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 twelve 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 65,000 cases yearly in the United States. The incidence of pancreatic cancer is increasing worldwide. 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 51,750 deaths in the United States in 2024. Pancreatic cancer is the fourth most common cause of cancer-related deaths [1, 2, 3].
• 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 [4, 5, 6].
  • Familial cancer syndromes that increase pancreatic cancer risk: Peutz-Jeghers syndrome, Lynch syndrome, Von Hippel-Lindau syndrome, familial atypical multiple-mole melanoma syndrome, and ataxia-telangiectasia [6, 7].
• Risk factors:
  • Family history: hazard ratio (HR) =1.5 for an affected first-degree relative [4, 7]
  • Non-Hereditary chronic pancreatitis: HR =2.2 [7, 8]
  • Diabetes mellitus: present in 60-80% of patients with pancreatic cancer; frequently improves following tumor resection. Relative risk 2.08 (95% CI 1.87-2.32) [5, 7, 8, 9, 10].
  • Environmental risk factors:
  • Cigarette smoking: HR 1.5-2.5; the risk decreases by ~50% two years after discontinuing smoking [5, 6, 7, 8, 10, 11, 12].
  • Occupational exposures: employees in chemical, petrochemical and rubber industries, hairdressing; possibly due to increased exposures to aromatic amines [5, 7].
  • Obesity and physical inactivity [5, 7, 13, 14].
  • Diet high in fats/meats, low in fruits/vegetables [5, 7, 8].
  • Heavy coffee and alcohol consumption were once considered to increase risk but now are more controversial. Alcohol consumption is compounded by cigarette smoking and likely only limited to heavy drinkers, if there is an effect [3, 4, 5, 7, 15].
• Helicobacter pylori infections: especially CagA strains [7].
• History of partial gastrectomy or cholecystectomy: possibly due to elevated levels of circulating cholecystokinin [7, 10, 14].

Molecular Pathogenesis:multiple combinations of genetic mutations are usually present [5, 6, 7].

• 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 of 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 40 for patients with hereditary pancreatitis and at 50 years or 10 years before the age at which pancreatic cancer was first diagnosed in family members of individuals with a positive family history [16, 17].

Clinical Presentation

• History: the initial presentation is usually nonspecific, and may include anorexia, malaise, nausea, fatigue, dull mid epigastric pain, back pain, new onset diabetes mellitus, pancreatitis, and depression. [18]
  • Head of the pancreas tumors: steatorrhea, pruritis, dark urine, weight loss, and painless obstructive jaundice.
  • Pancreatic body or tail tumors: weight loss and pain are 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 mid epigastric 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 [5, 6, 19, 20].
  • Helical CT scan with contrast or MRI: usually the initial diagnostic and staging study, with sensitivity of 86% and 84%, respectively; particularly useful to predict tumor resectability and in patients without jaundice; CT angiography can provide additional information regarding vessel involvement [21].
  • 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 [5, 22, 23].
    • Values >1000 U/ml are frequently associated with surgically unresectable lesions [22].
  • 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: obtaining a tissue sample is the only definitive means for diagnosing pancreatic cancer [5].
  • 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, but 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 [5, 6].
  • Staging laparoscopy: sensitivity of 92%, specificity of 88%; can be used to identify clinically occult peritoneal, capsular, and serosal implants to reduce the number of apparently operable cases by 10-15% [5, 6, 20, 24].
  • Staging laparoscopy is 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; 51% of patients present with metastasis at the time of diagnosis [1, 3, 6, 16, 24].
  • Most common sites of metastasis: liver, peritoneal cavity, and lungs.
• Prognosis: one-year overall survival is 23%, and five-year survival is 12% [3].
  • 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 outcomes are seen in current smokers and patients with positive margins and involve adjacent structures [6, 25, 27, 28, 29, 30].

Treatment

• Localized, resectable disease
  • Surgery: the only potentially curative treatment modality for patients with pancreatic cancer; the highest cure rates occur in patients with Stage I to IIB disease.
    • Since 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 [5, 19, 20, 24].
    • 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 [5, 6].
    • 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 (10.5%); and dehiscence [25, 26].
      • 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 [5, 6, 25].
  • 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 [31].
• Adjuvant chemoradiotherapy: patients with pancreatic carcinomas should receive postoperative chemotherapy following resection, with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil for 6 months per the PRODIGE 24 trial. For those who cannot tolerate FOLFIRINOX, other options include gemcitabine and capecitabine. Postoperative chemoradiotherapy may be considered for patients who have a positive resection margin or pathologically involved lymph nodes [28, 29].
  • RTOG 0848 showed that patients with resected periampullary adenocarcinoma who received adjuvant chemotherapy + radiotherapy improved disease-free survival, but not overall survival [30].
  • PRODIGE-24 compared adjuvant FOLFIRINOX to gemcitabine for 24 weeks. The use of FOLFIRINOX showed an improvement in the median disease free survival when compared to gemcitabine (21.6 months vs. 12.8 months) and improved median overall survival (54.4 months vs 35 months) [28].
  • 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 months, p=0.099) [29].
• Localized, Borderline resectable
  • For patients who are not initially resectable but have localized disease, there is no standardized approach. One approach is the use of neoadjuvant chemotherapy (FOLFIRINOX preferred, but gemcitabine is also an option) followed by restaging scans to assess for operability. If the patient is a surgical candidate, he or she should proceed to surgical resection, followed by additional chemotherapy. Some consider neoadjuvant chemotherapy followed by chemoradiation prior to surgery if the patient has not responded favorably to chemotherapy alone.
• Locally advanced, unresectable disease
  • Patients with a good performance status should consider enrolling in a clinical trial. While there is no universally accepted approach, a standard option is chemotherapy, typically with 4-6 months of FOLFIRINOX or gemcitabine and abraxane followed by restaging scans. Patients with a poor performance status should receive gemcitabine alone or best supportive care [5, 32-35].
  • Radiation therapy: irradiation can improve the quality of life in select patients with unresectable disease. Radiation is most successful when combined with radiosensitizing chemotherapy such as capecitabine.
  • Chemoradiotherapy: patients who can tolerate combined modality treatment can achieve survival benefits with chemoradiation, followed by maintenance chemotherapy, as compared with radiation alone.
    • LAP-07 randomized patients with locally advanced disease to gemcitabine +/- erlotinib. If there was no evidence of progression after 4 months there was a second randomization between remaining on the same chemotherapy or chemoradiotherapy. While there was no difference in overall survival, locoregional progression was improved with chemoradiation [36].
• Metastatic disease
  • Patients with a good performance status should consider enrolling in a clinical trial or receiving FOLFIRINOX chemotherapy, or gemcitabine, either as a single or double agent. Patients with a poor performance status should palliative therapy and best supportive care [5].
• 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 [20]:
  • Epidermal growth factor receptor (EGFR) inhibitors : overexpression of EGFR is a negative predictor of survival; EGFR small-molecule tyrosine kinase inhibitors (erlotinib [Tarceva] ) can be used in combination with gemcitabine for the treatment of advanced disease for patients who have EGFR overexpression. However, it is not commonly used [37].
  • KRAS inhibitors: For patients who did not respond to other therapies and have a KRAS G12C mutation, treatment with KRAS inhibitors Adagrasib (Krazati) and sotorasib (Lumakras) is an option.
  • Other mutation-specific drugs that have been used for pancreatic cancer include olaparib for patients with a germline BRCA mutation and larotrectinib and entrectinib for tumors with NTRK mutations [38].
  • Immunotherapy: other current research attempts to utilize checkpoint immunotherapy or CAR-T for pancreatic cancer.