Pancreatic Cancer – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Pancreatic cancer: Malignant cells are found in the tissue of the pancreas; also called pancreatic exocrine cancer.
  • Carcinoma of the pancreas ranks as the 4th leading cause of cancer death in the US.
  • Cancer of the exocrine pancreas is rarely curable and has an overall 5-year relative survival rate of <4%.
  • 60–70% arise in the head, 15% in the body, 5% in the tail; 20% diffusely involve the whole gland.
  • Fewer than 20% of pancreatic cancers are localized at diagnosis. For those patients with localized disease and small cancers(<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection can yield actuarial 5-year survival rates of 18–24%.
  • For patients with advanced cancers, the overall survival is <1% at 5 years, with most patients dying within 1 year.

Epidemiology

In 2003–2007, the median age at diagnosis for cancer of the pancreatic was 72 years of age (1).

Incidence

  • It is estimated that 42,470 men and women were diagnosed with cancer of the pancreas in 2009 (21,040 men; 21,420 women); deaths: 35,240.
  • It is more common in individuals of the black race and the white race, 16.7 and 10.3 in 100,000 men and 14.4 and 10.3 in 100,000 women, respectively. Hispanic and Asian/Pacific Islander individuals had an incidence of 10.9 and 8.3 in 100,000 men and 10.1 and 8.3 in 100,000 women, respectively (2).

Prevalence

On January 1, 2007, in the US, there were approximately 16,936 men and women (14,979 men and 16,201 women) alive who had a history of cancer of the pancreas (2).

Risk Factors

  • Smoking: RR = at least 1.5. It has been estimated that cessation of smoking could eliminate approximately 25% of pancreatic cancer deaths in the US.
  • Diabetes: RR = 2.1 (95%, CI: 1.6–2.8)
  • History of partial gastrectomy or cholecystectomy: 2- to 5-fold increased risk 15–20 years after partial gastrectomy
  • Familial aggregation/genetic factors: 5–10% of patients have a 1st-degree relative with the disease.
  • Hereditary chronic pancreatitis: Cumulative risk by ages 50 and 75 is 10% and 54%, respectively.
  • Chronic pancreatitis: Tropical and nontropical
  • Coffee and alcohol consumption: Studies fail to convincingly demonstrate a relationship.
  • Aspirin and NSAID use: Large cohorts have not found any link.

Genetics

  • Multifactorial: Activation of oncogenes (e.g., K-ras mutation 90%); inactivation of tumor suppressor genes (e.g., p16/CDKN2A [95%], TP53 [75 to 85], SMAD4[30], and BRCA2genes[10%]); and defects in DNA mismatch repair genes (e.g., hMLH1 and hMSH2 [4% of pancreatic tumors])
  • Hereditary pancreatitis: The cumulative risk of pancreatic cancer in affected family members is 10%, 19%, and 54% at ages 50, 60, and 75, respectively.
  • Inherited cancer syndromes:
    • Peutz-Jeghers syndrome: Related genes: PRSS1 and STK 11; lifetime risk is as high as 36%.
    • Hereditary breast/ovarian cancer: 5% lifetime risk for pancreas cancer. Related genes: BRCA2 and BRCA1
    • Familial atypical multiple-mole melanoma syndrome: 19% lifetime risk. Related gene: CDKN2A
    • Ataxia-telangiectasia: Related gene: ATM
    • Li-Fraumeni syndrome: Related Gene: p53

Diagnosis

History

Weight loss 90%; pain 75% (progressive midepigastric dull ache that often radiates to the back); malnutrition 75%; jaundice 70%; anorexia 60%; pruritus 40%; diabetes mellitus 15%; weakness, fatigue, malaise 30–40%; acholic stools, dark urine, steatorrhea. Atypical diabetes mellitus, unexplained thrombophlebitis.

Physical Exam

  • Palpable abdominal mass or ascites in 20%
  • Jaundice: 70% if head of pancreas obstructs bile duct, only 10% with body or tail pancreatic carcinoma
  • Courvoisier sign (painless jaundice with a palpable gallbladder) 33%; usually is associated with pancreatic head tumors, periampullary carcinoma, and primary bile duct tumors; hepatomegaly in advanced disease.
  • Virchow node (left supraclavicular) and Sister Mary Joseph node (umbilical) in metastatic disease; palpable rectal shelf (nonspecific sign of carcinomatosis)
  • Migratory thrombophlebitis; Trousseau sign; superficial thrombophlebitis associated with pancreatic cancer
  • Pancreatic panniculitis: Subcutaneous areas of nodular fat necrosis

Diagnostic Tests & Interpretation

Endoscopic ultrasound-guided biopsy is the best modality for obtaining a tissue diagnosis. Has a sensitivity of ∼75–90% and specificity of virtually 100% for the diagnosis of a pancreatic mass.

Lab

Routine laboratory tests may reveal a elevated serum bilirubin concentration and alkaline phosphatase activity, and the presence of anemia.

Initial lab tests

Elevated CA 19-9 80% sensitivity, 90% specificity; individuals with Lewis-negative blood group antigen phenotype (5–10%) are unable to synthesize CA 19-9.

Follow-Up & Special Considerations

Following or during definitive therapy, increase in CA 19-9 levels may identify patients with progressive tumor growth. Normal CA 19-9 does not exclude recurrence.

Imaging

Mass within the pancreas, which often obstructs the pancreatic duct or biliary tree.

Initial approach

  • Abdominal US:75–89% sensitivity and 90–99% specificity; dilated bile ducts or the presence of a mass in the head of the pancreas.
  • Endoscopic US: CT and EUS are complementary for staging pancreatic cancer. EUS is a more accurate modality for local T and N staging and for predicting vascular invasion
  • CT and CT angiography scans: 85–90% sensitivity and 90–95% specificity; useful for evaluation of distant metastasis.
  • ERCP: 90% sensitivity and 95% specificity
  • MRI offers no significant diagnostic advantage over contrast-enhanced CT.
  • MR cholangiopancreatography: 90% sensitivity and 95% specificity. Preferred in specific settings: Gastric outlet or duodenal stenosis or patients who have had surgical rearrangement (Billroth II) or ductal disruption. To detect bile duct obstruction occurring in the setting of chronic pancreatitis. For patients in whom attempted ERCP is either totally unsuccessful or provides incomplete information because of pancreatic duct obstruction.

Diagnostic Procedures/Surgery

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  • Staging studies for resectability include CT angiography, MRI, endoscopic US, laparoscopic US, and cytology.
  • Percutaneous FNA biopsy using either US or CT guidance: 80–90% sensitivity and 98–100% specificity
  • Endoscopic US is the most sensitive noninvasive test to diagnose vascular invasion: 90% specificity and 73% sensitivity.
  • Endoscopic US–guided biopsy: 85–90% sensitivity and virtually 100% specificity for pancreatic mass
  • Staging laparoscopy and US: 92% sensitivity, 88% specificity, and 89% accuracy
  • Positive peritoneal cytology has a positive predictive value of 94%, specificity of 98%, and sensitivity of 25% for determining unresectability (3).
  • PET scan: 90% sensitivity but 70% specificity; limited anatomic information
  • Staging system: TNM definition: AJCC, 2002.
    • Primary tumor (T):
      • TX: Primary tumor cannot be assessed.
      • T0: No evidence of primary tumor
      • TIS: Carcinoma in situ
      • T1: Tumor is limited to the pancreas and is ≤2 cm in greatest dimension.
      • T2: Tumor is limited to the pancreas and is >2 cm in greatest dimension.
      • T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery.
      • T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumors).
    • Regional lymph nodes (N):
      • NX: Regional lymph nodes cannot be assessed.
      • N0: No regional lymph node metastasis
      • N1: Regional lymph node metastasis
    • Distant metastasis (M):
      • MX: Distant metastasis cannot be assessed.
      • M0: No distant metastasis
      • M1: Distant metastasis
  • AJCC stage groupings:
    • Stage 0: Tis, N0, M0
    • Stage IA: T1, N0, M0
    • Stage IB: T2, N0, M0
    • Stage IIA: T3, N0, M0
    • Stage IIB: T1, N1, M0; T2, N1, M0; T3, N1, M0
    • Stage III: T4, any N, M0
    • Stage IV: Any T, any N, M1

Pathological Findings

  • 90% duct cell carcinoma
  • Others: Acinar cell, papillary mucinous, signet ring, adenosquamous, mucinous, giant cell, small cell, cystadenocarcinoma, undifferentiated, unclassified carcinoma

Differential Diagnosis

  • Duodenal cancer, cholangiocarcinoma, lymphoma, islet cell tumor, sarcoma
  • Nonmalignant conditions: Choledocholithiasis, pancreatitis, biliary tract stricture, autoimmune pancreatitis, sclerosing pancreatitis, adenoma

Treatment

Surgical resection offers the only chance of cure. There is no role for resection of adenocarcinoma in the presence of metastatic disease.

Medication

  • Analgesics
  • Stage I and II:
    • Radical pancreatic resection ± postoperative 5-FU chemotherapy and radiation therapy (4,5)[A]
    • RTOG-9704 trial compared postoperative infusional 5-FU plus infusional 5-FU and concurrent radiation or adjuvant gemcitabine plus infusional 5-FU and concurrent radiation. The addition of gemcitabine to postoperative adjuvant 5-FU CRT significantly improved median overall survival in patients with pancreatic head adenocarcinoma: 20.5 months in the gemcitabine arm versus 16.9 months in the 5-FU arm; 3-year survival was 31% versus 22%. (P = 0.09; HR = 0.82; CI: 0.65–1.03) (6)[A].
    • CONKO-001 trial: Gemcitabine for 6 months for patients after complete resection of pancreatic cancer significantly increased disease-free survival to 13.4 months in the gemcitabine arm (95% CI: 6.1–7.8; P <0.001) versus 6.9 months in the observation group. No significant difference in overall survival was seen between groups.
  • Stage III:
    • Chemoradiation: Controversial
    • Standard: Chemotherapy with gemcitabine
    • Palliative decompression of biliary obstruction by endoscopic, surgical, or radiologic methods
    • Intraoperative radiation therapy and/or implantation of radioactive sources
  • Stage IV:
    • Chemotherapy: Gemcitabine 1-year survival was 18% versus 2% with 5-FU (P = 0.003). Gemcitabine with erlotinib modestly prolonged survival (4)[A].
    • Pain-relieving procedures (celiac or intrapleural block) and supportive care
    • Palliative decompression
    • For patients who are refractory to gemcitabine monotherapy, 2nd-line therapy has not been clearly shown to affect survival.

Additional Treatment

  • For patients with resected tumors, postoperative radiation therapy with other chemotherapeutic agents
  • For patients with resected tumors, postoperative chemotherapy alone. The RLUH-NCRI-ESPAC-3V2 trial is evaluating postoperative chemotherapy with either 5-FU/leucovorin or gemcitabine versus no additional treatment. (Results pending) (7)

Additional Therapies

  • Biliary decompression with endoprostheses or transhepatic drain catheters
  • Celiac axis and intrapleural nerve blocks can provide highly effective and long-lasting pain control for some patients.

Surgery/Other Procedures

Disease that is limited to the pancreas and peripancreatic nodes (stage I–IIB) is most likely to be cured by radical resection. Absolute contraindications for resection include the presence of metastases in the liver, peritoneum, omentum, or any distant site. Relative contraindications are involvement of the bowel mesentery, portomesenteric vasculature, and celiac axis and its tributaries.

  • Standard treatment options:
    • Pancreaticoduodenectomy, Whipple procedure, en bloc resection of the head of the pancreas, distal common bile duct, duodenum, jejunum, and gastric antrum
    • Total pancreatectomy
    • Distal pancreatectomy, for tumors of the body and tail
  • Nonstandard surgeries:
    • Pylorus-preserving pancreaticoduodenectomy, regional pancreatectomy
    • Palliative bypass
      • Biliary decompression; gastrojejunostomy for gastric outlet obstruction; duodenal endoprosthesis for obstruction

Ongoing Care

Diet

Frequently, malabsorption caused by exocrine insufficiency contributes to malnutrition; pancreatic enzyme replacement can help to alleviate.

Prognosis

Criteria for resectable disease (∼20%):

  • No extrapancreatic disease
  • Patent superior mesenteric vein and portal vein, celiac axis and superior mesenteric artery not involved, no bulky nodes
  • Median survival: 10–20 months
  • 5-year survival: ∼30% if node-negative; 10% if node-positive
  • Distant (cancer has metastasized): 1.9% 5 years’ relative survival
  • For patients with localized disease and small cancers (<2 cm) with no lymph node involvement and no extension beyond the capsule of the pancreas, complete surgical resection can yield a 5-year survival rate of 18–24%.

Complications

  • Diabetes mellitus, malabsorption
  • Surgical complications: Intraabdominal abscess, postgastrectomy syndromes, pancreatico-jejunostomy, gastric and biliary anastomotic leaks; operative mortality varies from 1–16%.

References

1. American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society, 2009.

2. Altekruse SF, et al. SEER Cancer Statistics Review, 1975–2007, National Cancer Institute Bethesda, MD, http://seer,cancer,gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010

3. Merchant NB, Conlon KC, Sasigo P, et al. Positive peritoneal cytology predicts unresectable pancreatic adenocarcinoma. J Am Coll Surg. 1999;188(4):421–6.

4. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol. 2005;23(16):A-1, 1s.

5. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–10.

6. Oettle H, Post S, Neauhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267–77.

7. ESPAC-3(V2) Phase III Adjuvant Trial in Pancreatic Cancer Comparing 5FU and D-L-Folinic Acid vs. Gemcitabine. Leeds, UK: National Cancer Research Network Trials Portfolio, 2004. http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID = 669

Codes

ICD9

  • 157.0 Malignant neoplasm of head of pancreas
  • 157.1 Malignant neoplasm of body of pancreas
  • 157.2 Malignant neoplasm of tail of pancreas
  • 157.3 Malignant neoplasm of pancreatic duct
  • 157.4 Malignant neoplasm of islets of langerhans
  • 157.8 Malignant neoplasm of other specified sites of pancreas
  • 157.9 Malignant neoplasm of pancreas, part unspecified

Snomed

  • 372003004 primary malignant neoplasm of pancreas (disorder)
  • 372119009 primary malignant neoplasm of head of pancreas (disorder)
  • 93715005 primary malignant neoplasm of body of pancreas (disorder)
  • 94082003 primary malignant neoplasm of tail of pancreas (disorder)
  • 93939009 primary malignant neoplasm of pancreatic duct (disorder)
  • 93843007 primary malignant neoplasm of islets of Langerhans (disorder)

Clinical Pearls

  • The sudden onset of diabetes mellitus in nonobese adults aged >40 years warrants evaluation for pancreatic cancer.
  • Cancer of the exocrine pancreas is rarely curable and has an overall 5-year relative survival rate of <4%. Fewer than 20% of pancreatic cancer cases are localized at diagnosis.
  • CT scan and endoscopic ultrasound are complementary modalities for diagnosis and staging of pancreatic cancer

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