Pancreatic Cancer

Introduction

Pancreatic cancer is a particularly devastating malignancy with nearly as many deaths as newly diagnosed cases each year. Overall, the five-year survival rate is less than five percent, and pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States. The prognosis for patients with pancreatic cancer remains extremely poor, despite more advanced radiologic imaging, increasing use of serum tumor markers, a better understanding of risk factors and molecular pathogenesis, and improved surgical techniques, radiation regimens and chemotherapeutic agents. The incorporation of targeted therapies with traditional treatment regimens in a multimodality approach will provide patients with the best chance to combat this especially fatal malignancy.

Epidemiology and Etiology

• Incidence of 32,180 cases yearly in the United States. The incidence of pancreatic cancer had greatly increased from the 1930s to the 1970s, but has remained relatively stable over the past thirty years. Pancreatic cancer is rare before the age of 45, but the incidence rises sharply thereafter. The median age at diagnosis is 69 years for whites and 65 years for blacks. Incidence is highest in blacks. Mortality of 31,800 deaths in the United States in 2005. Pancreatic cancer is the fourth most common cause of cancer-related deaths in men and the fifth most common cause in women [1].
• Etiology: is multifactorial and dependent on both genetic and environmental factors.
• Hereditary: 5-10% of patients have a first-degree relative with pancreatic cancer; patients from affected families often present at an earlier age than those with nonhereditary disease [2, 3, 4].
• • F amilial cancer syndromes that increase pancreatic cancer risk: Peutz-Jeghers syndrome, Von Hippel-Lindau syndrome, familial atypical multiple-mole melanoma syndrome, and ataxia-telangiectasia [4, 5].
• Risk factors:
• • Family history: hazard ratio (HR) =1.5 for an affected first-degree relative [2, 5]
  • Nonhereditary chronic pancreatitis: HR =2.2 [5, 6]
  • Diabetes mellitus: present in 60-80% of patients with pancreatic cancer; frequently improves following tumor resection [3, 5, 6, 7]
  • Environmental risk factors:
  • • Cigarette smoking: HR 1.5-2.5; the risk decreases by ~50% two years after discontinuing smoking [3, 4, 5, 6, 7, 8, 9]
    • Occupational exposures: employees in chemical, petrochemical and rubber industries, hairdressing; possibly due to increased exposures to aromatic amines [3, 5]
    • Heavy coffee and alcohol consumption [3, 4, 5, 7]
    • Obesity and physical inactivity [3, 5, 10, 11]
    • Diet high in fats/meats, low in fruits/vegetables [3, 5, 6]
  • Helicobacter pylori infections: especially CagA strains [5]
  • History of partial gastrectomy or cholecystectomy: possibly due to elevated levels of circulating cholecystekinin [5, 7, 11]
  • Molecular Pathogenesis : multiple combinations of genetic mutations are usually present [3, 4, 5]
  • • Inactivation of tumor suppressor genes: CDKN2A gene somatic inactivation (in =85% of tumors), p53 gene mutations and telomere dysfunction (50-60% of tumors), DPC4 (SMAD4) gene abnormalities (55% of tumors), BRCA2 gene mutations (10% of patients with hereditary pancreatic cancer), and STK11 gene abnormalities
    • Activation of oncogenes: K-ras oncogene mutations (=90% of tumors)
    • Defects in DNA mismatch repair genes: MLh4 and MLH2 gene defects and Sonic Hedgehog signaling pathway defects (<5% of tumors; mutations are usually somatic in origin)

Screening Recommendations

• There is no current role for universal screening for pancreatic malignancies or high-risk genetic abnormalities. Patients at a high risk for developing pancreatic cancer may choose active surveillance.
  • The American Gastroenterological Association recommends that screening with a spiral CT or endoscopic ultrasound should begin at age 35 for patients with hereditary pancreatitis and 10 years before the age at which pancreatic cancer was first diagnosed in family members of individuals with a positive family history [12].

Clinical Presentation

• History: the initial presentation is usually nonspecific, and may include: anorexia, malaise, nausea, fatigue, dull midepigastric pain, back pain, and depression.
• • Head of the pancreas tumors : steatorrhea, pruritis, dark urine, weight loss, and painless obstructive jaundice.
  • Pancreatic body or tail tumors : weight loss and pain is present in ~80% of patients; pain is usually an intermittent, dull aching in the upper abdomen that radiates to the back and is made worse by eating; early diagnosis for body and tail tumors is rare since common bile duct obstruction and jaundice usually do not occur.
  • Less common presentations: recent onset of atypical diabetes mellitus, acute pancreatitis, unexplained thrombophlebitis.
• Physical exam : the most common findings include weight loss and midepigastric tenderness.
• • Less common signs: Courvoisier sign (nontender, enlarged gallbladder palpable at the right costal margin in patients with jaundice), Virchow's node (left supraclavicular lymphadenopathy), and pancreatic panniculitis (subcutaneous areas of nodular fat necrosis).
  • Late findings: abdominal mass or ascites (present in 20% of patients), hepatomegaly from liver metastases, splenomegaly from portal vein obstruction, and a palpable rectal shelf.
• Lab studies: often normal or nonspecific. Patients may present with anemia, thrombocytosis, and evidence of obstructive jaundice (increases in bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, ALT, and AST) or malnutrition (low serum albumin and cholesterol).
• Radiologic studies : primary means of establishing a diagnosis of pancreatic carcinoma [3, 4, 13, 14].
• • Helical CT scan with contrast : usually the initial diagnostic and staging study, with sensitivity of 85-90%, specificity of 90-95%; particularly useful to predict tumor resectability and in patients without jaundice; CT angiography can provide additional information regarding vessel involvement.
  • Endoscopic ultrasound : alternative initial study for diagnosis and staging; sensitivity and specificity both ~90%; particularly useful for localized tumors <3 cm, to assess nodal status, and to predict vascular invasion.
  • ERCP : therapeutically indicated for patients presenting with cholangitis or requiring palliation of biliary obstruction; diagnostic sensitivity and specificity both ~90%; requires intraductal contrast and is more likely to miss tumors in the uncinate process, accessory duct, and pancreatic tail.
  • MRCP : not routinely used, but is the ideal preoperative study to define the anatomy of the biliary tree and pancreatic duct.
• Serum tumor markers: used to aid in the diagnosis of pancreatic cancer and to postoperatively monitor the response to surgery and chemotherapy (levels that return to normal after treatment are associated with increased patient survival).
• • Cancer-associated antigen 19-9 (CA 19-9) : the sensitivity and specificity increase with increasing tumor size and CA 19-9 values; at levels greater than 37 U/ml (sensitivity of 77%, specificity of 87%), CA 19-9 is most accurate for discriminating pancreatic cancer from benign pancreatic diseases or biliary cancers [3, 15, 16].
  • • Values >1000 U/ml are frequently associated with surgically unresectable lesions [15].
  • Other serum tumor markers: CA 50, CA 242, CA 125, and CEA (all are less sensitive and less specific than CA 19-9).
• Diagnostic studies: o btaining a tissue sample is the only definitive means for diagnosis pancreatic cancer [3].
• • Percutaneous fine needle aspiration: sensitivity of 85-95%, specificity of 98-100%; often avoided in low-risk patients with resectable tumors due to theoretical concerns of tumor cell dissemination intraperitoneally or along the needle path.
  • Pancreatic ductal brushings or biopsies from ERCP: alternative means of obtaining a tissue sample; also not routinely performed.

Natural Course and Pathology

• Histopathology:
  • Exocrine carcinomas : 90-95% of all pancreatic cancers; arise from exocrine cells that secrete digestive enzymes.
  • Ductal carcinoma is the most common type (80-90% of tumors), and ductal adenocarcinoma is the most common subtype.
  • Endocrine carcinomas : ~5% of cancers; arise from endocrine cells that secrete hormones.
  • Metastatic : rare and most often originate from breast, lung, or melanoma primary malignancies.
  • Other : liposarcomas, leiomyosarcomas, fibrosarcomas, and lymphomas.
• Gross pathology: most often a firm mass with ill-defined margins; ductal dilation and fibrous atrophy of the parenchyma are common.
  • Location of pancreatic tumors: 70-75% in the head of the pancreas, 15-20% in the body, and 5-10% in the tail.
  • Average size of tumors at diagnosis: 2.5-3.5 cm in the pancreatic head and 5-7 cm in the body and tail.
• Staging:
  • Staging is categorized in accordance with the American Joint Committee on Cancer using the TNM staging scheme [3, 4] .
  • Staging laparoscopy: sensitivity of 92%, specificity of 88%; can be used to identify subradiologic peritoneal, capsular, and serosal implants to reduce the number of apparently operable cases by 10-15% [3, 4, 14, 17] .
  • Staging laparoscopy often unnecessary in patients with a low risk of tumor dissemination, but is being used more frequently in higher-risk patients who are non-jaundiced, have body or tail tumors, or have major but incomplete vascular involvement.
• Natural Course: often rapid tumor progression, especially with body and tail lesions; 45-50% of patients present with metastasis at the time of diagnosis [4, 12, 17] .
  • Most common sites of metastasis: liver, peritoneal cavity, and lungs.
• Prognosis: one-year overall survival is 23%, and five-year survival is ~4% [1] .
  • Median survival: metastatic disease (3-6 months); locally advanced, unresectable disease (8-12 months); resected disease (10-20 months).
• Prognostic factors: lymph node involvement (strongest predictor), poorly differentiated tumors, tumors >2 cm, extent of the tumor at resection, and initial patient performance status are the strongest predictors of poor outcome. Weaker correlations with poor outcome are seen in current smokers and patients with positive margins and involved adjacent structures [4, 18, 19, 20, 21, 22] .

Treatment

• Localized, resectable disease
• • Surgery: t he only potentially curative treatment modality for patients with pancreatic cancer; the highest cure rates occur in patients with Stage I to IIB disease.
  • • S ince many patients have advanced disease at the time of diagnosis, only 15-20% of all patients and 10-12% of patients with body and tail tumors are candidates for surgery [3, 13, 14, 17].
    • General criteria for unresectability: distant metastases, SMA or celiac encasement, SMV or portal occlusion, aortic or IVC invasion or encasement, and rib or vertebral invasion [3,4].
    • Head of the pancreas malignancies : a Whipple procedure (pancreaticoduodenectomy) is the standard operation for pancreatic head tumors and involves a subtotal pancreatectomy, duodenectomy, partial jejunectomy, hemigastrectomy, and cholecystectomy.
    • • Complications: 1-5% perioperative mortality rate; 19% with delayed gastric emptying; 14% with pancreatic fistulas; clinically significant postoperative pancreatic leaks; wound infections; bleeding; and dehiscence [18].
      • Results: five-year survival rates following a Whipple procedure are 20-30% in completely resected patients, 25-42% in node-negative patients, and 5-10% in node-positive patients. Overall median survival following surgery is 10-20 months [3, 4, 18].
    • Body and tail malignancies : a distal subtotal pancreatectomy, usually with a splenectomy, is the standard procedure for body or tail tumors.
    • • Results: overall median survival following surgery of only 10-13 months, with high perioperative morbidity and mortality [23].
  • Adjuvant chemoradiotherapy: although controversial, patients with pancreatic carcinomas may achieve survival benefits with the administration of postoperative chemoradiotherapy with 5-fluorouracil (5-FU) or gemcitabine [Gemzar], followed by maintenance chemotherapy.
  • • The Gastrointestinal Tumor Study Group (GITSG) Trial 9173 randomized 43 postoperative patients to observation or adjuvant chemoradiotherapy with 5-FU. Patients in the treatment group had a significantly higher median disease-free survival (11 months vs. 9 months, p=0.04) and overall survival (20 months vs. 11 months, p=0.03) [20].
    • The European Organization for Research and Treatment of Cancer (EORTC) 40891 Trial randomized 218 postoperative patients with pancreatic head or periampullary tumors to observation or adjuvant chemoradiotherapy with 5-FU. Among patients with pancreatic head tumors, the treatment group had a median survival that trended higher than the control group (17.1 months vs. 12.6 month, p=0.099) [21].
    • The European Study Group for Pancreatic Cancer ESPAC-1 Trial randomized 289 postoperative patients to observation, chemoradiotherapy (5-FU bolus), chemotherapy (leucovorin bolus followed by 5-FU), or chemoradiotherapy and chemotherapy. In this study, the median survival was higher in patients who received chemotherapy (20.1 months vs. 15.5 months, p=0.009) and lower in patients who received chemoradiotherapy (15.5 months vs. 17.9 months, p=0.05) [22].
    • • Following the ESPAC-1 Trial, despite its numerous study flaws, many centers in Europe have discontinued the administration of radiation in favor of giving adjuvant chemotherapy alone. In the United States, the standard of care continues to be the administration of adjuvant chemoradiotherapy, followed by maintenance chemotherapy.
• Locally advanced, unresectable disease
• • Patients with a good performance status should consider enrolling in a clinical trial. They should receive combined chemoradiotherapy with bolus 5-FU or gemcitabine, followed by maintenance chemotherapy, or else receive chemotherapy with gemcitabine alone. Patients with a poor performance status should receive gemcitabine alone or best supportive care [3].
  • Radiation therapy: irradiation can improve the quality of life and prolong survival in select patients with unresectable disease. Radiation is most successful when combined with chemotherapy.
  • Chemoradiotherapy: patients who can tolerate combined modality treatment can achieve survival benefits with chemoradiation, followed by maintenance chemotherapy, as compared with radiation alone.
  • • GITSG compared radiation only vs. radiation plus 5-FU in 194 patients with locally advanced, unresectable disease. Patients who received chemotherapy had significantly improved median survival (9.4 months vs. 5.2 months, p<0.01) and one-year survival (40% vs. 10%) [24].
    • Gemcitabine has largely replaced 5-FU in the treatment of patients with locally advanced disease. A randomized trial comparing chemoradiotherapy with gemcitabine vs. 5-FU found that patients in the gemcitabine arm had significantly improved median survival (14.5 months vs. 6.7 months, p=0.027), time to progression (7.1 months vs. 2.7 months, p=0.019), response rate (50% vs. 13%, p=0.005), and pain control (39% vs. 6%, p=0.043) [25].
    • Gemcitabine may be combined with targeted therapies (see below), but should be administered as the sole chemotherapeutic agent. In the Eastern Cooperative Oncology Group Trial E2297, 327 patients with advanced disease were randomized to receive gemcitabine alone or gemcitabine followed by 5-FU. The addition of 5-FU did not significantly improve median survival (6.7 months vs. 5.4 months, p=0.09) [26].
• Metastatic disease
• • Patients with a good performance status should consider enrolling in a clinical trial or receive gemcitabine-based chemotherapy, either as a single or double agent. Patients with a poor performance status should receive gemcitabine alone or best supportive care [3].
  • Best supportive care/palliation:
  • • Pain : opioid analgesics are the treatment of first choice; chemical splanchnicectomy/celiac plexus neurolysis is 80-90% effective; radiation therapy is 35-65% effective and can also improve cachexia and obstructive symptoms.
    • Symptomatic bile duct obstruction and jaundice : endoscopically placed expandable stents (metal are preferred over plastic stents) or surgical biliary decompression.
    • Duodenal and gastric outlet obstructions : late developments in 15-25% of patients; expandable stents or gastrojejunostomy with biliary bypass.
    • Clinical depression : especially common in pancreatic cancer patients; antidepressants, psychostimulants, psychosocial interventions, and anxiolytics.
    • Malnutrition : pancreatic enzyme replacement (lipase).
  • Targeted/biologic therapies [14] :
  • • Epidermal growth factor receptor (EGFR) inhibitors : overexpression of EGFR is a negative predictor of survival; monoclonal antibodies that inhibit EGFR ligand binding (cetuximab [Erbitux ]) and EGFR small-molecule tyrosine kinase inhibitors (erlotinib [Tarceva] ) are currently being studied in conjunction with gemcitabine for the treatment of advanced disease.
    • Matrix metalloproteinases (MMPs) inhibitors : MMPs are abnormally upregulated in patients with pancreatic cancer; the administration of MMPs inhibitors (marimastat) have been shown to increase survival in patients with locally advanced disease.
    • Angiogenesis inhibitors : vascular endothelial growth factor (VEGF) expression is abnormally elevated in patients with pancreatic cancer. Recombinant humanized monoclonal antibodies to VEGF (bevacizumab [Avastin]) are being studied as part of a multimodality treatment approach for patients with locally advanced disease.
    • Immunotherapy : attempts to activate the immune system to specifically combat tumor cells; an antigastrin immunogen (G17DT), which functions by increasing antibodies that block gastrin-simulated growth, has been shown to extend survival in patients with advanced disease who were unable to undergo chemotherapy treatment.