eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Pancreatic Cancer

Richard A Erickson, MD, FACP, FACG, Professor of Medicine, Division of Gastroenterology, Department of Internal Medicine, Texas A&M University Health Science Center; Director, Scott and White Clinic and Hospital
Claire R Larson, MD, Staff Physician, Department of General Surgery, Texas A & M School of Medicine, Scott and White Hospital; Mohsen Shabahang, MD, PhD, FACS, Assistant Professor of Surgery, Division of Surgical Oncology, Director of Surgical Residency, Texas A&M Health Science Center, Scott and White Clinic

Updated: Apr 7, 2009

Introduction

Background

Pancreatic cancer is the fourth leading cause of death among both men and women, comprising 6% of all cancer-related deaths. The incidence of pancreatic cancer has risen slowly over the years. The disease is notoriously difficult to diagnose in its early stages. At the time of diagnosis, 52% of all patients have distant disease and 26% have regional spread. The relative 1-year survival is only 24% and the overall 5-year survival rate for this disease is less than 5%. 

Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm resected from the pancreatic body and tail. Although the tumor was considered to have been fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1 year.

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 or metastasize to any surface in the abdominal cavity via peritoneal spread. Ascites may result, and this has an ominous prognosis. Pancreatic cancer may spread to the skin as painful nodular metastases. Pancreatic cancer uncommonly metastasizes to bone. It is rare for pancreatic cancer to spread to the brain. It can, however, produce meningeal carcinomatosis.

The molecular genetics of pancreatic adenocarcinoma have been well studied.^1,2,3 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 p53 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 p16 and 10% have K-ras mutations.

Families with BRCA-2 mutations, which are associated with a high risk of breast cancer, also have an excess of pancreatic cancer.⁴ Assaying pancreatic juice for the genetic mutations associated with pancreatic adenocarcinoma is invasive but may be useful for the early diagnosis of the disease;⁵ this approach is problematic as genetic mutations in the pancreatic juice may be found associated with inflammatory pancreatic disease.

Certain precursor lesions have been associated with pancreatic tumors arising from the ductal epithelium of the pancreas.  The main morphologic form associated with ductal adenocarcinoma of the pancreas has been pancreatic intraepithelial neoplasia or PIN. These lesions arise from specific genetic mutations and cellular alterations that all contribute to the development of invasive ductal adenocarcinoma. The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening. Thereafter p16/CDKN2A is inactivated. Finally, the inactivation of TP53 and MAD4/DPC4 occur. These mutations have been correlated with increasing development of dysplasia, and thus the development of ductal carcinoma of the exocrine pancreas.

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

Frequency

United States

In 2008, an estimated 37,680 new cases of pancreatic cancer (18,770 in men and 18,910 in women) will have been diagnosed in the United States; 34,290 persons (17,500 men and 16,790 women) will have died of the disease in 2008.⁶

The overall incidence of pancreatic cancer is approximately 8-10 cases per 100,000 persons per year.^7,8 Although the overall incidence of pancreatic cancer has been relatively stable for decades, the incidence of pancreatic cancer in males has been slowly dropping over the past 2 decades, while the incidence in females has increased slightly. These trends probably represent the effect of changing smoking rates for men and women.

International

Worldwide, pancreatic cancer ranks 13th in incidence but 8th as a cause of cancer death.⁷ The highest incidence rate is approximately 13 cases per 100,000 persons per year in black males in the United States. Native Hawaiian males and men of Korean, Czech, Latvian, and New Zealand Maori ancestry also have high incidence rates, that is, 11 cases per 100,000 persons per year. Most other countries have incidence rates of 8-12 cases per 100,000 persons per year. In some areas of the world, pancreatic cancer is quite infrequent; for example, the incidence in India is less than 2 cases per 100,000 persons per year.

Mortality/Morbidity

Pancreatic cancer is the fourth leading cause of death among both men and women, comprising 6% of all cancer-related deaths. The incidence of pancreatic cancer has risen slowly over the years. The death rate has risen from 5 per 100,000 population in 1930 to more than 10 per 100,000 in 2003. The disease is notoriously difficult to diagnose in its early stages. At the time of diagnosis, 52% of all patients have distant disease and 26% have regional spread. 

The relative 1-year survival is only 24%, and the overall 5-year survival rate for this disease is less than 5%. This number has not changed significantly over the years. A 5-year survival in pancreatic cancer is no guarantee of cure; patients who survive for 5 years after successful surgery may still die of recurrent disease years after the 5-year survival point. The occasional patient with metastatic disease or locally advanced disease who survives beyond 2-3 years may die of complications of local spread, such as bleeding esophageal varices.

Pancreatic carcinoma is unfortunately usually a fatal disease. The collective median survival time of all patients is 4-6 months. Most patients eventually succumb to the consequences of local invasion and metastatic cancer, and true long-term cures are rare. However, neuroendocrine and cystic neoplasms of the pancreas such as mucinous cystadenocarcinomas or intraductal papillary mucinous neoplasms (IPMN) have much better survival rates than pancreatic adenocarcinoma.

In patients able to undergo a successful curative resection (only about 20% of patients), median survival time ranges from 12-19 months, and the 5-year survival rate is 15-20%. The best predictors of long-term survival after surgery are a tumor diameter of less than 3 cm, no nodal involvement, negative resection margins, and diploid tumor DNA content.

Race

• The incidence rate of pancreatic cancer for black males in the United States from 2000 to 2003 was 16.2 cases per 100,000 persons per year, and the incidence for black females was 13.7 cases per 100,000 persons per year⁹ .
• For white males in the United States, the incidence is 12.7 cases per 100,000 persons per year, and for white females the incidence is 9.8 cases per 100,000 persons per year.
• The reasons for the 1.3 to 1.4 increase in pancreatic cancer in African Americans are unclear. Certainly, differences in dietary habits and the frequency of cigarette smoking are recognized among different groups. Obesity has been identified as a possible risk factor for pancreatic cancer and may contribute to the higher incidence of this disease among blacks. However, these variations may also be related to the underlying frequency of predisposing genetic mutations for pancreatic cancer or to other unknown factors.

Sex

In the United States, slightly more women than men are diagnosed each year with pancreatic cancer; slightly more men than women die of the disease.

Age

• Age is the most significant risk factor for pancreatic cancer.
• In the absence of predisposing conditions, such as familial pancreatic cancer and chronic pancreatitis, pancreatic cancer is unusual in persons younger than 45 years. After age 50 years, the frequency of pancreatic cancer increases linearly. At age 70, mortality incidence due to pancreatic cancer is approximately 60 deaths per 100,000 persons per year.
• The median age at diagnosis is 69 years in whites and 65 years in blacks; some single institution data reported from large cancer centers suggest that the median age at diagnosis in both sexes has fallen to 63 years of 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.

• Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise, nausea, fatigue, and mid-epigastric or back pain.
• Significant weight loss is a characteristic feature of pancreatic cancer.
• These initial symptoms can be easily attributed to other processes unless a physician has a high index of suspicion for the possibility of underlying pancreatic carcinoma. Delayed diagnosis is a common problem in patients with pancreatic cancer, with fewer than a third of patients in the past being diagnosed within 2 months of the onset of their symptoms. The availability of CT scans has shortened that interval.
• Pain is the most common presenting symptom in patients with pancreatic cancer. Typically, it is mid epigastric in location, with radiation of the pain sometimes occurring to the mid- or lower-back region. Back radiation of the pain is a worrisome sign indicating retroperitoneal invasion of the splanchnic nerve plexus by the tumor. Often, the pain is unrelenting in nature with night-time pain often being a predominant complaint. Some patients may note increased discomfort after eating. The pain may be worse when the patient is lying flat. About one third of patients may not have pain at the time of initial presentation; one third of patients have moderate pain and one third of patients have severe pain. All patients experience pain at some point in their clinical course.
• Weight loss may be related to cancer associated anorexia and/or subclinical malabsorption from pancreatic exocrine insufficiency caused by pancreatic duct obstruction by the cancer. Patients with malabsorption usually complain about diarrhea and malodorous, greasy stools. Nausea and early satiety from gastric outlet obstruction and delayed gastric emptying from the tumor may also contribute to weight loss.
• The onset of diabetes mellitus within the previous year is sometimes associated with pancreatic carcinoma. However, only about 1% of cases of new-onset diabetes mellitus in adults are actually related to occult pancreatic cancer.¹⁰ However, pancreatic cancer should be at least thought of in a patient older than 70 years with a new diagnosis of diabetes without any other diabetic risk factors.
• The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless obstructive jaundice.
  • Patients with this sign may come to medical attention before their tumor grows large enough to cause abdominal pain.
  • These patients usually notice a darkening of their urine and lightening of their stools before they or their families notice the change in skin pigmentation. Physicians can usually recognize clinical jaundice when the total bilirubin reaches 2.5-3 mg%. Patients and their families do not usually notice clinical jaundice until the total bilirubin reaches 6-8 mg%. Urine darkening, stool changes, and pruritus are often noticed by patients before clinical jaundice.
  • Pruritus may accompany and often precedes clinical obstructive jaundice. Pruritus can often be the patient's most distressing symptom.
• Depression is reported to be more common in patients with pancreatic cancer than in patients with other abdominal tumors. In some patients, depression may be the most prominent presenting symptom. This may be, in part, secondary to the high frequency of delayed diagnosis with this disease. In addition, although patients may not communicate it to their families, they are often aware that some serious illness, like cancer, is occurring in them.
• Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis also occur with higher frequency in patients with pancreatic cancer and may be their first presentation. Marantic endocarditis may develop in pancreatic cancer occasionally being confused with subacute bacterial endocarditis.

Physical

The physical examination findings in a patient with pancreatic cancer usually involves evidence of significant weight loss and some mild-to-moderate midepigastric tenderness together with other more specific signs. 

• Patients with clinical jaundice may also have a palpable gallbladder (ie, Courvoisier sign) and may have evidence of skin excoriations from unrelenting pruritus.
• Patients presenting with or developing advanced intraabdominal disease may have ascites, a palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction.
• Subcutaneous metastases (referred to as a Sister Mary Joseph nodule or nodules) in the paraumbilical area signify advanced disease.
• A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer's shelf).
• A metastatic node may be palpable behind the medial end of the left clavicle (Virchow's node). However, other nodes in the cervical area may also be involved. Indeed, prior to the advent of CT scanners to assess intraabdominal disease, pancreas cancer accounted for some 25% of adenocarcinoma of the cervical nodes, primary site unknown.

Causes

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

• Smoking
  • Smoking is the most common environmental risk factor for pancreatic carcinoma.
  • People who smoke have at least a 2-fold increased risk for pancreatic cancer. Current smokers with over a 40 pack-year history of smoking may have up to a 5-fold increase risk of the disease. Smokeless tobacco also increases the risk of pancreatic cancer. It takes 5-10 years of discontinued smoking to reduce the increased risk of smoking to approximately that of nonsmokers.
• Dietary factors
  • Alcohol consumption does not appear to be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis.
  • In a number of studies, obesity, especially central, has been associated with a higher incidence of pancreatic cancer. The incidence is lower in those with a diet rich in fresh fruits and vegetables. Fruits and vegetables rich in folate and lycopenes (such as tomatoes) may be especially good at reducing the risk of developing pancreatic cancer. Red meat consumption, especially processed, is associated with a higher risk of pancreatic cancer. Poultry and dairy product consumption does not increase the risk of this disease. Supplemental antioxidants such as vitamin C or E do not appear to decrease the risk of pancreatic cancer or other gastrointestinal cancers and may actually be associated with excess mortality.
  • Despite early reports to the contrary, coffee consumption is not associated with an increased risk of pancreatic cancer. 
• Diabetes mellitus
  • Numerous studies have examined the relative risk of pancreatic cancer in persons with diabetes mellitus.
  • Meta-analysis of 30 studies concluded that patients with diabetes mellitus of at least 5-years' duration have a 2-fold increased risk of developing pancreatic carcinoma. Pancreatic cancer may follow 18-36 months after a diagnosis of diabetes mellitus in elderly patients with no family history of diabetes mellitus.
• Chronic pancreatitis
  • Long-standing chronic pancreatitis is a substantial risk factor for the development of pancreatic cancer. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer. This risk increased linearly with time, with 4% of patients who had chronic pancreatitis for 20 years' duration developing pancreatic cancer.
  • The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. The mean age of development of pancreatic cancer in these patients is approximately 57 years. The relative risk of pancreatic cancer in hereditary pancreatitis is increased more than 50-fold, and the cumulative risk rate of pancreatic cancer by age 70 years is 40%. This cumulative risk increases to 75% in those families with a paternal inheritance pattern.
• Genetic factors
  • Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease.¹¹
  • The inherited disorders that increase the risk of pancreatic cancer include hereditary pancreatitis, multiple endocrine neoplasia (MEN), hereditary nonpolyposis rectal cancer (HNPCC), familial adenomatous polyposis (FAP) and Gardner syndrome, familial atypical multiple mole melanoma (FAMMM) syndrome, von Hippel-Lindau syndrome (VHL), and germline mutations in the BRCA1 and BRCA2 genes. Hereditary pancreatitis has been associated with a cumulative risk of developing pancreatic cancer at 40%.¹²  MEN-1 and VHL are other genetic syndromes associated with pancreatic endocrine tumor development. 
    • Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the time, and these pancreatic tumors are noted to be the leading cause of disease-specific mortality.¹³  von Hippel-Lindau syndrome has been associated with malignancy in 17% of masses found in the pancreas in people with this syndrome.¹⁴  
    • Syndromes associated with increased risk of the development of colon cancer such as HNPCC and FAP (and Gardner syndrome) have also shown an increased correlation with existence of pancreatic cancer but the statistics unfortunately have not been impressive. One cohort study of 1391 patients with FAP only showed 4 to develop pancreatic adenocarcinoma, and in patients with HNPCC, no statistics are currently available to show incidence of pancreatic cancer in these patients.¹⁵ FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and incidence in sporadic cases to be 98%. Germline mutations in BRCA1 and BRCA2 have only been shown to moderately increase risk of developing pancreatic cancer by 2.3- to 3.6-fold, but BRCA2 has been associated more commonly with pancreatic cancer at an incidence of 7%.¹¹
  • The above disorders have specific genetic abnormalities associated with the noted increased risk of pancreatic cancer. Pancreatic cancer in hereditary pancreatitis is associated with a mutation in the PRSS1 gene. Pancreatic cancer appearing in FAP and HNPCC has been associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively. FAMMM and pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine tumors of the pancreas associated with VHL are thought to develop by way of the inactivation of the VHL tumor suppressor gene.¹¹

Differential Diagnoses

Other Problems to Be Considered

Intestinal ischemia
Gastric lymphoma
Pancreatic lymphoma
Hepatocellular carcinoma (hepatoma)

Workup

Laboratory Studies

• General laboratory studies
  • The laboratory findings in patients with pancreatic cancer are usually nonspecific. As with many chronic diseases, a mild normochromic anemia may be present.
  • Thrombocytosis is also sometimes observed in patients with cancer.
  • Patients presenting with obstructive jaundice show significant elevations in bilirubin (conjugated and total), alkaline phosphatase, gamma-glutamyl transpeptidase, and to a lesser extent, aspartate aminotransferase and alanine aminotransferase.
  • Serum amylase and/or lipase levels are elevated in less than half of patients with resectable pancreatic cancers and are elevated in only one quarter of patients with unresectable tumors. However, about 5% of patients with pancreatic cancer present initially as acute pancreatitis in which case amylase and lipase will be uniformly elevated. Thus, pancreatic cancer should be in the differential diagnosis of an elderly patient presenting for the first time with acute pancreatitis without any known precipitating factors.
  • Liver metastases alone are not associated with clinical jaundice but may result in relatively low-grade elevations of serum alkaline phosphatase and transaminase levels.
  • Patients with advanced pancreatic cancers and weight loss may also have general laboratory evidence of malnutrition (eg, low serum albumin or cholesterol level).
• Tumor markers
  • The major useful tumor marker for pancreatic carcinoma is carbohydrate antigen 19-9 (CA 19-9).
    • CA 19-9 is a murine monoclonal antibody originally made against colorectal cancer cells. The CA 19-9 antigen is a sialylated oligosaccharide that is most commonly found on circulating mucins in cancer patients.¹⁶ It is also normally present within the cells of the biliary tract and can be elevated in acute or chronic biliary disease. Some 5-10% of patients lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of CA 19-9, monitoring disease with this tumor marker will not be possible.
    • The reference range of CA 19-9 is less than 33-37 U/mL in most laboratories. Of patients with pancreatic carcinoma, 75-85% have elevated CA 19-9 levels. In the absence of biliary obstruction, intrinsic liver disease or benign pancreatic disease, a CA 19-9 value greater than 100 U/mL is highly specific for malignancy, usually pancreatic.
    • Evaluation of CA 19-9 levels has been used as an adjunct to imaging studies for helping determine the resectability potential of pancreatic carcinoma. Fewer than 4% of patients with a CA 19-9 level of more than 300 U/mL have been found to have resectable tumors.
    • Unfortunately, CA 19-9 is least sensitive for small early-stage pancreatic carcinomas and thus has not proven to be effective for the early detection of pancreatic cancer or as a screening tool.¹⁶
    • An elevated CA 19-9 level is found in 0.2% of an asymptomatic population older than 40 years. Of these elevations, 80% are false-positive results. If only symptomatic patients are studied, 4.3% have elevated CA 19-9 levels. Two thirds of these results are false positive. Although no standardized role has been set for CA 19-9 in the diagnosis of pancreatic carcinoma, it has growing importance in the staging and follow-up of patients with this disease. Patients presenting with low levels of CA 19-9 (<100 IU) are unlikely to have occult metastatic disease and therefore may not need a staging laparoscopy prior to resection if other imaging shows no advanced disease. Additionally, during surgical, chemotherapeutic, and/or radiotherapeutic treatment for pancreatic cancer, a falling CA 19-9 seems to be a useful surrogate finding for clinical response to the therapy. If biliary obstruction is not present, a rising CA 19-9 suggests progressive disease.
    • Preoperative CA19-9 levels may be of prognostic value with high levels indicating poorer outcome and less chance of resectability^17,18 . Preoperative values above 50 U/mL have been shown to be associated with higher chances of recurrence.
  • Carcinoembryonic antigen (CEA) is a high molecular weight glycoprotein found normally in fetal tissues. It has commonly been used as a tumor marker in other gastrointestinal malignancies.
    • The reference range is less than or equal to 2.5 mg/mL.
    • Only 40-45% of patients with pancreatic carcinoma have elevations in CEA levels.
    • Multiple other benign and malignant conditions can lead to elevated CEA levels; thus, CEA is not a sensitive or specific marker for pancreatic cancer.
  • Many other tumor markers have been studied in pancreatic cancer, but none has yet been shown to have general clinical utility in this disorder. As with all cancers, there is growing interest in molecular diagnosis using powerful techniques such as gene expression microarrays and proteomics. These novel tests are adding to our understanding of the basic defects causing pancreatic neoplasms and pathobiology. However, these are still research tools at present.

Imaging Studies

• General considerations
  • A number of continually evolving imaging modalities are available to help diagnose pancreatic carcinoma in patients in whom the disease is suggested clinically. These include computed tomography (CT) scanning, transcutaneous ultrasonography (TUS), endoscopic ultrasonography (EUS), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), and positron emission tomography (PET) scanning. Which of these modalities is used at a particular institution may depend largely on the local availability and expertise with the procedure as well as local cancer protocols.
  • Additional considerations in the choice of diagnostic modality include the accuracy of the imaging procedure for providing staging information, its ability to simultaneously obtain tissue samples for cytologic or histologic confirmation of the diagnosis, and its capacity to facilitate therapeutic procedures such as biliary stent placement or celiac neurolysis.
• Computed tomography scanning
  • Because of its ubiquitous availability and ability to image the whole abdomen and pelvis, abdominal CT scanning continues to be the mainstay of initial diagnostic modalities used for assessing patients suspected to have pancreatic carcinoma.
  • The quality of CT scanners has been rapidly evolving. The speed of image acquisition, 3D imaging, and slices as thin as 2-3 mm have revolutionized the technology.
  • Newer models using spiral (ie, helical) CT scanning with multiple detectors and dual or triple-phase contrast enhancement have significantly improved the sensitivity and specificity of abdominal CT findings in patients with pancreatic carcinoma. Triple-phase spiral CT findings are approximately 90% accurate for helping determine the resectability potential of pancreatic carcinoma. However, small tumors can still be missed even with the most advanced CT scanning currently available. Multidetector, pancreas protocol CT is at least as accurate as endoscopic ultrasound in overall determination of the resectability of pancreatic carcinoma. In fact, CT may be more accurate than EUS in predicting involvement of the superior mesenteric artery.¹⁹
  • Because of higher rate of enhancement by the normal pancreas, malignant tumors appear as lower density lesions.²⁰ These are often associated with obstruction of the pancreatic duct. 
  • When lesions are visible, CT scanning can also be used to direct fine-needle aspiration of pancreatic masses.
• Transcutaneous ultrasonography
  • Even though it is less expensive and generally more readily available than CT scanning, TUS has less utility in pancreatic carcinoma than CT scanning because the pancreas is often obscured by overlying gas from the stomach, duodenum, and colon.
  • Additionally, the depth of the pancreas from the abdominal wall limits transcutaneous ultrasonic imaging to lower frequency (2-5 MHz), and, thus, a lower-resolution ultrasonographic image is obtained. Therefore, TUS can help detect only 60-70% of pancreatic carcinomas, and similar to CT scanning, more than 40% of the lesions smaller than 3 cm are missed.
  • TUS is very useful as an initial screening test in evaluating patients who present with possible obstructive jaundice. By helping to detect intrahepatic or extrahepatic bile duct dilation, abdominal ultrasonography can rapidly and accurately assess whether or not a patient has biliary obstruction. However, other studies, such as abdominal CT scanning, EUS, ERCP, or magnetic resonance cholangiopancreatography (MRCP), usually should then be performed to definitively diagnose the source of biliary obstruction.
• Endoscopic ultrasonography
  • EUS obviates the physical limitations of TUS by placing a high-frequency ultrasonographic transducer on an endoscope, which is then positioned in the stomach or duodenum endoscopically to help visualize the head, body, and tail of the pancreas. Unlike CT, the patient requires conscious sedation for this procedure.
  • Additionally, because of the proximity of the pancreas to the EUS transducer, high-frequency ultrasonography (7.5-12 MHz) can be used to produce very high-resolution (submillimeter) images. Where expert EUS is available, it has proven to be the most sensitive and specific diagnostic test for pancreatic cancer. A negative endoscopic ultrasound is nearly 100% specific at ruling out the presence of a pancreatic neoplasm.
  • In numerous series, EUS has detection rates of 99-100% for all pancreatic carcinomas, including those smaller than 3 cm. EUS is as accurate as ERCP or MRCP for assessing the etiology of obstructive jaundice.
  • An additional significant diagnostic advantage is EUS-guided fine-needle aspiration, which allows for the simultaneous cytologic confirmation of pancreatic carcinoma at the time of EUS diagnosis.
  • EUS appears to be equivalent to dual-phase spiral CT scanning for assessing tumor resectability potential. It is probably superior to CT at assessing the T stage of the tumor, especially looking for portal vein involvement in pancreatic head lesions. EUS is probably inferior to CT in assessing arterial involvement and distant metastases.¹⁹ Both EUS and CT are poor at detecting occult nodal involvement.
• Endoscopic retrograde cholangiopancreatography
  • ERCP is highly sensitive at detecting pancreatic and/or biliary ductal abnormalities in pancreatic carcinoma. Of patients with pancreatic adenocarcinoma, 90-95% have abnormalities on ERCP findings. However, the changes observed on ERCP are not always highly specific for pancreatic carcinoma and can be difficult to differentiate from changes observed in patients with chronic pancreatitis.
  • ERCP is more invasive than the other diagnostic imaging modalities available for pancreatic carcinoma. ERCP also carries a 5-10% risk of significant complications with the procedure. Because of this morbidity, it is usually reserved as a therapeutic procedure for biliary obstruction or for the diagnosis of unusual pancreatic neoplasms such as intraductal pancreatic mucinous neoplasms (IPMN).
  • Brush cytology and forceps biopsy at the time of ERCP have been used to diagnose pancreatic carcinoma histologically; however, in most series, the yield of a cytologic diagnosis with these procedures has been less than 50%.
  • ERCP findings provide only limited staging information, but ERCP does have the advantage of allowing for therapeutic palliation of obstructive jaundice with either a plastic or metal biliary stent.
• Magnetic resonance imaging
  • Interest in using MRI for abdominal imaging continues to grow. The role of MRI in pancreatic cancer has been less well studied than the role of CT scanning. It does not appear to be superior to spiral CT scanning. Dynamic gadolinium enhanced 3D gradient echo MRI may offer enhanced sensitivity at detecting small pancreatic lesions. However, in patients with jaundice, magnetic resonance cholangiopancreatography (MRCP) can be used as a noninvasive method for imaging the biliary tree and pancreatic duct.
  • Whether MRCP is as sensitive and specific for pancreaticobiliary pathology as other procedures is still being investigated. Because of the difficulty of working within intense magnetic fields, MRI is limited in performing MRI-directed needle aspirations; however, this technology is undergoing rapid change.
• Positron emission tomography scanning
  • PET scanning uses 18F-fluorodeoxyglucose (FDG) to image both the primary tumor and metastatic disease.
  • PET scanning appears to be especially useful in detecting occult metastatic disease. Its role in pancreatic cancer evaluation management is still under investigation. False-positive PET scans have been reported in pancreatitis.
  • By itself, PET does not seem to offer additional benefits to high quality CT scan. However, one recent study showed that combining PET scanning with simultaneous CT (PET-CT) changed management in 16% of pancreatic cancer patients being considered for operation.
• Evaluation algorithm
  • Most patients suspected of having pancreatic carcinoma are initially studied with transcutaneous abdominal ultrasonography and/or spiral CT scanning (usually not done initially with dual-phase contrast thin-cut pancreatic protocols). Patient management thereafter can vary from institution to institution depending on local expertise, interest, and protocols.
  • If patients have obvious hepatic metastatic disease based on initial TUS or CT findings, they undergo a CT- or TUS-guided biopsy of one of the liver metastases and then proceed to palliative therapy.
  • Patients with a suggested or definite pancreatic mass observed on abdominal CT scanning or TUS or those who are still considered to have pancreatic cancer but do not have an obvious pancreatic mass need to have more definitive imaging studies. This can be done using high-quality thin-cut multidetector CT scanning with dual phase contrast and/or by other procedures such as endoscopic ultrasonography.
  • In the author's institution, where high-quality endoscopic ultrasonography and EUS-guided fine-needle aspiration is readily available, EUS plays a central role in the definitive diagnosis and staging of patients with pancreatic carcinoma (see Staging).
  • If a pancreatic mass is observed on EUS images, EUS-guided fine-needle aspiration is performed to confirm the disease cytologically. At the same time, the condition is staged using EUS to determine resectability potential. Patients thought to have resectable tumors based on EUS findings proceed directly to operative intervention. If tumors are deemed unresectable based on EUS findings and patients have obstructive jaundice, they proceed directly to therapeutic stent placement with ERCP while under the same endoscopic sedation. Most patients then undergo dedicated pancreas protocol multidetector CT scanning to complete preoperative staging if the initial CT scan was not of the highest quality. MRI, MRCP, and PET scanning are rarely used in the authors' evaluation algorithm unless other procedures are still nondiagnostic in a patient with a high suspicion of pancreatic cancer or altered gastric anatomy precludes endoscopic ultrasound examination.
  • Patients with unresectable disease are offered chemotherapy for their disease. In institutions without EUS and EUS-guided fine-needle aspiration capabilities, spiral CT scanning with CT-guided pancreatic fine-needle aspiration or biopsy plays the central role in evaluation.
  • Abdominal TUS can also be used as an initial diagnostic study especially in the jaundiced patient. However, this approach rarely obviates eventually performing abdominal CT scanning or EUS in patients in whom disease is a strong possibility.
• 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 and is highly dependent on the institution.²¹
    • Arguments in favor of preoperative biopsy include proof of pathology prior to surgery, exclusion of unusual pathology, provide evidence of disease before initiation of multidisciplinary treatment such as neoadjuvant chemotherapy.
    • Arguments against preoperative biopsy of pancreatic lesions state that the biopsy results will not alter therapy, biopsy may result in seeding and interfere with the definitive surgery, and the cost of the procedure.
    • 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.
  • 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. Cost-benefit analyses have also confirmed that it is the most cost-effective mode of tissue acquisition in suspected pancreatic cancer.
  • The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT scanning.
• Preoperative staging laparoscopy
  • Some centers advocate performing a staging laparoscopy before proceeding to attempted resection. The purpose of the laparoscopic staging is to avoid subjecting patients with liver or peritoneal metastases to unnecessary surgery.  Some surgeons advocate the use of routine staging laparoscopy in all patients with pancreatic cancer. Their argument is that up to 20% of attempted pancreatic resections can be prevented because of the laparoscopic findings.  Others are proponents of more selective use.^22,23,24 They advocate the use of the following criteria: CA19-9 above 150 U/mL, low volume ascites, body of pancreas tumors, borderline resectable tumors, size above 3 cm, and common bile duct lymphadenopathy. Any patient with one of the above-mentioned characteristics would undergo staging laparoscopy. 
  • Another argument for selective versus routine staging laparoscopy is the fact that in many cases where the tumor is deemed unresectable, laparoscopy would not have shown the vascular invasion or retroperitoneal invasion that ultimately leads to unresectability of tumor.  

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. Intraductal mucinous pancreatic neoplasms can be benign or malignant and usually manifest as a cystic dilation of the pancreatic ductal system.

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.

Pancreatic cancer. Hematoxylin and eosin stain of a pancreatic carcinoma. Note the intense desmoplastic response around the neoplastic cells. The large amount of fibrotic reaction in these tumors can make obtaining adequate tissue by fine-needle aspiration difficult.

Pancreatic cancer. Cytologic samples from fine-needle aspirations (rapid Papanicolaou stain) of pancreatic adenocarcinomas. (A) Well differentiated, (B) moderately differentiated, (C) moderate to poorly differentiated, (D) poorly differentiated tumor.

Staging

Cancer of the exocrine pancreas is classified by the tumor, nodal, metastases (TNM) staging system. The staging for pancreatic cancer was most recently modified by the American Joint Committee on Cancer (AJCC) in 2002.

• Staging of pancreatic tumors is as follows (AJCC, 2002):
  • Tumor (T)
    • TX - Primary tumor cannot be assessed
    • T0 - No evidence of primary tumor
    • Tis - Carcinoma in situ
    • T1 - Tumor limited to the pancreas, 2 cm or smaller in greatest dimension
    • T2 - Tumor limited to the pancreas, larger than 2 cm in greatest dimension
    • T3 - Tumor extension beyond the pancreas (eg, duodenum, bile duct, portal or superior mesenteric vein) but not involving the celiac axis or superior mesenteric artery
    • T4 - Tumor involves the celiac axis or superior mesenteric arteries
  • 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
• Stage grouping for pancreatic cancer is as follows:
  • Stage 0 - Tis, N0, M0
  • Stage IA - T1, N0, M0
  • Stage IB - T2, N0, M0
  • Stage IIA - T3, N0, M0
  • Stage IIB - T1-3, N1, M0
  • Stage III - T4, Any N, M0
  • Stage IV - Any T, Any N, M1
• At initial presentation, only 20% of patients present with stage I disease, 40% present with locally advanced disease, and 40% present with disease metastatic to nodes or distant sites.
• To date, studies show that EUS is approximately 70-80% accurate for correctly staging pancreatic carcinoma. EUS appears to better assess involvement of the portal vein/superior mesenteric vein. Multidetector CT scanning with dual-phase contrast probably has similar or better overall accuracy and is especially good at assessing major arterial involvement or distant metastases. EUS is better than CT scanning to help detect abnormal lymph nodes around the pancreas and celiac axis. Furthermore, with the addition of EUS-guided fine-needle aspiration, EUS can help cytologically document metastatic disease in suggestive lymph nodes.

Pancreatic cancer. T staging for pancreatic carcinoma. T1 and T2 stages are confined to the pancreatic parenchyma. T3 lesions invade local structures such as the duodenum, bile duct, and/or major peripancreatic veins, and T4 lesions invade surrounding organs (eg, stomach, colon, liver) or invade major arteries such as the superior mesenteric or celiac arteries.

Treatment

Medical Care

There is consensus on the fact that surgery is the primary mode of treatment for pancreatic cancer. However, an important role exists for the use of chemotherapy and/or radiation therapy in an adjuvant setting, neoadjuvant setting, and in the treatment of patients with unresectable disease. 

Chemotherapy

• The 2 most active agents have been 5-fluorouracil (5-FU) and, more recently, gemcitabine. The addition of targeted therapy in the form of epidermal growth factor receptor antagonists (ie, erlotinib) has had a synergistic effect.
• In patients with metastatic disease, the combination of gemcitabine and erlotinib has led to a significantly higher median survival and 1-year survival than the use of gemcitabine alone.²⁵ This has led to FDA approval of erlotinib to be used in combination with gemcitabine in advanced unresectable pancreatic cancer. The recommendation that this combination should now constitute standard therapy for metastatic or unresectable local disease is premature and problematic. The improvements in response rates seen, although significant, were not great and were obtained with no small amount of patient toxicity.
  • The combination should be used with considerable care, and the use of gemcitabine alone should still be considered as appropriate therapy for patients with metastatic disease. Gemcitabine alone should also be considered as appropriate therapy for patients with unresectable disease; there is no meaningful significant benefit obtained to adding radiotherapy in this situation. Such an addition simply increases toxicity.²⁶
  • The addition of bevacizumab to the combination of gemcitabine and erlotinib does not improve the response rate of the combination alone.²⁷  The combination of gemcitabine and capecitabine has previously been investigated to determine whether their use together improves overall survival. Unfortunately, recent clinical trials have not shown that combining these 2 agents produces any change in clinical response or quality of life.^28,29
  • Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patients refractory to gemcitabine.³⁰  There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m ² over one half hour intravenously.
  • Combinations of gemcitabine with any of cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not been of superior benefit to gemcitabine alone.
• In the adjuvant setting, several studies (including the GITSG, ESPAC, CONKO) had suggested the possibility that chemotherapy with or without radiation therapy would significantly improve median survivals following surgical resection of operable disease.^31,32 These studies were not definitive and not widely accepted as justification for offering either modality for adjuvant therapy. Gemcitabine alone has now been shown to significantly affect survival following resection for operable disease. It prolongs survival in the adjuvant setting when compared to surgery alone.³³
  • The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery only arms respectively (p<0.001). The 5-year survival rates were 21% and 9% for the gemcitabine and surgery only arms respectively (p<0.001). Postsurgical adjuvant treatment with gemcitabine doubled the 5-year survival rate when compared to surgery and observation alone.
  • This trial is definitive and transformative. Adjuvant therapy with gemcitabine is now accepted as standard therapy for surgically resected pancreatic cancer.³⁴
• The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy. The rationale for neoadjuvant therapy includes the following: 
  • Pancreatic cancer is a systemic disease and should be treated systemically from the start.
  • Patients will be able to tolerate the toxic effects of chemotherapy more readily before undergoing major pancreatic resection than after. 
  • The tumor will shrink and the resection will be less cumbersome, leading to an improved overall survival.   
• Several trials conducted at M.D. Anderson Cancer Center have shown median survival as high as 25 months.^35,36 No form of neoadjuvant therapy in pancreatic carcinoma should be regarded as a standard form of therapy; this remains an area for clinical trial study.

Palliative therapy

• Pain
  • Patients not undergoing resection for pancreatic cancer should have therapy focused on palliating their major symptoms. Pain relief is crucial in these patients. Narcotic analgesics should be used early and in adequate dosages. Combining narcotic analgesics with tricyclic antidepressants or antiemetics can sometimes potentiate their analgesic effects. In some patients, narcotics are insufficient and other approaches must be considered.
  • Neurolysis of the celiac ganglia may provide significant long-term pain relief in patients with refractory abdominal pain. This can be performed either transthoracically or transabdominally by invasive radiology or anesthesiology, transgastrically using EUS-guided fine-needle injection, or intraoperatively when assessing the patient's potential for resection.
  • Radiation therapy for pancreatic cancer can palliate pain but does not affect the patient's survival.
  • Some patients may be experiencing pain from the obstruction of the pancreatic or biliary ducts, especially if the pain significantly worsens after eating. These patients may benefit from endoscopic decompression with stents.
• Jaundice
  • Obstructive jaundice warrants palliation if the patient has pruritus or right upper quadrant pain or has developed cholangitis. Some patient's anorexia also seems to improve after relief of biliary obstruction. Biliary obstruction from pancreatic cancer is usually best palliated by the endoscopic placement of plastic or metal stents. The more expensive and permanent metallic stents appear to have a longer period of patency and are preferable in patients with an estimated lifespan of more than 3 months. Plastic stents usually need to be replaced every 3-4 months.
  • Patients can also undergo operative biliary decompression, either by choledochojejunostomy or cholecystojejunostomy, at the time of an operation for resectability assessment.
• Duodenal obstruction: Approximately 5% of patients develop duodenal obstruction secondary to pancreatic carcinoma. These patients can be palliated operatively with a gastrojejunostomy or an endoscopic procedure. Endoscopic stenting of duodenal obstruction is usually reserved for patients who are poor operative candidates. Some surgeons empirically palliate patients with a gastrojejunostomy at the time of an unsuccessful attempt at pancreatic resection in an effort to prevent the later need for this operation.

Surgical Care

Prior to any surgical procedures, the resectability of malignant pancreatic tumors needs to be established. Pancreatic masses are characterized as resectable, unresectable, or borderline resectable. The latter is usually based on both the experience and technical skill of the surgeon involved in treatment as well as the overall health of the patient and his or her wishes. Typically, extrapancreatic disease precludes curative resection, and surgical treatment may be palliative at best. 

Historically, vascular involvement has been considered a contraindication to resective cure. The invasion of the superior mesenteric or portal vein is no longer an absolute contraindication.³⁷  These veins can be resected partially with as much as 50% narrowing of the lumen. Also, complete reconstruction is possible especially using native veins as replacement (ie, internal jugular, greater saphenous, or splenic). Nonetheless, invasion of the superior mesenteric, celiac, and hepatic arteries still presents a barrier to resection. No evidence indicates that a vascular reconstruction which permits an attempt at surgical resection improves or contributes to survival.

After a thorough preoperative workup, the surgical approach can be tailored to the location, size, and locally invasive characteristics of the tumor. Curative resection options include pancreaticoduodenectomy, with or without sparing of the pylorus, total pancreatectomy, or distal pancreatectomy. Each procedure is associated with its own set of perioperative complications and risks, and these points should be taken into consideration by the surgical team and discussed with the patient when considering the goal of resection.

Pancreaticoduodenectomy (Whipple procedure)

Patients who will most likely benefit from this procedure have a tumor located in the head of the pancreas or the periampullary region. The Whipple procedure is not strictly the surgical approach for pancreatic head tumors. Pancreatic ductal tumors, cholangiocarcinoma (bile duct cancer), and duodenal masses will all require this resection. The operation traditionally involves the following: removal of the pancreatic head, duodenum, gallbladder, and the antrum of the stomach with surgical drainage of the distal pancreatic duct and biliary system, usually accomplished through anastomosis to the jejunum. The primary reason for removing such a large quantity of intraabdominal structures is that they all share a common blood supply.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%.³⁸  Many forms of morbidity are associated with the operation. One of these is delayed gastric emptying. This occurs in approximately 25% of patients. This condition may require nasogastric decompression and will lead to a longer hospital stay.³⁹ Other morbidities include pancreatic anastomotic leak. This can be treated with adequate drainage. Postoperative abscesses are not uncommon. It is unclear whether preoperative biliary drainage leads to increased rates of postoperative infection.⁴⁰

The standard Whipple operation may be altered in order to include a pylorus-sparing procedure. This modification was previously incorporated to increased nutritional strength in these patients as the increased-gastric emptying associated with antrectomy caused nutritional deficiencies. Although many believe that delayed gastric emptying is worsened by this modification, studies have proven both resections to be equivalent in that regard. Another source of controversy is the extent of lymphadenectomy that is necessary in a Whipple operation. In an elegant study, Pawlik et al found the ratio of positive nodes to total nodes removed was an important prognostic factor.⁴¹ This was even more significant than margin positivity.⁴²

Distal pancreatectomy

This procedure possesses a lower mortality rate than the standard Whipple procedure at 3.5%, but its use in curative resection remain limited.³⁸ Essentially, a distal pancreatectomy may be an effective procedure for tumors located in the body and tail of the pancreas. Unfortunately, masses located in this area present later than the periampullary tumors and hence have a higher unresectability rate. The procedure involves isolation of the distal portion of the pancreas containing the tumor followed by resection of that segment, with oversewing of the distal pancreatic duct. The main complications for distal pancreatectomy involve pancreatic stump leak, hemorrhage, or endocrine insufficiency.⁴³ Once again, the best treatment for the pancreatic leak is adequate drainage.

Total pancreatectomy

Although this procedure is the least commonly done with the highest associated mortality at 8.3%, it may still remain a valuable instrument in the surgical cure of pancreatic cancer.³⁸ The indication is cases in which the tumor involves the neck of the pancreas. This can either be a situation in which the tumor originates from the neck or is growing into the neck. These patients obviously get insulin-dependent diabetes. In some cases, the diabetes can be hard to control. Despite this, the morbidity of a total pancreatectomy is comparable to that of a Whipple procedure.⁴⁴

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. This approach is only indicated when this combination therapy is the subject of a clinical trial.

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.

Antineoplastic agents

These agents inhibit cell growth and proliferation. They are used for chemotherapy.

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.

Dosing

Adult

Multiple 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

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause myelosuppression (particularly thrombocytopenia); toxicities include flulike syndrome, LFT abnormality, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic uremic syndrome

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.

Dosing

Adult

15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d

Pediatric

Not established

Interactions

Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents

Contraindications

Documented hypersensitivity; bone marrow suppression; serious infection; topical administration in pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment

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.

Dosing

Adult

100 mg PO qd 1 h ac or 2 h pc

Pediatric

Not established

Interactions

Predominantly 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)

Contraindications

None known

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution 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)

Capecitabine (Xeloda)

Prodrug of fluorouracil that undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA, and to a lesser degree with RNA synthesis.

Dosing

Adult

2500 mg/m² PO divided bid (12 h apart) at end of a meal for 2 wk followed by 1 wk of rest period given as 3 wk cycle

Pediatric

Not established

Interactions

Aluminum/magnesium hydroxide antacids or meals increase drug absorption; increased risk of bleeding with anticoagulants (monitor INR and PT frequently), NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents; coadministration with leucovorin may cause diarrhea, dehydration, and death from severe enterocolitis; may increase phenytoin levels

Contraindications

Documented hypersensitivity to drug or related products; severe renal impairment (CrCl <30 mL/min); dihydropyrimidine dihydrogenase (DPD) deficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adjust dose in moderate renal impairment (CrCl 30-50 mL/min); discontinue drug if intractable diarrhea, bone marrow suppression, myocardial ischemia, or stomatitis develop; caution in patients that have received extensive pelvic radiation or alkylating therapy; hand and foot syndrome characterized by numbness, dysesthesia/paresthesia, tingling, erythema, blistering, severe pain, desquamation, and painless or painful swelling may occur

Follow-up

Deterrence/Prevention

• Smoking is the most significant reversible risk factor for pancreatic cancer. Estimates indicate that smoking accounts for up to 30% of cases of pancreatic cancer.
• A diet high in energy intake and low in fresh fruits and vegetables increases the risk of pancreatic cancer.
• Alcohol consumption does not increase the risk of pancreatic cancer unless it leads to chronic pancreatitis. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer.

Prognosis

• The mean survival for patients with unresectable disease remains 4-6 months, with a 5-year survival rate of less than 3%.
• The median survival for patients who undergo successful resection (only 20% of patients) is approximately 12-19 months, with a 5-year survival rate of 15-20%. Although discouraging, these results are still markedly better than those for patients with unresectable pancreatic carcinoma.

Patient Education

For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Pancreatitis and Pancreatic Cancer.

Miscellaneous

Medicolegal Pitfalls

• Pancreatic cancer in its early stages is a protean disease that can be difficult to distinguish from other much more common disorders. Early diagnosis is therefore often a problem. Many patients have sought care for symptoms for weeks to months before a definitive diagnosis of pancreatic cancer is made.
• Failure to accurately stage patients preoperatively can also be a problem. Patients with advanced disease should avoid fruitless attempts at resection. However, patients with potentially resectable disease should be offered this option because complete resection is the only therapy for pancreatic carcinoma associated with a significant improvement in survival.
• Adequate pain control should be provided for patients with unresectable disease.

Multimedia

Media file 1: Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm resected from the pancreatic body and tail. Although the tumor was considered to have been fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1 year.

Media file 2: Pancreatic cancer. Hematoxylin and eosin stain of a pancreatic carcinoma. Note the intense desmoplastic response around the neoplastic cells. The large amount of fibrotic reaction in these tumors can make obtaining adequate tissue by fine-needle aspiration difficult.

Media file 3: Pancreatic cancer. T staging for pancreatic carcinoma. T1 and T2 stages are confined to the pancreatic parenchyma. T3 lesions invade local structures such as the duodenum, bile duct, and/or major peripancreatic veins, and T4 lesions invade surrounding organs (eg, stomach, colon, liver) or invade major arteries such as the superior mesenteric or celiac arteries.

Media file 4: Pancreatic cancer. Computerized tomographic scan showing a pancreatic adenocarcinoma of the pancreatic head. The gallbladder (gb) is distended because of biliary obstruction. The superior mesenteric artery (sma) is surrounded by tumor, making this an unresectable T4 lesion.

Media file 5: Pancreatic cancer. Abdominal CT scan of a small, vaguely seen, 2-cm pancreatic adenocarcinoma (mass) causing obstruction of both the common bile duct (cbd) and pancreatic duct (pd).

Media file 6: Pancreatic cancer. Endoscopic ultrasound of a 2.2-cm pancreatic adenocarcinoma of the head of the pancreas obstructing the common bile duct (CBD) but not invading the portal vein (PV) or superior mesenteric vein (SMV). Findings from endoscopic ultrasound–guided fine-needle aspiration revealed a moderately to poorly differentiated adenocarcinoma. Abdominal CT findings did not show this mass, and an attempt at endoscopic retrograde cholangiopancreatography at another institution was unsuccessful.

Media file 7: Algorithm for evaluation of a patient with suspected pancreatic cancer. CT scanning for definitive diagnosis and staging must be with thin-cut, multidetector, spiral CT scanning using dual-phase contrast imaging to allow for maximal information. This schema varies among institutions depending on local expertise, research interest, and therapeutic protocols for pancreatic carcinoma.

Media file 8: Pancreatic cancer. Tip of linear array echoendoscope (Pentax FG 36UX) with 22-gauge aspiration needle exiting from biopsy channel. Insert shows magnification of aspiration needle tip. Note that the needle exits from the biopsy channel such that it appears continuously in the view of the ultrasonic transducer on the tip of the echoendoscope.

Media file 9: Pancreatic cancer. Cytologic samples from fine-needle aspirations (rapid Papanicolaou stain) of pancreatic adenocarcinomas. (A) Well differentiated, (B) moderately differentiated, (C) moderate to poorly differentiated, (D) poorly differentiated tumor.

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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

Contributor Information and Disclosures

Author

Richard A Erickson, MD, FACP, FACG, Professor of Medicine, Division of Gastroenterology, Department of Internal Medicine, Texas A&M University Health Science Center; Director, Scott and White Clinic and Hospital
Richard A Erickson, MD, FACP, FACG is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Coauthor(s)

Claire R Larson, MD, Staff Physician, Department of General Surgery, Texas A & M School of Medicine, Scott and White Hospital
Claire R Larson, MD is a member of the following medical societies: American College of Surgeons and American Medical Association
Disclosure: Nothing to disclose.

Mohsen Shabahang, MD, PhD, FACS, Assistant Professor of Surgery, Division of Surgical Oncology, Director of Surgical Residency, Texas A&M Health Science Center, Scott and White Clinic
Mohsen Shabahang, MD, PhD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, Association for Academic Surgery, Society of Surgical Oncology, Texas Medical Association, and Western Surgical Association
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

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