January 17, 2007

Pancreatic Cancer

Synonyms and related keywords: pancreatic cancer, pancreas cancer, pancreatic carcinoma, pancreas carcinoma, gastrointestinal cancer, GI cancer, gastrointestinal carcinoma, GI carcinoma, pancreas tumor, pancreatic tumor, malignancy, exocrine, endocrine, pancreatic adenocarcinoma, chronic pancreatitis from alcohol


INTRODUCTION

Background: In the United States, approximately 30,000 people die of pancreatic cancer each year. Among cancers of the gastrointestinal tract, it is the third most common malignancy and the fifth leading cause of cancer-related mortality. The disease is difficult to diagnose in its early stages, and most patients have incurable disease by the time they present with symptoms. The overall 5-year survival rate for this disease is less than 5%.

Pathophysiology: Pancreatic cancers can arise from both the exocrine and endocrine portions of the pancreas. Of pancreatic tumors, 95% develop from the exocrine portion of the pancreas, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% occur in the body of the pancreas, and 5-10% occur in the tail. Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver, and less commonly, to the lungs. It can also directly invade surrounding visceral organs such as the duodenum, stomach, and colon.

The molecular genetics of pancreatic adenocarcinoma have been well studied. Of these tumors, 80-95% have mutations in the KRAS2 gene, and 85-98% have mutations, deletions, or hypermethylation in the CDKN2 gene. Of these cancers, 50% have mutations in TP53 and about 55% have homozygous deletions or mutations of Smad4. Some of these mutations can also be found in high-risk precursors of pancreatic cancer. For example, in chronic pancreatitis, 30% of patients have detectable mutations in TP16 and 10% have K-ras mutations. Although studies are underway, the genetic mutations associated with pancreatic adenocarcinoma are not yet clinically useful in screening for or diagnosing the disease.

As in other organs, chronic inflammation is a predisposing factor in the development of pancreatic cancer. Patients with chronic pancreatitis from alcohol, especially those with familial forms, have much higher incidence and an earlier age of onset of pancreatic carcinoma.

Frequency:

Mortality/Morbidity:

Race:

Sex: The male-to-female ratio for pancreatic cancer is 1.2-1.5:1.

Age:


CLINICAL

History: The early clinical diagnosis of pancreatic cancer is fraught with difficulty. Unfortunately, the initial symptoms are often quite nonspecific and subtle in onset.

Physical: The physical examination findings in a patient with pancreatic cancer are usually limited to evidence of significant weight loss and some mild-to-moderate midepigastric tenderness.

Causes: Overall, estimates indicate that 40% of pancreatic cancer cases are sporadic in nature. Another 30% are related to smoking, and 20% are associated with dietary factors. Only 5-10% are hereditary in nature. Fewer than 5% of all pancreatic cancers are related to underlying chronic pancreatitis.


DIFFERENTIALS

Abdominal Aortic Aneurysm
Ampullary Carcinoma
Bile Duct Strictures
Bile Duct Tumors
Cholangitis
Cholecystitis
Choledochal Cysts
Choledocholithiasis
Cholelithiasis
Duodenal Ulcers
Gastric Cancer
Gastric Ulcers
Neoplasms of the Endocrine Pancreas
Pancreatitis, Acute
Pancreatitis, Chronic


Other Problems to be Considered:

Intestinal ischemia
Gastric lymphoma
Pancreatic lymphoma
Hepatocellular carcinoma (hepatoma)


WORKUP

Lab Studies:

Imaging Studies:

    • ERCP is also used frequently for evaluating patients with jaundice or patients with possible pancreatic masses based on findings from imaging modalities if EUS is not available.
    • The most difficult clinical situation in which to diagnose pancreatic carcinoma is in the patient with underlying chronic pancreatitis. In this situation, all of the above imaging studies may show abnormalities that may not help differentiate between pancreatic carcinoma and chronic pancreatitis. Even tumor markers can be elevated in patients with chronic pancreatitis. In these patients, one must often combine multiple imaging modalities, close clinical follow-up, serial imaging studies, and occasionally empiric resection to diagnose an underlying pancreatic carcinoma.

Other Tests:

  • Needle aspiration
    • The necessity of obtaining a cytologic or tissue diagnosis of pancreatic cancer prior to operation remains controversial.
      • Some centers advocate the practice of aggressively operating on all patients thought to have pancreatic cancer and argue against a preoperative tissue diagnosis.
      • The contention in these centers is that negative findings after preoperative fine-needle aspiration may just be sampling error and, thus, should not stop a pancreaticoduodenectomy if a potentially resectable pancreatic neoplasm is strongly suggested based on preoperative testing.
      • Additionally, preoperative attempts at fine-needle aspiration or biopsy of the pancreas might contaminate the peritoneum with tumor cells.
    • Other surgeons are hesitant to perform an operation with as much potential for morbidity as a pancreaticoduodenectomy on patients without a positive tissue or cytologic diagnosis of cancer. Additionally, tissue diagnosis is almost always required prior to initiation of chemotherapy, radiation therapy (whether palliative or neoadjuvant), or nonoperative palliation of obstructive jaundice using permanent metallic stents.
      • Studies of the risk of peritoneal contamination with CT-guided biopsy have suggested that this risk is actually very low. EUS-guided fine-needle aspiration provides the additional advantage of aspiration through tissue that would ultimately be included in the operative field should the patient undergo resection.
      • Additionally, the histology of a pancreatic tumor can change the surgical approach to the tumor. For example, a pancreatic lymphoma should be treated medically rather than with operative resection.
      • Finally, patients and their families usually want a definitive diagnosis prior to making major therapeutic decisions.
    • EUS-guided fine-needle aspiration has proven to be the most effective means for making a definitive cytologic diagnosis of pancreatic carcinoma. Using EUS-guided fine-needle aspirations, a cytologic diagnosis can be made in 85-95% of patients. A recent study has also suggested that transcutaneous aspiration may be associated with a higher risk of peritoneal tumor spread than aspiration with EUS. Thus, for potentially resectable tumors, EUS-guided fine-needle aspiration is the preferred biopsy technique, if it is available and if a biopsy needs to be obtained.
    • The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT scanning.
  • Staging laparoscopy or laparotomy
    • Some centers advocate performing a staging laparoscopy or laparotomy before proceeding to attempted resection. A few centers also advocate performing intraoperative laparoscopic ultrasonography to help further assess the tumor stage and to look for occult metastases.
    • Using this approach, a significant number of patients are found to have previously unsuspected peritoneal or liver metastases. The operations avoided by staging laparoscopy largely depend on how aggressively and accurately the patient was staged preoperatively.
Histologic Findings: Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of the exocrine pancreas are benign. Less common histologic appearances of exocrine pancreatic cancers include giant cell carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary connective tissue cancers of the pancreas can occur. The most common of these is primary pancreatic lymphoma.

Cystic neoplasms of the pancreas account for fewer than 5% of all pancreatic tumors. These consist of benign serous cystadenomas, premalignant mucinous cystadenomas, and cystadenocarcinomas.

Patients can also develop tumors of the islet cells of the pancreas. These can be functionally inactive islet cell carcinomas or benign or malignant functioning tumors such as insulinomas, glucagonomas, and gastrinomas.

Staging: Once an imaging modality has helped establish a probable diagnosis of pancreatic cancer, the next issue is whether the lesion is amenable to surgical resection. Only 20% of all patients presenting with pancreatic cancer are ultimately found to have easily resectable tumors with no evidence of local advancement. No survival benefit is achieved for patients undergoing noncurative resections for pancreatic carcinoma. Thus, to avoid operating on patients who cannot benefit from the operation, accurate preoperative staging is very important.

Cancer of the exocrine pancreas is classified by the tumor, nodal, metastases (TNM) staging system. The staging for pancreatic cancer has recently been modified by the American Joint Committee on Cancer (AJCC).


TREATMENT

Medical Care: The only therapy that has definitively been shown to increase the survival of patients with pancreatic cancer is surgical resection. For patients with disease not amenable to curative resection, little has been shown to significantly impact survival. The mean survival for patients with unresectable disease remains 4-6 months. Other therapies for pancreatic cancer should include palliation of the major symptoms of disease.

Chemotherapy

Palliative therapy

Surgical Care: Only 15-20% of patients with pancreatic carcinoma present with easily resectable disease with no evidence of local advancement (no nodal invasion or invasion into major venous structures). No additional survival benefit is achieved if the patient undergoes incomplete resection because of tumor extension into unresectable structures. Thus, the major goal of accurate preoperative staging for pancreatic cancer is to avoid performing a nonbeneficial abdominal operation that entails a 6- to 8-week recovery period on a patient with a median survival time of only 4-6 months.

The vast majority of patients ultimately found to have resectable disease have tumors of the head of the pancreas. Unfortunately, patients presenting with cancer of the body or tail of the pancreas have almost uniformly unresectable disease at the time of presentation and rarely survive over the long term, even if they undergo resection. Pancreatic body and tail lesions often manifest later in the disease, with larger lesions that have invaded deeply into the retroperitoneum or spread distantly into the peritoneum or liver.

The major determinant of resectability is the local invasion of the tumor into the vascular structures surrounding the pancreatic head. In cancers of the pancreatic head, the relationships among the cancer and the portal vein, superior mesenteric vein, and the celiac or superior mesenteric artery are critical. If the cancer has invaded into the portal or superior mesenteric vein, then a potentially curative resection may require either excision of part of the vessels or venous grafting. In expert hands, this can be accomplished with minimal additional morbidity; however, it may require the assistance of a vascular surgeon. Not all pancreatic surgeons advocate attempts at venous resection. In high-volume centers, curative resections with or without venous resection carry similar prognoses. Invasion or encasement of the superior mesenteric or celiac arteries makes an attempt at curative resection impossible.

In most series, documented metastases to peripancreatic lymph nodes are considered a poor prognostic finding and may be a relative contraindication to attempting a curative resection. As discussed in Imaging Studies, dual-phase spiral CT scanning and EUS appear to be the most accurate imaging tools for determining the potential resectability of pancreatic carcinomas. Preresection laparoscopy or exploratory laparotomy and intraoperative ultrasonography have also been advocated to determine which patients will fare best with attempts at curative resection.

  • Pancreaticoduodenectomy (Whipple operation)
    • The standard operation for carcinoma of the head of the pancreas is a pancreaticoduodenectomy (Whipple procedure). This operation involves en bloc resection of the pancreatic head; the first, second, and third portions of the duodenum; the distal antrum; and the distal common bile duct.
    • The patient's gastrointestinal tract is reconstructed with a gastrojejunostomy.
    • The common bile duct and residual pancreas are anastomosed into a segment of small bowel.
    • A more recent variation of the operation spares the pylorus, allowing for a more natural physiologic emptying of the stomach. Some surgeons prefer total pancreatectomy to avoid the risks of anastomotic leaks and pancreatic fistulas. This has the disadvantage of leaving the patient with brittle diabetes mellitus postoperatively.
    • Historically, pancreaticoduodenectomy has been associated with significant mortality and morbidity. However, in high-volume referral centers, the mortality rate for this operation has consistently been less than 5%, with a morbidity rate of approximately 30%. Unfortunately, even in patients in whom all of the visible tumor has been successfully resected, the 5-year survival rate averages only 15-20%, although some recent series report survival rates up to 36%. This is still markedly better than the less than 3% 5-year survival rate with unresectable pancreatic cancer.
    • Median survival time is approximately 12-19 months in patients who undergo successful resection versus 4-6 months of survival for unresectable pancreatic carcinoma.
  • Neoadjuvant chemoradiation
    • Some institutions use neoadjuvant chemotherapy and radiation therapy to try to improve the resectability potential of locally advanced cancers.
    • Early results are promising; however, no prospective, randomized, controlled trials have been conducted to offer support for this approach.

Consultations: The management of pancreatic carcinoma is a multidisciplinary process. Most patients initially present to their primary care practitioner with general symptoms such as abdominal pain, weight loss, or fatigue. Patients may also be seen initially by a gastroenterologist if they present with obstructive jaundice. Typically, the management of pancreatic cancer would entail consultations with a gastroenterologist, medical oncologist, general surgeon or surgical oncologist, and possibly a radiation oncologist.

  • A gastroenterologist would usually be involved either for evaluation of the cause of the patient's presenting symptoms (eg, abdominal pain, nausea, weight loss, diarrhea) or for definitive diagnosis of the cause of jaundice by EUS and/or ERCP. Consultation with a gastroenterologist is needed if an endoscopically placed stent is needed for palliation of obstructive jaundice. If a gastroenterologist is able to provide EUS-guided fine-needle aspiration, then this is the preferred biopsy technique for pancreatic neoplasms, especially if resection is considered an option. Consultation with a gastroenterologist may also be required to place an enteral stent for palliation of duodenal obstruction by tumor.
  • Consultation with a medical oncologist is often needed to select and administer neoadjuvant, adjuvant, or primary chemotherapy for the disease. Consultation with a medical oncologist is also useful for management of other common cancer symptoms such as pain and nausea.
  • Consultation with a surgeon is needed when the patient's imaging studies suggest that operative resection may be feasible. The surgeon may perform diagnostic laparoscopy or even laparoscopic ultrasonography prior to an attempt at definitive resection. If curative resection is not possible, consultation with a surgeon may still be useful to consider operative palliation of biliary and/or duodenal obstruction. Consult with a surgeon or surgical oncologist who is very experienced in performing pancreaticoduodenectomies.
  • Consultation with a radiologist may be needed for special issues such as obstructive jaundice that is difficult to manage where percutaneous transhepatic cholangiography may be needed.
  • Consultation with a radiation oncologist is usually considered at the discretion of a medical oncologist when combined chemoradiation may be beneficial.

Diet:

  • As with most patients with advanced cancer, patients with pancreatic carcinoma are often anorexic. Usually, pharmacologic stimulation of appetite is not successful, but it may be tried.
  • Patients may have some degree of malabsorption secondary to exocrine pancreatic insufficiency caused by the cancer obstructing the pancreatic duct. Patients with malabsorption diarrhea and weight loss may benefit from pancreatic enzyme supplementation. Their diarrhea may also be improved with avoidance of high-fat or high-protein diets.

MEDICATION

The most active single agents for pancreatic cancer have been 5-fluorouracil (5-FU) and gemcitabine. Gemcitabine appears to be slightly more active than 5-FU. Objective responses, meaning actual regression of tumor, have been 20% or less.

Drug Category: Antineoplastic agents -- These agents are used for chemotherapy.
Drug Name
Gemcitabine (Gemzar) -- A frequently quoted trial showed a small but statistically significant improvement in overall survival with gemcitabine versus 5-FU (5.7 vs 4.4 mo). Additionally, gemcitabine improved the quality of life in approximately 25% of patients.
Adult DoseMultiple regimens are used, most common is 1000 mg/m2 once weekly for up to 7 wk or until toxic effects not tolerated; follow with 1 wk rest with subsequent cycles of once weekly infusion for 3 consecutive wk out of every 4 wk; the dose is dramatically reduced if combined with radiation therapy
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy D - Unsafe in pregnancy
PrecautionsMay cause myelosuppression (particularly thrombocytopenia); toxicities include flulike syndrome, LFT abnormality, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic uremic syndrome
Drug Name
Fluorouracil (Adrucil, Efudex, Fluoroplex) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with RNA synthesis and function. Has some effect on DNA. Useful in symptom palliation for patients with progressive disease. Commonly used in patients with gastrointestinal malignancies. Response rates are typically less than 20% in pancreatic cancer.
Adult Dose15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; serious infection; topical administration in pregnancy
InteractionsIncreased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Pregnancy D - Unsafe in pregnancy
PrecautionsNausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment
Drug Name
Erlotinib (Tarceva) -- Pharmacologically classified as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. FDA approved in combination with gemcitabine for first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer.
Adult Dose100 mg PO qd 1 h ac or 2 h pc
Pediatric DoseNot established
ContraindicationsNone known
InteractionsPredominantly metabolized by CYP3A4; potent CYP3A4 inhibitors may decrease clearance (eg, ketoconazole increased AUC by two-thirds), caution with other strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin [TAO], voriconazole); CYP3A4 inducers may decrease AUC (ie, rifampin decreased AUC by two-thirds)
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution with hepatic impairment; may cause interstitial lung disease (including fatalities), elevated INR and bleeding; instruct patient to immediately seek medical attention for severe or persistent diarrhea, nausea, anorexia, vomiting, onset or worsening of unexplained shortness of breath or cough, or eye irritation; commonly causes rash and diarrhea (diarrhea unresponsive to loperamide may require dose reduction or temporary therapy interruption)


FOLLOW-UP

Deterrence/Prevention:

Prognosis:

Patient Education:


MISCELLANEOUS

Medical/Legal Pitfalls:

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