modifiable risk factors
    1. Smoking Cessation
    2. Address Alcohol Use Disorder
    3. Address Obesity
  4. Screening indications
    1. Refer patients with significant Family History to geneticist
    2. Moderate to high risk of Pancreatic Cancer may prompt screening (see above)
  5. Avoid harmful measures
    1. Antioxidants risk harm and do NOT prevent gastrointestinal cancers
      1. Bjelakovic (2004) Lancet 364(9441): 1219-28 [PubMed]

XXI. Prognosis

  1. At diagnosis, only 12 to 20% of cancers are localized
  2. Stage 0 Pancreatic Cancer has a 10 year survival 93%
  3. Five year survival overall is 11%
    1. Localized Pancreatic Cancer (Stage 1A): 37 to 38%
    2. Regional Pancreatic Cancer: 12 to 16%
    3. Metastatic Pancreatic Cancer: 3%
  4. Best prognostic findings post-resection
    1. Negative margins
    2. Tumor DNA content
    3. Smaller pancreatic tumor size
    4. No Lymph Node metastases (or other metastases)
    5. CA 19-9 level reduction by at least 50% after treatment

XXII. Resources

  1. Pancreatic Cancer Statistics (NCI)
    1. https://seer.cancer.gov/statfacts/html/pancreas.html

XXIII. References

  1. (2019) Am Fam Physician 100(12): 770A-C [PubMed]
  2. Bryce (2024) Am Fam Physician 109(3): 245-50 [PubMed]
  3. De La Cruz (2014) Am Fam Physician 89(8): 626-32 [PubMed]
  4. Freelove (2006) Am Fam Physician 73(3):485-92 [PubMed]
  5. Li (2004) Lancet 363:1049-57 [PubMed]

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