Pancreatic Cancer

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Practice Essentials

Pancreatic cancer is the tenth most common cancer in men and the ninth most common in women, but it is the fourth leading cause of cancer deaths, being responsible for 7% of all cancer-related deaths in men and 8% in women. 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. See the image below.



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Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm resected from the pancreatic body and tail. Although the tumo....

Signs and symptoms

The initial symptoms of pancreatic cancer are often quite nonspecific and subtle in onset. Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise, nausea, fatigue, and midepigastric or back pain.

Patients with pancreatic cancer may present with the following signs and symptoms:

See Clinical Presentation for more detail.

Diagnosis

Pancreatic cancer is notoriously difficult to diagnose in its early stages.[1]

Testing

The laboratory findings in patients with pancreatic cancer are usually nonspecific. Patients with advanced pancreatic cancers and weight loss may have general laboratory evidence of malnutrition (eg, low serum albumin or cholesterol level).

Potentially useful tests in patients with suspected pancreatic cancer include the following:

Imaging studies

Imaging studies that aid in the diagnosis of pancreatic cancer include the following:

See Workup for more detail.

See also Pancreatic Adenocarcinoma Imaging: What You Need to Know, a Critical Images slideshow, to help identify which imaging studies to use to identify and evaluate this disease.

Management

Surgery is the primary mode of treatment for pancreatic cancer. However, an important role exists for chemotherapy and/or radiation therapy.

Surgical options

Curative resection options include the following:

Chemotherapy

Antineoplastic agents and combinations of agents used in managing pancreatic carcinoma include the following:

Adjuvant therapy with gemcitabine is accepted as standard therapy for surgically resected pancreatic cancer.[7]  However, a study demonstrating markedly superior survival with modified FOLFIRINOX compared with gemcitabine in this setting promises to be practice changing.[8, 9]

Neoadjuvant therapy

The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy, but increasing evidence supports its use in patients with resectable disease. Neoadjuvant regimen options include the following[2] :

Palliative Therapy

Palliative therapy may be administered for the following conditions associated with pancreatic cancer:

See Treatment and Medication for more detail.

Background

Although pancreatic cancer accounts for only about 3% of all cancers in the United States, it is the fourth leading cause of cancer deaths in both men and women, being responsible for 7% of all cancer-related deaths. The average lifetime risk of developing pancreatic cancer is about 1 in 67.[10] (See Epidemiology.)

Pancreatic cancer 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 rate for pancreatic cancer is only 28%, and the overall 5-year survival is 7%.[11] (See Prognosis and Workup.)

Types of pancreatic cancer

Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of the exocrine pancreas are benign. (See Etiology and Histologic Findings.)

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.

An adenocarcinoma of the pancreas is seen below. (See Histologic Findings.)



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Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm resected from the pancreatic body and tail. Although the tumo....

Pathophysiology

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 it can 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. Metastasis to bone is uncommon.

Pancreatic cancer rarely spreads to the brain, but it can produce meningeal carcinomatosis.

Etiology

Pancreatic cancers can arise from the exocrine and endocrine portions of the pancreas, but 93% of them develop from the exocrine portion, 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.

Tobacco smoking is the most common recognized risk factors for pancreatic cancer. Others include obesity, high alcohol consumption, history of pancreatitis and diabetes, family history of pancreatic cancer, and possibly selected dietary factors.[12] Only 5-10% are hereditary in nature.[13]

Because excess risk for pancreatic cancer is greater in patients recently diagnosed with diabetes mellitus, it has been suggested that diabetes may be at least in part a consequence or an early manifestation of pancreatic cancer. However, the International Pancreatic Cancer Case-Control Consortium reported that a 30% excess risk for pancreatic cancer persists for more than 2 decades after diabetes diagnosis, which supports the hypothesis that diabetes has a causal role in pancreatic cancer.[14]

Less than 5% of all pancreatic cancers are related to underlying chronic pancreatitis. Alcohol consumption does not appear to be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis.

The risk factors for pancreatic cancer are discussed in more detail below.

Smoking

Smoking is the most common environmental risk factor for pancreatic carcinoma. Estimates indicate that smoking accounts for up to 30% of cases of pancreatic cancer.

People who smoke have at least a 2-fold greater risk for pancreatic cancer than do nonsmokers. Current smokers with over a 40 pack-year history of smoking may have up to a 5-fold risk greater risk for 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.

Obesity and dietary factors

In a number of studies, obesity, especially central, has been associated with a higher incidence of pancreatic cancer. For example, Li et al found that being overweight or obese during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset, while obesity at an older age was associated with lower overall survival.[15] Several other studies have supported a link between early obesity and the risk of pancreatic cancer.[16, 17]

The incidence of pancreatic cancer is lower in persons 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 pancreatic cancer.[18, 19]

Consumption of red meat, especially of the processed kinds, is associated with a higher risk of pancreatic cancer. Poultry and dairy product consumption does not increase the risk of this disease.[20]

Despite early reports to the contrary, coffee consumption is not associated with an increased risk of pancreatic cancer.[21]

Diabetes mellitus

Numerous studies have examined the relative risk of pancreatic cancer in persons with diabetes mellitus. A systematic review 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.

The National Comprehensive Cancer Network (NCCN)  acknowledges long-standing diabetes mellitus as a risk factor for pancreatic cancer. The NCCN also notes an association between sudden onset of type II diabetes mellitus in an adult older than 50 years and a new diagnosis of pancreatic cancer, although in those cases the diabetes is thought to be caused by the cancer.[2]

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.[22]

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 persons whose family has a paternal inheritance pattern.[23]

Chronic pancreatitis from alcohol consumption is also associated a much higher incidence and an earlier age of onset of pancreatic carcinoma.[24]

Genetic factors

Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease.[25]

The molecular genetics of pancreatic adenocarcinoma have been well studied.[26, 27, 28] Of these tumors, 80-95% have mutations in the KRAS2 gene; 85-98% have mutations, deletions, or hypermethylation in the CDKN2 gene; 50% have mutations in p53; and about 55% have homozygous deletions or mutations in 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.[29]

Assaying pancreatic juice for the genetic mutations associated with pancreatic adenocarcinoma is invasive, but it may be useful for the early diagnosis of the disease.[30] However, this approach is problematic, because genetic mutations in the pancreatic juice may be found in patients 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 is pancreatic intraepithelial neoplasia (PIN). These lesions arise from specific genetic mutations and cellular alterations that contribute to the development of invasive ductal adenocarcinoma.[31]

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 with the development of ductal carcinoma of the exocrine pancreas.

Based on more recent data from sequencing of human tumors, pancreatic cancer is a genetically complex and heterogeneous disease.[32] This is confounded by considerable variability in terms of the genetic malformations and pathways involved between individual tumors. In addition, the long time from early to clinically manifested disease (21.2 y on average) allows for an accumulation of complex genetic changes, which probably explains the fact that it is often resistant to chemotherapy and radiation therapy.[33, 34]

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 40% cumulative risk of developing pancreatic cancer at 40%.[23] 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.[35] Von Hippel-Lindau syndrome has been associated with malignancy in 17% of masses found in the pancreas in people with this syndrome.[36]

Syndromes associated with an 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 have not been impressive.

In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma. No statistics are available to show the incidence of pancreatic cancer in patients with HNPCC.[37]

FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and the incidence in sporadic cases to be 98%.[38]

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.[25]

Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the 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%.[25]

Race-related factors

Black males in the United States have the highest incidence rate of pancreatic cancer.[39] (See Epidemiology, below.) The reasons for the higher incidence of pancreatic cancer in African Americans are unclear. Certainly, differences in risk factors for pancreatic cancer, such as dietary habits, obesity, and the frequency of cigarette smoking, are recognized among different population groups and may contribute to the higher incidence of this disease among blacks.

However, Arnold et al found that excess pancreatic cancer in blacks cannot be attributed to currently known risk factors, suggesting that as-yet undetermined factors play a role in the disease process.[40] One possibility is a difference in the underlying frequency of predisposing genetic mutations for pancreatic cancer.

Epidemiology

Incidence in the United States

The American Cancer Society estimates that in the United States in 2019, about 56,770 new cases of pancreatic cancer (29,940 in men and 26,830 in women) will be diagnosed.[10] The overall incidence rate of pancreatic cancer increased by about 1% per year from 2006 to 2015.[11]

International incidence

Worldwide, pancreatic cancer ranks 11th in incidence but 7th as a cause of cancer death.[41] The age-standardized rate (ASR) incidence ranges widely, from 7.7 per 100,000 population in Europe to 2.2 per 100,000 population in Africa. Among individual countries, ASRs range from 0.81 per 100,000 in males in India to 15.3 per 100,000 in males in Latvia and the Republic of Moldova.[41]

Race predilection

From 2011 to 2015, the highest incidence rate of pancreatic cancer in the United States was 16.9 cases per 100,000 persons per year, in black men. The incidences in men in other racial/ethnic groups were as follows[10] :

The incidences in US women during that period were as follows[10] :

Age predilection

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.

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.

Mortality

Although pancreatic cancer constitutes only about 3% of all cancers in the United States, it is the fourth leading cause of cancer deaths in both men and women, being responsible for 7% of all cancer-related deaths in men and 8% in women.The American Cancer Society estimates that in the United States in 2019, about 45,750 people (23,800 men and 21,950 women) will die of pancreatic cancer.[11]

Prognosis

Pancreatic carcinoma is unfortunately usually a fatal disease. The collective median survival time for all patients is 4-6 months.

The relative 1-year survival rate for patients with pancreatic cancer is only 28%, and the overall 5-year survival rate is 9%, having increased from 3% between 1975 and 1977.[10] By stage, 5-year relative survival is 34.3% for localized disease, 11.5% for regional disease, and 2.7% for distant disease.[10] At the time of diagnosis, 52% of patients have distant disease.[11] (However, patients with neuroendocrine and cystic neoplasms of the pancreas, such as mucinous cystadenocarcinomas or intraductal papillary mucinous neoplasms [IPMN], have much better survival rates than do patients with pancreatic adenocarcinoma.)

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.

In patients able to undergo a successful curative resection (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 deoxyribonucleic acid (DNA) content.

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%.

Tingle et al reported that in patients with unresectable pancreatic ductal adenocarcinoma, the combination of the neutrophil-albumin ratio (NAR) and the Ca19-9 level allows stratification into three groups with significantly different overall survival, as follows[42] :

Patient Education

Smoking is the most significant reversible risk factor for 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.[22]

For patient education information, see the Liver, Gallbladder, and Pancreas Center and Cancer and Tumors Center, as well as Pancreatitis and Pancreatic Cancer.

History

The early clinical diagnosis of pancreatic cancer is fraught with difficulty. Unfortunately, the initial symptoms of the disease are often quite nonspecific and subtle in onset. Consequently, these symptoms can be easily attributed to other processes unless the physician has a high index of suspicion for the possibility of underlying pancreatic carcinoma.

Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise, nausea, fatigue, and midepigastric or back pain.

Significant weight loss is a characteristic feature of pancreatic cancer.

Midepigastric pain is a common symptom of pancreatic cancer, with radiation of the pain to the midback or lower-back region sometimes occurring. Radiation of the pain to the back is worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve plexus by the tumor.

Often, the pain is unrelenting in nature, with nighttime 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.

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. Even so, only about 1% of cases of new-onset diabetes mellitus in adults are related to occult pancreatic cancer.[14] Nevertheless, pancreatic cancer should be at least thought of in a patient older than 70 years with a new diagnosis of diabetes and 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 in part be 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 a serious illness of some kind is occurring in them.

A study by Turaga et al determined that male patients with pancreatic adenocarcinoma have a risk of suicide that is almost 11 times higher than the remainder of the population.[43] Patients who undergo surgery are more likely to commit suicide, specifically in the early postoperative period.

Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis also occur with higher frequency in patients with pancreatic cancer and may be the first presentation. Marantic endocarditis may develop in pancreatic cancer, occasionally being confused with subacute bacterial endocarditis.

Physical Examination

Pain is the most common presenting symptom in patients with pancreatic cancer. As previously mentioned, the pain typically takes the form of mild to moderate midepigastric tenderness. In some cases, radiation of the pain to the midback or lower-back region occurs. Such radiation is worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve plexus by the tumor.

However, at the time of initial presentation, about one third of patients may not have pain, one third have moderate pain, and one third have severe pain. All patients experience pain at some point in their clinical course.

Patients with clinical jaundice may also have a palpable gallbladder (ie, Courvoisier sign) and may have skin excoriations from unrelenting pruritus.

Patients presenting with or developing advanced intra-abdominal 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 computed tomography (CT) scanners to assess intra-abdominal disease, pancreatic cancer accounted for some 25% of adenocarcinomas of the cervical nodes, primary site unknown.

Approach Considerations

The laboratory findings in patients with pancreatic cancer are usually nonspecific. However, 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  the following:

Which of these modalities is used at a particular institution may depend largely on the local availability of and expertise with the procedure, as well as local cancer protocols. Additional considerations in the choice of diagnostic modality include the following:

The most difficult clinical situation in which to diagnose pancreatic carcinoma is in the patient with underlying chronic pancreatitis. In such cases, all of the above imaging studies may show abnormalities that may not help to 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.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

Laboratory Findings

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 with acute pancreatitis, in which case amylase and lipase would 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

Carbohydrate antigen 19-9

The CA 19-9 antigen is a sialylated oligosaccharide that is most commonly found on circulating mucins in cancer patients.[44] 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 of 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 to 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.[44]

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 CA 19-9 levels may be of prognostic value, with high levels indicating poorer outcome and less chance of resectability.[45, 46] Preoperative values above 50 U/mL have been shown to be associated with higher chances of recurrence.

Carcinoembryonic antigen

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 elevated CEA levels.

Because benign and malignant conditions other than pancreatic cancer can lead to elevated CEA levels, CEA is not a sensitive or specific marker for pancreatic cancer.

Research

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.

Computed Tomography

Because of its ubiquitous availability and its 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. (See the images below.)



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Pancreatic cancer. Computerized tomographic scan showing a pancreatic adenocarcinoma of the pancreatic head. The gallbladder (gb) is distended because....



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Pancreatic cancer. Abdominal CT scan of a small, vaguely seen, 2-cm pancreatic adenocarcinoma (mass) causing obstruction of both the common bile duct ....

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 scanner 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-scan findings in patients with pancreatic carcinoma.

Multidetector CT scanning (MDCT) using a pancreas protocol is at least as accurate as EUS in the overall determination of the resectability of pancreatic carcinoma. In fact, CT scanning may be more accurate than EUS in predicting involvement of the superior mesenteric artery.[47]

NCCN guidelines recommend MDCT angiography as the preferred imaging tool for dedicated pancreatic imaging. Thin (preferably sub-millimeter) axial sections should be acquired using a dual-phase pancreatic protocol, with images obtained in the pancreatic and portal venous phase of contrast enhancement. Coverage may be extended to cover the chest and pelvis for complete staging, depending on institutional preferences.

[2]

 

Other features of CT imaging include the following:

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

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 ultrasonogram is obtained. Therefore, TUS can help to detect only 60-70% of pancreatic carcinomas, and similar to CT scanning, more than 40% of the lesions smaller than 3 cm are missed.

However, 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.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

Endoscopic Ultrasonography

EUS obviates the physical limitations of TUS by placing a high-frequency, ultrasonographic transducer on an endoscope (see the first image below), 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. (Adenocarcinoma of the pancreatic head is seen in the second image below.)



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Pancreatic cancer. Tip of linear array echoendoscope (Pentax FG 36UX) with 22-gauge aspiration needle exiting from biopsy channel. Insert shows magnif....



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Pancreatic cancer. Endoscopic ultrasound of a 2.2-cm pancreatic adenocarcinoma of the head of the pancreas obstructing the common bile duct (CBD) but ....

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 ultrasonogram is nearly 100% specific at ruling out the presence of a pancreatic neoplasm.

In numerous series, EUS has been found to have 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 scanning as a means of assessing the T stage of the tumor, especially when the clinician is looking for portal vein involvement in pancreatic head lesions.

EUS is probably inferior to CT scanning in assessing arterial involvement and distant metastases.[47] EUS and CT scanning are poor at detecting occult nodal involvement.

On the whole, the NCCN guidelines recommend EUS as complementary to CT. However, if no mass is evident in the pancreas on CT protocol imaging, the NCCN recommends EUS before other evaluation options. EUS is also valuable if there is possible involvement of blood vessels or lymph nodes.[2]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

Endoscopic Retrograde Cholangiopancreatography

ERCP is a highly sensitive means of detecting pancreatic and/or biliary ductal abnormalities in pancreatic carcinoma. Among 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. 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; in most series, however, 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.

MRI

Interest in using MRI for abdominal imaging continues to grow. The role of MRI in pancreatic cancer has been less well studied than has the role of CT scanning, although the modality does not appear to be superior to spiral CT scanning. Dynamic, gadolinium-enhanced, 3D, gradient-echo MRI may offer enhanced sensitivity in the detection of small pancreatic lesions. However, in patients with jaundice, 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.

The NCCN notes that MRI is most often used as a problem-solving tool, particularly for characterization of liver lesions that are indeterminate on CT; when pancreatic tumors are suspected, but are not visible on CT; or when contrast-enhanced CT cannot be obtained (eg, because of severe allergy to iodinated intravenous contrast material).

[2]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

PET Scanning

PET scanning uses 18F-fluorodeoxyglucose (FDG) to image 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 scanning does not seem to offer additional benefits to high-quality CT scanning. However, studies in which PET scanning was combined with simultaneous CT scanning (PET-CT) suggested that PET-CT scanning is more sensitive than conventional imaging for the detection of pancreatic cancer and that PET-CT–scan findings sometimes change clinical management.[49, 50]

The NCCN guidelines consider PET-CT an evolving technology; its role in the diagnosis of pancreatic cancer is not yet established.[2]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

Needle Aspiration

The necessity of obtaining a cytologic or tissue diagnosis of pancreatic cancer prior to surgery remains controversial and is highly dependent on the institution.[51]

Arguments in favor of preoperative biopsy include its ability to provide proof of pathology prior to surgery, exclude unusual pathology, and provide evidence of disease before the initiation of multidisciplinary treatment, such as neoadjuvant chemotherapy.

Arguments against preoperative biopsy of pancreatic lesions are that the biopsy results will not alter therapy, that biopsy may result in seeding and interfere with definitive surgery, and that the procedure increases the cost of care.

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. For example, a retrospective study by Turner et al found that EUS-guided fine needle aspiration was 80% accurate for the detection of pancreatic carcinoma and was 94% accurate when atypical and suspicious samples are considered positive.[52]

A study by Micames et al suggested that percutaneous aspiration may be associated with a higher risk of peritoneal tumor spread than is aspiration with EUS.[53]

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.

In a presentation delivered at the 2013 annual meeting of the American Society for Clinical Pathology, Huffman et al described a new risk-stratification system for EUS–guided fine-needle aspiration cytology results that can help determine when pancreatic lesions are malignant.[54] The researchers identified the following 3 morphologic characteristics as being significantly associated with pancreatic malignancy:

The risk of malignancy was low when none of these 3 criteria are met, moderate when 1 was met, and high when 2 or 3 were met.[54]

The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT scanning.

Histologic Findings

As previously mentioned, 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. (See the images below.)



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Pancreatic cancer. Hematoxylin and eosin stain of a pancreatic carcinoma. Note the intense desmoplastic response around the neoplastic cells. The larg....



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Pancreatic cancer. Cytologic samples from fine-needle aspirations (rapid Papanicolaou stain) of pancreatic adenocarcinomas. (A) Well differentiated, (....

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. An estimated 40% of pancreatic endocrine tumors are nonfunctional; of these, up to 90% are malignant.[55]

Islet cell tumors in patients with inherited syndromes such as multiple endocrine neoplasia are less likely to occur singly than in patients without these syndromes, and in the case of multiple endocrine neoplasia type 1, are more frequently gastrinomas than insulinomas. These variations of tumor function affect diagnosis and treatment strategies.[55]

Staging

Once an imaging modality has helped to establish a probable diagnosis of pancreatic cancer, the next issue is whether the lesion is amenable to surgical resection. Pancreatic masses are characterized as resectable, unresectable, or borderline resectable. The last designation, borderline resectable, is usually based on the experience and technical skill of the surgeon involved in treatment, as well as on the overall health of the patient and on his or her wishes.

Only 20% of all patients presenting with pancreatic cancer are ultimately found to have easily resectable tumors with no evidence of local advancement. Noncurative resections for pancreatic carcinoma provide no survival benefit. 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, node, metastasis (TNM) staging system. The staging for pancreatic cancer was modified by the American Joint Committee on Cancer (AJCC) in 2002.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

AJCC staging of pancreatic tumors is as follows[56] :

Tumor (T)

See the list below:

Regional lymph nodes (N)

See the list below:

Distant metastasis (M)

See the list below:

Stage grouping for pancreatic cancer is as follows:

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.

NCCN guidelines recommend multi-detector computed tomography (MDCT) angiography, using a dual-phase pancreatic protocol, as the preferred modality for dedicated pancreatic imaging.[2] This technique is especially good for assessing major arterial involvement or distant metastases.

EUS is better than CT scanning for detection of 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.

The image below visually demonstrates the stages of pancreatic cancer.



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Pancreatic cancer. T staging for pancreatic carcinoma. T1 and T2 stages are confined to the pancreatic parenchyma. T3 lesions invade local structures ....

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, including the NCCN panel, advise more a selective approach to staging laparoscopy, recommending its use in patients with any of the following indications[57, 58, 59, 2] :

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.

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. (See the image below.)



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Algorithm for evaluation of a patient with suspected pancreatic cancer. CT scanning for definitive diagnosis and staging must be with thin-cut, multid....

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 using other procedures, such as EUS.

In the author's institution, where high-quality EUS and EUS-guided fine-needle aspiration are readily available, EUS plays a central role in the definitive diagnosis and staging of patients with pancreatic carcinoma.

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 if 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 if altered gastric anatomy precludes endoscopic ultrasonographic 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.

Approach Considerations

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

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. However, the invasion of the superior mesenteric or portal vein is no longer an absolute contraindication.[60] These veins can be resected partially with as much as 50% narrowing of the lumen. In addition, 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; and 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.

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that decisions about resectability involve input from a multidisciplinary group of specialists at a high-volume center. The NCCN panel also agreed that selecting patients for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities, overall performance, and age.[2]

Guidelines on pancreatic cancer from the European Society for Medical Oncology (ESMO) advise that complete surgical resection is the only potentially curative treatment available; however, 5-yr overall survival is only 10-20%, and long-term survival in patients with node-positive disease is rare. ESMO recommendations include the following[61] :

In patients with unresectable locally advanced pancreatic cancer, local ablation has been explored as a treatment option. A systematic review concluded that the following strategies appear to be feasible and safe[62] :

Several of these ablative techniques have been shown to provide pain relief and improved survival. For example, medial survival of up to 25.6 months with RFA and 24.0 months with SBRT has been reported. Promising quality-of-life outcomes have been reported for SBRT.[62]

Chemotherapy

In patients with metastatic disease, the combination of gemcitabine and erlotinib has led to a significantly higher median survival and 1-year survival than has the use of gemcitabine alone.[63] This has led to US Food and Drug Administration (FDA) approval of erlotinib for use 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.[64]

The combination of gemcitabine and capecitabine in advanced pancreatic cancer has been investigated by several groups. A randomized, multicenter, phase III clinical trial in 319 patients by the Central European Cooperative Oncology Group found that clinical response or quality of life was no better with the combination than with gemcitabine alone.[65]

This finding contrasts with the results of the phase III United Kingdom National Cancer Research Institute GEMCAP trial, an open-label, randomized study of gemcitabine alone versus gemcitabine combined with capecitabine in 533 patients. Compared with gemcitabine alone, treatment with the gemcitabine-capecitabine combination produced a significantly higher objective response rate (12.4% vs 19.1%, respectively) and progression-free survival and was associated with a trend toward improved overall survival.

In addition, a meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of the gemcitabine-capecitabine combination. Accordingly, these researchers recommended considering gemcitabine-capecitabine as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.[66]

Results of the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) show that the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine significantly improves overall survival in treatment-naive patients with metastatic pancreatic cancer compared with gemcitabine alone.[4] Overall survival was approximately 2 months longer in patients treated with combination therapy (8.5 vs 6.7 months). One-year and 2-year survival rates were also higher in the combination therapy group (35% vs 22% and 9% vs 4%, respectively).

The results of a European phase III trial (ACCORD/PRODIGE) that compared the nongemcitabine regimen FOLFIRINOX (leucovorin plus 5-fluorouracil [LV5-FU] plus oxaliplatin plus irinotecan) to gemcitabine in patients with metastatic pancreatic cancer were reported in May 2011.[3] The median survival on the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the gemcitabine arm. Of note, the incidence of adverse events and febrile neutropenia was significantly higher on the FOLFIRINOX arm, despite the fact that only patients with ECOG performance status of 0-1 were included in this trial.

It remains to be seen how well this regimen will be integrated into the care of patients with pancreatic cancer and good performance status worldwide. The NCCN recommends FOLFIRINOX as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance status.[2]

The phase III PRODIGE 24/CCTG PA.6 trial demonstrated that modified FOLFIRINOX (mFOLFIRINOX) also provides significantly longer survival than gemcitabine in patients with pancreatic ductal adenocarcinomas who have undergone R0 or R1 resection.[8]  This study is potentially practice changing.[9]

At a median follow-up of 33.6 months, the median disease-free survival in PRODIGE 24/CCTG PA.6 was 21.6 months in the mFOLFIRINOX group versus 12.8 months in the gemcitabine group; median overall survival was 54.4 vs 35.0 months, respectively. Time until the appearance of metastases was a median of 30.4 months with mFOLFIRINOX versus 17.0 months with gemcitabine). Overall, more patients experienced severe side effects (mainly hematologic) in the mFOLFIRINOX group than in the gemcitabine group (76% vs 53%), but the side effects were manageable.[8]

Paclitaxel protein bound was approved by the FDA in September 2013 for metastatic pancreatic cancer.[5] The treatment regimen includes paclitaxel protein bound 125 mg/m2 plus gemcitabine 1000 mg/m2 IV over 30-40 min on days 1, 8, and 15 of each 28-day cycle. The NCCN also recommends the combination as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance status.[2] This regimen may be considered instead of FOLFIRINOX in patients unlikely to tolerate toxicities associated with FOLIRINOX.[4]

For patients with metastatic or locally advanced unresectable disease who have poor performance status, the NCCN recommends gemcitabine monotherapy.[2]

Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patient's refractory to gemcitabine.[6] There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m² over 30 minutes intravenously.

Combinations of gemcitabine with cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not shown superior benefit over gemcitabine alone.

A new encapsulated form of irinotecan in a long-circulating nanoliposome (Onivyde) was approved by the FDA in October 2015 for patients with advanced pancreatic cancer who have been previously treatment with gemcitabine-based chemotherapy. Irinotecan liposomal is indicated for use in combination with fluorouracil and leucovorin.

Approval of irinotecan liposomal was based on a 3-arm, randomized, open-label study (NAPOLI-1 trial), which was conducted in 417 patients with metastatic pancreatic adenocarcinoma whose cancer had progressed after treatment with gemcitabine alone or in combination with other agents. The regimen used in the trial was a combination of liposomal irinotecan (70 mg/m² IV infused over 90 min [dosage for free-base irinotecan]) administered prior to fluorouracil (2400 mg/m² infused over 46 h) and racemic leucovorin (400 mg/m² infused over 30 min) every 2 weeks.

Patients treated with this combination of liposomal irinotecan plus fluorouracil/leucovorin lived for an average of 6.1 months, compared with 4.2 months for those treated with only fluorouracil/leucovorin or 4.2 months for patients treated with irinotecan liposomal alone. Improvement in progression-free survival was also observed, to a median of 3.1 months with irinotecan liposomal plus fluorouracil/leucovorin compared with 1.5 months for fluorouracil/leucovorin alone.[67]

Adjuvant Therapy

Several studies (including the GITSG, ESPAC, CONKO) suggested the possibility that chemotherapy, with or without radiation therapy, would significantly improve median survivals following surgical resection of operable disease.[68, 69] These studies were not definitive and not widely accepted as justification for offering either modality for adjuvant therapy.

However, a large, retrospective study supported the use of adjuvant chemoradiotherapy. Yang et al analyzed a registry of 2,877 patients who underwent surgical resection with curative intent for pancreatic adenocarcinoma; approximately half received no adjuvant therapy, and approximately a quarter received postoperative chemoradiotherapy. A significant survival benefit was found for the chemoradiotherapy patients.[70] In 2011, the NCCN panel recommended the measurement of serum CA 19-9 levels after surgery and before adjuvant therapy.[2]

A study by Neuhaus et al in 368 patients with resected pancreatic cancer found that adjuvant gemcitabine prolongs survival when compared with surgery alone.[71] The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery-only arms of the study, respectively. The 5-year survival rates were 21% and 9% for the gemcitabine and surgery-only arms, respectively.

This trial was definitive and transformative. Adjuvant therapy with gemcitabine is now accepted as standard therapy for surgically resected pancreatic cancer.[7]  However, the superior survival demonstrated with modified FOLFIRINOX (mFOLFIRINOX) may well make that regimen the standard of care for nonmetastatic pancreatic ductal adenocarcinoma in patients who have undergone surgical resection and have a good performance status (see Chemotherapy).[9]

A systematic review and meta-analysis by Wan et al found that adjuvant therapy with metformin signficantly reduced the risk of death in Asian patients with pancreatic cancer (hazard ratio [HR]=0.74]), but not in whites. Mortality risk was reduced in patients with stage I-II disease treated with metformin (HR=0.76, 95% CI=0.68-0.86) as well as in those with stage I-IV disease (HR=0.88, 95% CI=0.79-0.99), but not in those with stage III-IV disease.[72]

Neoadjuvant therapy

The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy. The rationale for using neoadjuvant therapy includes the assertions that (1) pancreatic cancer is a systemic disease and should be treated systemically from the start, (2) patients will be able to tolerate the toxic effects of chemotherapy more readily before undergoing major pancreatic resection than after, and (3) the tumor will shrink with neoadjuvant therapy, 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.[73, 74] 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.

The NCCN recommends considering neoadjuvant therapy for patients with resectable or borderline resectable tumor. Possible regimens include the following[2] :

A study by Dhir et al in 193 patients with resectable  or borderline resectable pancreatic ductal carcinoma concluded that FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel are viable options for neoadjuvant treatment. After adusting for covariates, however, overall survival was found to be 4.9 months longer with FOLFIRINOX than with gemcitabine-paclitaxel.[75]

In a retrospective study of 49 stage III locally advanced/borderline resectable patients who were initially unresectable, were downstaged through chemotherapy, and subsequently underwent surgical resection, prolonged preoperative chemotherapy was associated with excellent overall survival and high rates of lymph node–negative disease.[76, 77] A study by Loeherer et al found an improvement in overall survival from 9.2 months to 11.4 months with the addition of concurrent external beam radiation therapy to gemcitabine alone.[78]

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 so much of the intraabdominal structures is that they all share a common blood supply.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%.[79] 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.[80] Other morbidities include pancreatic anastomotic leak. This can be treated with adequate drainage. Postoperative abscesses are not uncommon.

Although preoperative biliary drainage was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by tumors of the pancreatic head, van der Gaag et al found that routine use of this maneuver increases the rate of complications. In a multicenter, randomized trial, 202 patients with obstructive jaundice and a bilirubin level of 40–250 mmol/L (2.3-4.6 mg/dL) were assigned to undergo either preoperative biliary drainage for 4-6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. The rate of serious complications was higher in the biliary drainage group than in the early surgery group (74% vs 39%, respectively). No significant difference was noted in mortality or length of hospital stay between the 2 groups.[81]

Similarly, Limongelli et al found that preoperative biliary drainage predisposes patients to a positive intraoperative biliary culture, which in turn is associated with an increased risk of postoperative infectious complications and wound infection.[82]

The standard Whipple operation may be altered in order to include a pylorus-sparing procedure. This modification was previously incorporated to increase nutritional strength in these patients, because 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.[83] This was even more significant than margin positivity.[84]

Guidelines on pancreatic cancer from the European Society for Medical Oncology include the following treatment recommendations[61] :

Distal Pancreatectomy

This procedure possesses a lower mortality rate than the standard Whipple procedure does, at 3.5%, but its use in curative resection remains limited.[79] 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, and endocrine insufficiency.[85] Once again, the best treatment for the pancreatic leak is adequate drainage.

Total Pancreatectomy

Although this procedure is the least commonly performed and has the highest associated mortality rate (8.3%), it may still be a valuable instrument in the surgical cure of pancreatic cancer.[79]

The indication for the use of total pancreatectomy is in 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.[86]

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 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 experience 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 patients’ 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.

Diet

As with most patients with advanced cancer, patients with pancreatic carcinoma are often anorexic. Pharmacologic stimulation of appetite is usually unsuccessful, 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 by avoidance of high-fat or high-protein diets.

Consultations

The management of pancreatic carcinoma is a multidisciplinary process. Typically, the management of pancreatic cancer entails consultations with a gastroenterologist, medical oncologist, general surgeon or surgical oncologist, and, possibly, a radiation oncologist.

A gastroenterologist is usually involved either for evaluation of the cause of the patient's presenting symptoms (eg, abdominal pain, nausea, weight loss, diarrhea) or for a definitive diagnosis of the cause of jaundice by EUS and/or ERCP. Consultation with a gastroenterologist is also needed if an endoscopically placed stent is needed for palliation of obstructive jaundice.

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 the 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.

Guidelines Summary

Guidelines Contributor: Lewis J Rose, MD Clinical Associate Professor of Medical Oncology, Division of Regional Cancer Care, Kimmel Cancer Center, Thomas Jefferson University Hospital; Consulting Staff, LRCRZ Associates

Screening

Guidelines on pancreatic cancer screening have been issued by the following organizations:

The USPSTF found no evidence that screening for pancreatic cancer is effective in reducing mortality and recommends against routine screening in asymptomatic adults using abdominal palpation, ultrasonography, or serologic markers.[87]  The AAFP guidelines concur with the USPSTF recommendation.[88]

The USPSTF did not review the effectiveness of screening individuals at high risk for pancreatic cancer.

In 2012, the International CAPS Consortium, a panel of 49 multidisciplinary experts, released consensus guidelines for pancreatic cancer screening. While also recommending against routine screening in the general population, the members recommended screening with endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) for the following high-risk groups[89] :

(In practice, however, many carriers of p16, PALB2, or BRCA2 mutations opt for screening even if they do not have a relative with the disease.)

The panel agreed that to be considered successful, screening should detect and lead to treatment of T1N0M0 margin-negative pancreatic cancer and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). However, the group did not reach consensus on the optimal management of detected lesions, the age to begin screening, or screening intervals.

Use of Tumor Markers in Pancreatic Cancer

In its 2006 update, the American Society of Clinical Oncology (ASCO) expanded the scope of the guidelines for use of tumor markers in gastrointestinal cancer to include CA 19-9 as a marker for pancreatic cancer. The recommendations for evaluation of CA 19-9 levels are as follows[44] :

Both the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines for diagnosis and treatment of pancreatic cancer recommend the measurement of serum CA 19-9 levels after surgery and before adjuvant therapy to guide treatment and follow up.[61, 2]

Diabetes Mellitus as Risk Factor 

The NCCN guideline for pancreatic adenocarcinoma acknowledges long-standing diabetes mellitus as a risk factor for pancreatic cancer. The guideline also notes an association between sudden onset of type 2 diabetes mellitus in an adult older than 50 years and a new diagnosis of pancreatic cancer. NCCN guidelines states that clinicians should consider pancreatic cancer in patients with diabetes who have unusual symptoms such as continuous weight loss and abdominal problems.[2]

Diagnosis

The European Society of Medical Oncology (ESMO) recommendations for diagnosis of pancreatic cancer include the following[61] :

The NCCN guidelines recommend that diagnostic management involve multidisciplinary consultation and be done at a high-volume center with appropriate high-quality imaging that includes specialized pancreatic CT or MRI. Additional recommendations include the following[2] :

The NCCN recommends staging laparoscopy in patients who meet any of the following criteria[2] :

The NCCN guidelines aside, staging laparoscopy may not be absolutely necessary in a patient with a borderline resectable tumor, if the treatment team plans to use neoadjuvant chemotherapy to shrink the tumor before resection.

Localized Disease Management

Defining Resectability Status

The National Comprehensive Cancer Network (NCCN) has adopted criteria for defining resectability status, which the European Society of Medical Oncology (ESMO) also recommends. For tumors to be considered localized and clearly resectable, they must demonstrate the following[2] :

Borderline resectable tumors include the following:

The American Society of Clinical Oncology (ASCO) recommends primary surgical resection of the primary tumor and regional lymph nodes for all patients meeting the following criteria[90] :

Treatment

In 2016, the American Society of Clinical Oncology released guidelines for the treatment of potentially curable pancreatic cancer which included the following key recommendations[90] :

Preoperative therapy is recommended for patients who meet any of the following criteria[90] :

After preoperative treatment, patients should be restaged before making plans for surgery.

Postoperative recommendations include the following[90] :

The European Society of Medical Oncology (ESMO) recommendations for treatment of pancreatic cancer include the following[61] :

ESMO recommendations for treatment of resectable disease are as follows[61] :

For patients with borderline resectable lesions, ESMO recommends participation in clinical trials wherever possible. Otherwise, preoperativechemotherapy (gemcitabine or FOLFIRINOX) followed by chemoradiation and then surgery appears to be the best option.

NCCN treatment guidelines concur that resection is the only potentially curative treatment for pancreatic cancer, but note that 80% of patients present with incurably advanced disease. Key recommendations for treatment of localized disease include the following[2] :

Like ESMO, NCCN recommends considering preoperative neoadjuvant therapy for patients with resectable or borderline resectable tumors, but notes that "there is limited evidence to recommend specific neoadjuvant regimens off-study, and practices vary with regard to the use of chemotherapy and radiation." NCCN recommendations on neoadjuvant therapy in pancreatic carcinoma are as follows[2] :

Neoadjuvant regimen options include the following[2] :

 

 

Locally Advanced Disease

The 2016 ASCO guidelines include the following recommendations for treatment of locally advanced, unresectable disease[91] :

On completion of treatment, patients whose disease has stabilized or who have no disease progression should have a follow-up visit every 2 to 3 months in which they undergo liver and renal function tests. They should also be tested for CA 19-9 levels and undergo CT scans at least every 3 months in the first 2 years after completion of treatment, and every 6 months if disease remains stable.[91]

Patients who do not benefit from first-line treatment recommendations and who progress despite clinicians' best efforts should be treated according to the ASCO guidelines for the treatment of metastatic pancreatic cancer.[91]

In patients with locally advanced (unresectable) tumors, ESMO recommendations are as follows[61] :

NCCN treatment guidelines include the following recommendations[2] :

Metastatic Disease and Palliative Care

The 2016 ASCO guidelines include the following recommendations for treatment of metastatic disease[92] :

ASCO found no data to establish how long cancer-directed therapy should continue or whether a third-line treatment should be used. 

For patients with advanced/metastatic disease, ESMO recommendations are as follows[61] :

NCCN treatment guidelines include the following recommendations[2] :

Palliative Care

The National Comprehensive Cancer Network (NCCN) guidelines for palliative care include the following[2] :

The European Society of Medical Oncology (ESMO) guidelines for palliative care recommend morphine as the drug of choice for pain management. Parenteral or transdermal administration may be considered for patients with swallowing impairment or gastrointestinal obstructions. For patients with poor tolerance for opioids, percutaneous celiacoplexus blockade is suggested.[61]

Nutrition and Physical Activity

The American Cancer Society (ACS) has issued guidelines for cancer prevention that focus on recommendations for individual choices regarding diet and physical activity patterns. Because individual choices are impacted by community measures that can either facilitate or create barriers to healthy behaviors, recommendations for community action are also included.

The ACS guidelines include recommendations for maintaining a healthy weight, adopting a physically active lifestyle, consuming a healthy diet, and limiting alcohol consumption.

The guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion.

The ACS guidelines include the following specific dietary recommendations for patients with pancreatic cancer[93] :

Medication Summary

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.

Gemcitabine (Gemzar)

Clinical Context:  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. It is a pyrimidine antimetabolite that nhibits DNA polymerase and ribonucleotide reductase, which in turn inhibit DNA synthesis.

Fluorouracil (Adrucil)

Clinical Context:  This is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with ribonucleic acid (RNA) synthesis and function. Fluorouracil has some effect on DNA and is useful in symptom palliation for patients with progressive disease. It is commonly used in patients with gastrointestinal malignancies. Response rates are typically less than 20% in pancreatic cancer.

Erlotinib (Tarceva)

Clinical Context:  This agent is 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. Erlotinib has been approved by the FDA for use, in combination with gemcitabine, as a first-line treatment for locally advanced, unresectable, or metastatic pancreatic cancer.

Capecitabine (Xeloda)

Clinical Context:  Capecitabine is a 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.

Paclitaxel protein bound (Abraxane)

Clinical Context:  Paclitaxel protein bound is a microtubular inhibitor (albumin-conjugated formulation) and a natural taxane that prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition. It is indicated for metastatic adenocarcinoma of the pancreas as first-line treatment in combination with gemcitabine.

Irinotecan liposomal (Onivyde)

Clinical Context:  Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Irinotecan liposomal is used in combination with fluorouracil and leucovorin for metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Olaparib (Lynparza)

Clinical Context:  Olaparib is a poly (DP-ribose) polymerase (PARP) inhibitor. PARP enzymes are involved in normal cellular function (eg, DNA transcription and repair). It is indicated for maintenance treatment of adults with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Class Summary

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

How common is pancreatic cancer?What are the signs and symptoms of pancreatic cancer?What is the role of lab testing in the diagnosis of pancreatic cancer?Which imaging studies are performed in the workup of pancreatic cancer?How is pancreatic cancer treated?Which surgical interventions are used in the treatment of pancreatic cancer?Which chemotherapy agents are used in the treatment of pancreatic cancer?Which neoadjuvant therapy regimens are used in the treatment of pancreatic cancer?What is the role of palliative therapy in the treatment of pancreatic cancer?What is the life-time risk for pancreatic cancer?What are the survival rates for pancreatic cancer?What are the types of pancreatic cancer?What is the pathophysiology of pancreatic cancer?What causes pancreatic cancer?What is the role of smoking in the etiology of pancreatic cancer?What is the role of obesity in the etiology of pancreatic cancer?What is the role of diet in the etiology of pancreatic cancer?What is the risk of diabetes mellitus (DM) in the etiology of pancreatic cancer?What is the role of chronic pancreatitis in the etiology of pancreatic cancer?What is the role of genetics in the etiology of pancreatic cancer?Which patient groups are at highest risk for pancreatic cancer?What is the incidence of pancreatic cancer in the US?What is the global incidence of pancreatic cancer?What is the racial predilection of pancreatic cancer?Which age groups have the highest prevalence of pancreatic cancer by age?What are the mortality rates for pancreatic cancer?What is the prognosis of pancreatic cancer?What is included in patient education about pancreatic cancer?Which clinical history findings are characteristic of pancreatic cancer?What are the signs and symptoms of pancreatic cancer?Which physical findings are characteristic of pancreatic cancer?In which patients should a diagnosis of pancreatic cancer be considered?How prevalent is regional spread or distant disease at diagnosis of pancreatic cancer?Which disorders should be considered in the differential diagnoses of pancreatic cancer?What are the differential diagnoses for Pancreatic Cancer?Which tests are performed in the workup of pancreatic cancer?How is chronic pancreatitis differentiated from pancreatic cancer?What is the role of lab testing in the workup of pancreatic cancer?What is the role of carbohydrate antigen 19-9 testing in the evaluation of pancreatic cancer?What is the role of carcinoembryonic antigen testing in the evaluation of pancreatic cancer?What is the role of tumor markers in the diagnosis of pancreatic cancer?What is the role of CT scanning in the workup of pancreatic cancer?What is the role of transcutaneous ultrasonography (TUS) in the workup of pancreatic cancer?What is the role of endoscopic ultrasonography (EUS) in the workup of pancreatic cancer?What is the role of endoscopic retrograde cholangiopancreatography in the workup of pancreatic cancer?What is the role of MRI in the workup of pancreatic cancer?What is the role of PET scanning in the workup of pancreatic cancer?What is the role of fine needle aspiration (FNA) in the workup of pancreatic cancer?Which morphologic characteristics are associated with pancreatic cancer?Which histologic findings are characteristic of pancreatic cancer?How are pancreatic masses characterized by surgeons?How is pancreatic cancer staged?Which imaging studies are used for staging of pancreatic cancer?What is the role of preoperative staging laparoscopy in the management of pancreatic cancer?What are the indications of staging laparoscopy in the management of pancreatic cancer?What is the evaluation and treatment algorithm for pancreatic cancer?What is the role of germline testing in the diagnosis of pancreatic cancer?What is the role of molecular profiling in the diagnosis of pancreatic cancer?How is pancreatic cancer treated?What are the NCCN guidelines for treatment selection in pancreatic cancer?What are the ESMO treatment guidelines for pancreatic cancer?What is the role of local ablation in the treatment of pancreatic cancer?What is the role of chemotherapy in the treatment of pancreatic cancer?What is the role of adjuvant therapy in the treatment of pancreatic cancer?What is the role of neoadjuvant therapy in the treatment of pancreatic cancer?What are the NCCN guidelines for neoadjuvant therapy for pancreatic cancer?What is the efficacy of neoadjuvant therapy for the treatment of pancreatic cancer?What is the role of pancreaticoduodenectomy (Whipple procedure) in the treatment of pancreatic cancer?What are the ESMO guidelines for the use of pancreaticoduodenectomy (Whipple procedure) for the treatment of pancreatic cancer?What is the role of distal pancreatectomy in the treatment of pancreatic cancer?What is the role of total pancreatectomy in the treatment of pancreatic cancer?How is pain managed in pancreatic cancer?How is jaundice treated in pancreatic cancer?How is duodenal obstruction treated in pancreatic cancer?Which dietary modifications are used in the treatment of pancreatic cancer?Which specialist consultations are beneficial to patients with pancreatic cancer?Which organizations provide guidelines on pancreatic cancer screening?What are the USPSTF and AAFP guidelines for pancreatic cancer screening?What are international CAPS consortium guidelines for pancreatic cancer screening?What are the guidelines for the use of tumor markers in pancreatic cancer?According to NCCN guidelines, when should pancreatic cancer be considered in patients with diabetes mellitus?What are the ESMO diagnostic guidelines for pancreatic cancer?What are the NCCN diagnostic guidelines for pancreatic cancer?What are the NCCN guidelines for staging laparoscopy in patients with pancreatic cancer?What are the NCCN guidelines for germline testing in patients with pancreatic cancer?What are the criteria for defining resectability status in pancreatic cancer?What are the criteria for borderline resectable tumors in pancreatic cancer?What are the ASCO recommendations for primary surgical resection in pancreatic cancer?What are ASCO treatment guidelines for potentially curable pancreatic cancer?What are the ASCO criteria for preoperative therapy of pancreatic cancer?What are the ASCO guidelines for postoperative treatment of pancreatic cancer?What are the ESMO treatment guidelines for pancreatic cancer?What are the ESMO treatment guidelines for resectable pancreatic cancer?What are the NCCN treatment guidelines for localized pancreatic cancer?What are the NCCN guidelines for neoadjuvant therapy for pancreatic cancer?What are the NCCN recommended neoadjuvant regimens for pancreatic cancer?What are the ASCO treatment guidelines for locally advanced, unresectable pancreatic cancer?What are the ESMO recommendations for treatment of locally advanced pancreatic cancer?What are the NCCN treatment guidelines for locally advanced pancreatic cancer?What are the ASCO treatment guidelines for metastatic pancreatic cancer?What are the ESMO treatment guidelines for metastatic pancreatic cancer?What are the NCCN treatment guidelines for metastatic pancreatic cancer?What are the NCCN guidelines for the palliative care in pancreatic cancer?What are the ACS guidelines for nutrition and physical activity in the treatment of pancreatic cancer?Which medications are the most active against pancreatic cancer?What is the role of olaparib in the treatment of pancreatic cancer?Which medications in the drug class Antineoplastic agents are used in the treatment of Pancreatic Cancer?

Author

Tomislav Dragovich, MD, PhD, Chief, Section of Hematology and Oncology, Banner MD Anderson Cancer Center

Disclosure: Nothing to disclose.

Coauthor(s)

Claire R Larson, MD, Resident Physician, Department of General Surgery, Scott and White Hospital, Texas A&M Health Science Center College of Medicine

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

N Joseph Espat, MD, MS, FACS, Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Lewis J Rose, MD, Clinical Associate Professor of Medical Oncology, Division of Regional Cancer Care, Kimmel Cancer Center, Thomas Jefferson University Hospital; Consulting Staff, LRCRZ Associates

Disclosure: Nothing to disclose.

Lodovico Balducci, MD, Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

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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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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. 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.

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.

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).

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.

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.

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.

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.