Practice Essentials

Pancreatic cancer is the fourth leading cause of cancer deaths, being responsible for 7% of all
cancer-related deaths in both men and 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.
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.
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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:
 Significant weight loss: Characteristic feature of pancreatic cancer
 Midepigastric pain: Common symptom of pancreatic cancer, sometimes with radiation
of the pain to the midback or lower-back region
 Often, unrelenting pain: Nighttime pain often a predominant complaint
 Onset of diabetes mellitus within the previous year
 Painless obstructive jaundice: Most characteristic sign of cancer of head of the pancreas
 Pruritus: Often the patient's most distressing symptom
 Depression
 Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis: May be the
first presentation
 Palpable gallbladder (ie, Courvoisier sign)
 Developing, advanced intra-abdominal disease: Presence of ascites, a palpable
abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein
obstruction
 Advanced disease: Paraumbilical subcutaneous metastases (or Sister Mary Joseph
nodule or nodules)
 Possible presence of palpable metastatic mass in the rectal pouch (Blumer shelf)
 Possible presence of palpable metastatic cervical nodes: Nodes may be palpable behind
the medial end of the left clavicle (Virchow node) and other areas in the cervical region
See Clinical Presentation for more detail.
Diagnosis
Pancreatic cancer is notoriously difficult to diagnose in its early stages. [93]
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:
 CBC count
 Hepatobiliary tests: Patients with obstructive jaundice show significant elevations in
bilirubin (conjugated and total), ALP, GGT, and, to a lesser extent, AST and ALT
 Serum amylase and/or lipase levels: Elevated in less than 50% of patients with
resectable pancreatic cancers and in only 25% of patients with unresectable tumors
 Tumor markers such as CA 19-9 antigen and CEA: 75-85% have elevated CA 19-9
levels; 40-45% have elevated CEA levels
Imaging studies
Imaging studies that aid in the diagnosis of pancreatic cancer include the following:
 CT scanning
 Transcutaneous ultrasonography
 Endoscopic ultrasonography
 Magnetic resonance imaging
 Endoscopic retrograde cholangiopancreatography
 Positron emission tomography scanning
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:
 Pancreaticoduodenectomy (Whipple Procedure), with/without sparing of the pylorus
 Total pancreatectomy
  Distal pancreatectomy
Chemotherapy
Antineoplastic agents and combinations of agents used in managing pancreatic carcinoma
include the following:
 Gemcitabine monotherapy: For symptomatic patients with metastatic or locally
advanced unresectable disease with poor performance status [1]
 GTX regimen (gemcitabine, docetaxel and capecitabine) [1]
 Gemcitabine and albumin-bound paclitaxel [1]
 FOLFIRINOX (LV5-FU [leucovorin/5-fluorouracil] plus oxaliplatin plus irinotecan):
National Comprehensive Cancer Network recommends as first-line treatment for
patients with metastatic or locally advanced unresectable disease with good
performance status [1, 2]
 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 [3, 4]
 5-FU
 Erlotinib plus gemcitabine
 Capecitabine monotherapy or capecitabine plus erlotinib: May provide second-line
therapy benefit in patient's refractory to gemcitabine [5]
Adjuvant therapy with gemcitabine is accepted as standard therapy for surgically resected
pancreatic cancer. [6]
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.
Palliative Therapy
Palliative therapy may be administered for the following conditions associated with
pancreatic cancer:
 Pain: Pain relief is crucial for patients not undergoing resection for pancreatic cancer;
narcotic analgesics should be used early and in adequate dosages
 Jaundice: Obstructive jaundice warrants palliation if the patient has pruritus or right
upper quadrant pain or has developed cholangitis
 Duodenal obstruction secondary to pancreatic carcinoma: Can be palliated operatively
with a gastrojejunostomy or an endoscopic procedure
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. [7] (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%. [8] (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.)
Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm
resected from the pancreatic body and tail. Although the tumor was considered to have been
fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1
year.
Pathophysiology
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
95% 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. [94] Only 5-10% are hereditary in
nature. [9]
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. [37]
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. [10] Several other studies have supported a link between early obesity and the risk of
pancreatic cancer. [11, 12]
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. [13, 14]
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. [15]
Despite early reports to the contrary, coffee consumption is not associated with an increased
risk of pancreatic cancer. [16]
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. [1]
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. [17]
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. [18]
Chronic pancreatitis from alcohol consumption is also associated a much higher incidence
and an earlier age of onset of pancreatic carcinoma. [19]
Genetic factors
Approximately 5-10% of patients with pancreatic carcinoma have some genetic
predisposition to developing the disease. [20]
The molecular genetics of pancreatic adenocarcinoma have been well studied. [21,22, 23] 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. [24]
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. [25] 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. [26]
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. [27] 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. [28, 29]
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%. [18] 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. [30] Von Hippel-Lindau syndrome has been associated with malignancy in 17% of
masses found in the pancreas in people with this syndrome. [31]
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. [32]
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%. [33]
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.[20]
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%. [20]
Race-related factors
Black males in the United States have the highest incidence rate of pancreatic cancer. [34] (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. [35] 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 2017, about 53,670 new
cases of pancreatic cancer (27,970 in men and 25,700 in women) will be diagnosed. [7] In
whites, the overall incidence rate of pancreatic cancer increased by about 1% per year from
2004 to 2013, but in blacks the rate remained stable. [8]
International incidence
Worldwide, pancreatic cancer ranks 13th in incidence but 8th as a cause of cancer death. [36]
Most other countries have incidence rates of 8-12 cases per 100,000 persons per year. In
some areas of the world, pancreatic cancer is quite infrequent; for example, the incidence in
India is less than 2 cases per 100,000 persons per year.
Race predilection
The highest incidence rate of pancreatic cancer is 16.2 cases per 100,000 persons per year, in
black males in the United States. [34] The incidence for black females in the United States was
12.4 cases per 100,000 persons per year from 2001 to 2005.
For white males in the United States from 2001 to 2005, the incidence was 12.1 cases per
100,000 persons per year, and for white females, the incidence was 9.1 cases per 100,000
persons per year. [34]
Native Hawaiian males and men of Korean, Czech, Latvian, and New Zealand Maori
ancestry also have high incidence rates: 11 cases per 100,000 persons per year.
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. [7] The death rate from the disease rose from 5 per 100,000
population in 1930 to more than 10 per 100,000 in 2003. The American Cancer Society
estimates that in the United States in 2014, about 39,590 people (20,170 men and 19,420
women) will die of pancreatic cancer.[8]
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 7%, having increased from the 3% rate as calculated between
1975 and 1977. [8] (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%.
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.[17]
For patient education information, see the Liver, Gallbladder, and Pancreas Centerand 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. [37] 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. [38] 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.

Diagnostic Considerations
Pancreatic cancer is notoriously difficult to diagnose in its early stages, when it is a protean
disease that can be difficult to distinguish from other, much more common disorders. For
example, the National Comprehensive Cancer Network (NCCN) recommends that clinicians
consider pancreatic cancer in patients with diabetes who have unusual symptoms such as
continuous weight loss and abdominal problems. [1]
Many patients have sought care for symptoms for weeks or months before receiving a
definitive diagnosis of pancreatic cancer; in the past, fewer than a third of patients were
diagnosed within 2 months of the onset of their symptoms. However, the availability of CT
scanning has shortened that interval. Even so, at the time of diagnosis, 52% of all patients
with pancreatic cancer have distant disease and 26% have regional spread.
In addition to the differentials listed in the next section, diseases that can mimic the
symptoms of pancreatic cancer include the following:
 Abdominal aortic aneurysm
  Ampullary carcinoma
 Intestinal ischemia
 Gastric lymphoma
 Pancreatic lymphoma
 Hepatocellular carcinoma (hepatoma)
 Bile duct strictures
 Bile duct tumors
 Neoplasms of the endocrine pancreas
Differential Diagnoses
 Acute Pancreatitis
 Cholangitis
 Cholecystitis
 Choledochal Cysts
 Chronic Pancreatitis
 Gallstones (Cholelithiasis)
 Gastric Cancer
 Peptic Ulcer Disease

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:
 Computed tomography (CT)
 Transcutaneous ultrasonography (TUS)
 Endoscopic ultrasonography (EUS)
 Magnetic resonance imaging (MRI)
 Endoscopic retrograde cholangiopancreatography (ERCP)
 Positron emission tomography (PET)
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:
 Accuracy for providing staging information
 Allowance for simultaneous collection of tissue samples for cytologic or histologic
confirmation of the diagnosis
 Capacity to facilitate therapeutic procedures, such as biliary stent placement or celiac
neurolysis
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. [39] 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. [39]
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. [40, 41] 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.)

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.
View Media Gallery

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).
View Media Gallery
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. [42]
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.
[1]

Other features of CT imaging include the following:

 Because of a higher rate of enhancement by the normal pancreas, malignant tumors
appear as lower-density lesions [43] ; these are often associated with obstruction of the
pancreatic duct
 When lesions are visible, CT scanning can also be used to direct fine-needle aspiration
of pancreatic masses
 Small tumors can still be missed even with the most advanced CT-scanning techniques.
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.)
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.
View Media Gallery

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.
View Media Gallery
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. [42] 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. [1]
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).
[1]

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. [44, 45]
The NCCN guidelines consider PET-CT an evolving technology; its role in the diagnosis of
pancreatic cancer is not yet established. [1]
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. [46]
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. [47]
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.[48]
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. [49] The researchers identified the following 3 morphologic characteristics as being
significantly associated with pancreatic malignancy:
 Anisonucleosis
 Single atypical epithelial cells
 Mucinous metaplasia
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. [49]
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.)
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.
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.[50]
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. [50]
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 [51] :
Tumor (T)
See the list below:
 TX - Primary tumor cannot be assessed
 T0 - No evidence of primary tumor
 Tis - Carcinoma in situ
 T1 - Tumor limited to the pancreas, 2 cm or smaller in greatest dimension
 T2 - Tumor limited to the pancreas, larger than 2 cm in greatest dimension
 T3 - Tumor extension beyond the pancreas (eg, duodenum, bile duct, portal or superior
mesenteric vein) but not involving the celiac axis or superior mesenteric artery
 T4 - Tumor involves the celiac axis or superior mesenteric arteries
Regional lymph nodes (N)
See the list below:
 NX - Regional lymph nodes cannot be assessed
 N0 - No regional lymph node metastasis
 N1 - Regional lymph node metastasis
Distant metastasis (M)
See the list below:
 MX - Distant metastasis cannot be assessed
 M0 - No distant metastasis
 M1 - Distant metastasis
Stage grouping for pancreatic cancer is as follows:
 Stage 0 - Tis, N0, M0
 Stage IA - T1, N0, M0
 Stage IB - T2, N0, M0
 Stage IIA - T3, N0, M0
 Stage IIB - T1-3, N1, M0
 Stage III - T4, Any N, M0
 Stage IV - Any T, Any N, M1
At initial presentation, only 20% of patients present with stage I disease, 40% present with
locally advanced disease, and 40% present with disease metastatic to nodes or distant sites.
To date, studies show that EUS is approximately 70-80% accurate for correctly staging
pancreatic carcinoma. EUS appears to better assess involvement of the portal vein/superior
mesenteric vein.
NCCN guidelines recommend multi-detector computed tomography (MDCT) angiography,
using a dual-phase pancreatic protocol, as the preferred modality for dedicated pancreatic
imaging. [1] 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.
 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.
View Media Gallery
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[52, 53, 54, 1] :
 CA 19-9 level >150 U/mL
 Low volume ascites
 Tumors in the body of the pancreas
 Borderline resectable tumors,
 Tumor size >3 cm
 Common bile duct lymphadenopathy
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.)

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.
View Media Gallery
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. [55] 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. [1]
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 [56] :
 Optimal symptomatic treatment has a prime role in the management of metastatic
disease; patients may require stenting or bypass surgery for obstructive jaundice or
gastric outlet obstruction
 The role of chemotherapy is limited
  Gemcitabine has been associated with a small survival benefit compared with bolus 5-
fluorouracil
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 [57] :
 Radiofrequency ablation (RFA)
 Irreversible electroporation
 Stereotactic body radiation therapy (SBRT)
 High-intensity focused ultrasound (HIFU)
 Iodine-125
 Iodine-125–cryosurgery
 Photodynamic therapy
 Microwave ablation
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. [57]
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. [58] 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. [59]
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. [60]
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. [61]
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. [3] 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-lfuorouracil [LV5-FU] plus
oxaliplatin plus irinotecan) to gemcitabine were reported in May 2011. [2] 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.[1]
Paclitaxel protein bound was approved by the FDA in September 2013 for metastatic
pancreatic cancer. [4] 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. [1] This
regimen may be considered instead of FOLFIRINOX in patients unlikely to tolerate toxicities
associated with FOLIRINOX. [3]
For patients with metastatic or locally advanced unresectable disease who have poor
performance status, the NCCN recommends gemcitabine monotherapy. [1]
Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in
patient's refractory to gemcitabine. [5] 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.[85]
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. [62, 63] 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. [64] In 2011, the NCCN panel
recommended the measurement of serum CA 19-9 levels after surgery and before adjuvant
therapy. [1]
A study by Neuhaus et al in 368 patients with resected pancreatic cancer found that adjuvant
gemcitabine prolongs survival when compared with surgery alone. [65]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. [6]
Postoperative adjuvant chemotherapy with the oral agent S-1 (Taiho Pharmaceutical)
significantly increased overall survival compared with gemcitabine in a randomized study of
385 Japanese patients with stages I-III pancreatic cancer. The 2-year survival rate for S-1 was
70%, compared with 53% for gemcitabine, and the 2-year relapse-free survival rates for S-1
and gemcitabine were 49% and 29%, respectively. [66]
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. [67, 68] 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 agrees with this recommendation. [1]
The optimal treatment plan for patients with locally advanced, unresectable pancreatic cancer
is controversial. Commonly used approaches involve chemotherapy, as for metastatic disease,
or chemoradiation.
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. [69, 70] 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. [71]
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%. [72] 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. [73] 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. [74]
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. [75]
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. [76] This was even more significant than
margin positivity. [77]
Guidelines on pancreatic cancer from the European Society for Medical Oncology include the
following treatment recommendations [56] :
 Complete surgical resection is the only potentially curative treatment available.
However, 5-yr overall survival is only 10-20%; long-term survival in node-positive
tumors is rare
 Optimal symptomatic treatment has a prime role in the management of metastatic
disease; these patients may require stenting or bypass surgery for obstructive jaundice
or gastric outlet obstruction
 The role of chemotherapy is limited; gemcitabine has been associated with a small
survival benefit compared with bolus 5-fluorouracil
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. [72]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. [78] 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. [72]
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. [79]
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:
 U.S. Preventive Services Task Force (USPSTF)
 American Academy of Family Physicians (AAFP)
 International Cancer of the Pancreas Screening (CAPS) Consortium
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. [86] The AAFP guidelines concur with the
USPSTF recommendation. [87]
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 [88] :
 Individuals with two or more blood relatives, and at least one first-degree relative, with
pancreatic cancer
 Carriers of p16, PALB2, or BRCA2 mutations with a first-degree relative with
pancreatic cancer
 All individuals with Peutz-Jeghers syndrome
 Individuals with Lynch syndrome and a first-degree relative with pancreatic cancer
(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 [39] :
 CA 19-9 is least sensitive for small, early-stage pancreatic carcinomas and thus is not
effective for the early detection of pancreatic cancer or as a screening tool
 Use of CA 19-9 levels alone is not recommended for use in determining operability
 Rising levels of CA 19-9 postoperatively may predict recurrent disease, but
confirmation with imaging studies and/or biopsy is required.
 CA 19-9 can be measured at the start of treatment for locally advanced metastatic
disease and every 1-3 months during active treatment; elevation of levels in serial
determinations may be an indication of progressive disease, but confirmation with other
studies is required
 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
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. [56, 1]
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.[1]
Diagnosis
The European Society of Medical Oncology (ESMO) recommendations for diagnosis of
pancreatic cancer include the following [56] :
 Abdominal ultrasound for the initial examination
 Endoscopic ultrasound (EUS), contrast-enhanced multi-detector computed tomography
(MD-CT) and MRI combined with magnetic resonance cholangiopancreatography
(MRCP) for additional evaluation
 Endoscopic retrograde cholangiopancreatography (ERCP) only to relieve bile duct
obstruction
 ERCP and biliary stenting should be performed only if surgery is not possible
 Positron emission tomography (PET) is not recommended for diagnosis
 Biopsy is recommended only when imaging results of a pancreatic lesion are
ambiguous; EUS-guided biopsy is preferred and percutaneous sampling should be
avoided
 Metastatic lesions can be biopsied percutaneously under ultrasound or CT guidance or
during EUS
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 [1] :
 Patients should undergo triphasic multidetector CT with thin-slice, cross-sectional
imaging; the difference in contrast enhancement is highest during the second phase, so a
triphasic approach enables a clear distinction between a hypodense lesion and the rest of
the pancreas.
 Contrast MRI is acceptable when CT is not possible, but MRI has not been shown to be
more effective or accurate in diagnosing and staging pancreatic cancer; however, MRI
can be a useful adjunct in diagnosing high-risk patients.
 PET/CT is not a substitute for high-quality contrast-enhanced CT, but may be
considered after CT to detect small metastatic deposits.
  If no mass is evident in the pancreas on CT protocol imaging, EUS is recommended
before other evaluation options.
 EUS-guided fine-needle aspiration (FNA) offers better safety and lower risk of
peritoneal seeding than CT-guided FNA
The NCCN recommends staging laparoscopy in patients who meet any of the following
criteria [1] :
 CA 19-9 level >150 U/mL
 Low-volume ascites
 Tumor in the body of the pancreas
 Borderline resectable tumor
 Tumor size >3 cm
 Common bile duct lymphadenopathy
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 [1] :
 No distant metastases
 No evidence of superior mesenteric vein (SMV) or portal vein (PV) distortion
 Clear fat planes around the celiac axis, hepatic artery and superior mesenteric artery
(SMA)
Borderline resectable tumors include the following:
 No distant metastases Involvement of the SMV or PV with distortion or narrowing or
occlusion of the vein with vessel proximal and distal, allowing for resection and
replacement
 Gastroduodenal artery encasement up to the hepatic artery, without extension to the
celiac axis.
 Tumor abutment to the SMA <180° of the circumference of the vessel wall.
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 [89] :
  No clinical evidence for metastatic disease
 Performance status and comorbidity profile that can withstand major abdominal surgery
 No radiographic interface between primary tumor and mesenteric vasculature
 CA 19-9 level suggestive of localized disease
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 [89] :
 After histopathologic confirmation of the diagnosis, a multiphase CT scan of the
abdomen and pelvis using a pancreatic protocol or MRI should be performed to gauge
the anatomic relations of the tumor to other internal structures and to evaluate patients
for the presence of intra-abdominal metastases.
 Supplemental studies may include endoscopic ultrasound, diagnostic laparoscopy, or
both.
 Performance status, symptom burden, and comorbidity profile should be carefully
evaluated at baseline, and the goals of care should be shaped by patient preferences
before arriving at a multidisciplinary treatment plan.
 Patients should be informed about any relevant clinical trials for experimental or
palliative care.
Preoperative therapy is recommended for patients who meet any of the following criteria [89] :
 Radiographic findings are suspicious but not diagnostic for extrapancreatic disease
 Poor performance status or comorbidities not conducive to major abdominal surgery if
it is thought that their status might be reversed after treatment
 A radiographic interface between the primary tumor and mesenteric vasculaturea
radiographic interface that does not meet appropriate criteria for primary resection
 CA 19-9 level (in absence of jaundice) suggestive of disseminated disease
After preoperative treatment, patients should be restaged before making plans for surgery.
Post-operative recommendations include the following [89] :
 In the absence of medical or surgical contraindications, patients who did not receive
preoperative therapy should be offered 6 months of adjuvant chemotherapy with either
gemcitabine or fluorouracil plus folinic acid initiated within 8 weeks of surgical
resection.
 Patients who have not received preoperative therapy and who have microscopically
positive margins or node-positive disease after 4 to 6 months of adjuvant chemotherapy
should be offered adjuvant chemoradiation.
  For patients who underwent peroperative therapy, although evidence supporting the
duration of post-operative therapy is weak, the panel recommends that patients receive a
total of 6 months of adjuvant therapy, including time spent on the preoperative regimen.
 Adjuvant combination chemotherapy regimens are not recommended outside of a
clinical trial.
 Patients should receive ongoing supportive care for symptom burden that may result
from the operation and (preoperative and/or adjuvant) chemotherapy
 Patients who have completed treatment and have no evidence of disease should be
monitored for recovery of treatment-related toxicities and recurrence. Visits may be
offered at 3- to 6-month intervals but the role of serial cross-sectional imaging, the
extent to which surveillance intervals should be prolonged over time, and the duration
of recommended surveillance are all undefined
The European Society of Medical Oncology (ESMO) recommendations for treatment of
pancreatic cancer include the following [56] :
 Radical surgery is the only curative treatment and is mainly suitable for patients with
stage I and some patients with stage II
 In elderly patients (>75 years old), comorbidity can be a reason to abstain from
resection; the risk of perioperative mortality in patients undergoing pancreatic resection
can be estimated using a surgical outcomes analysis and research (SOAR)
pancreatectomy score
ESMO recommendations for treatment of resectable disease are as follows [56] :
 Pancreatoduodenectomy (Whipple procedure) is the treatment of choice for tumors of
the pancreatic head
 For tumors in the body or tail of the pancreas, distal pancreatectomy, including the
resection of the body and the tail of the pancreas and the spleen, is usually performed
 No evidence exists that extended lymphadenectomy is beneficial; standard
lymphadenectomy should involve the removal of ≥15 lymph nodes to allow adequate
pathologic staging
 Postoperative gemcitabine or 5-fluorouracil (5-FU) chemotherapy is recommended
 No chemoradiation should be given to patients after surgery except in clinical trials
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 [1] :
 Decisions about treatment and resectability should involve input from a
multidisciplinary group of specialists.
  Selection of patients for surgery should be based on the probability of cure, as
determined by resection margins; other factors include comorbidities, overall
performance status, and age.
 Postoperative adjuvant therapy improves outcomes but no definite standard has been
set. Options for patients who did not receive preoperative neoadjuvant therapy include
clinical trials (preferred), chemotherapy, or chemoradiation. When chemotherapy alone
is chosen, gemcitabine is preferred over 5-FU/leucovorin; capecitabine should only be
considered when other options are contraindicated.
 For patients who received neoadjuvant therapy, post-operative therapy options are
dependant on response to neoadjuvant therapy and other clinical considerations.
Like ESMO, NCCN recommends considering preoperative neoadjuvant thereapy for patients
with borderline resectable tumors. However, no form of neoadjuvant therapy in pancreatic
carcinoma should be regarded as standard; this remains an area for clinical trial study. [1]

Locally Advanced Disease

The 2016 ASCO guidelines include the following recommendations for treatment of locally
advanced, unresectable disease [90] :
 Multiphase CT scans to assess disease extent in the chest, abdomen, and pelvis. Other
staging studies should be performed only as dictated by symptoms
 Patients should also be assessed for baseline performance status, symptom burden, and
comorbidities, and clinicians again need to discuss the goals of treatment in
collaboration with a multidisciplinary team shaped by patient preferences.
 Patients should be informed about any relevant clinical trials for which they might be
eligible.
 Initial treatment should include some form of combination regimen for individuals who
have a performance status of 0 or 1, who have a favorable comorbidity profile, and who
want to and are able to undergo an aggressive medical regimen.
 There is no clear evidence to support one regimen over another and therapy may be
offered on the basis of extrapolation from data derived from studies in the metastatic
setting.
 Chemoradiotherapy (CRT) or stereotactic body radiotherapy (SBRT) may be offered to
patients with local progression but no metastases, provided they have a performance
status of 2 or less and a favorable comorbidity profile.
 CRT or SBRT may be offered to patients who have responded to an initial 6 months of
chemotherapy or have stable disease, have developed unacceptable chemotherapy-
related toxicities, or have a decline in performance status as a consequences of
chemotherapy toxicity
 If patients respond or their disease has at least stabilized after 6 months of induction
chemotherapy, CRT or SBRT may be offered as an alternative to continuing
chemotherapy alone
  SBRT may be offered even though evidence supporting SBRT is not robust.
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. [90]
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. [90]
In patients with locally advanced (unresectable) tumors, ESMO recommendations are as
follows [56] :
 The standard of care is 6 months of gemcitabine
 Chemoradiation may have a minor role, but no regimen other than the combination of
capecitabine and radiotherapy can be recommended
NCCN treatment guidelines include the following recommendations [1] :
 FOLFIRINOX or gemcitabine plus nab-paclitaxel is a first-line treatment for patients
who have good performance status
 Gemcitabine monotherapy, or palliative therapy and best supportive care, is
recommended for locally advanced unresectable disease in symptomatic patients with
poor performance status
Metastatic Disease and Palliative Care
The 2016 ASCO guidelines include the following recommendations for treatment of
metastatic disease [91] :
 First-line treatment for metastatic pancreatic cancer is the FOLFIRINOX regimen
consisting of leucovorin, fluorouracil, irinotecan, and oxaliplatin.
 The FOLFIRINOX regimen can be offered to anyone with a performance status of 0 or
1 and a favorable comorbidity profile who wants to and is able to withstand an
aggressive medical regimen. Alternatively, patients can be treated with gemcitabine
plus nanoparticle albumin-bound (NAB)-paclitaxel.
 For those with more advanced disease (performance status, 2) or who cannot tolerate a
more aggressive regimen but who still wish to received cancer-directed therapy,
gemcitabine can be given alone or together with either capecitabine or erlotinib.
 For patients with a performance status 3 or more with poorly controlled comorbid
conditions despite ongoing active medical care, r emphasis should be on optimizing
supportive care measures
 For patients who experience either disease progression on first-line therapy or
intolerable toxicity, gemcitabine plus NAB-paclitaxel may be used as second-line
therapy,
  If patients received gemcitabine plus NAB-paclitaxel as first-line treatment, fluorouracil
plus oxaliplatin, irinotecan, or nanoliposomal irinotecan can be given as second-line
therapy, provided patients want and can tolerate aggressive medical treatment
 For those who cannot tolerate aggressive therapy, clinicians can offer either
gemcitabine or fluorouracil as a second-line option.
 If patients are on cancer-directed therapy, they should undergo CT scan to assess first
response to treatment 2 to 3 months after treatment initiation.
 Patients should be offered aggressive treatment to control pain and other symptoms
related to the cancer or the treatment
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 [56] :
 For biliary stenting, the endoscopic method is safer than percutaneous insertion and is
as successful as surgical hepatojejunostomy
 Pain control is mandatory and frequently requires consultation with a pain specialist
 In patients with Eastern Cooperative Oncology Group (ECOG) performance status 3/4,
with significant morbidities and a very short life expectancy, only symptomatic
treatment can be considered
 In very selected patients with performance status 2 due to heavy tumor load,
gemcitabine and nab-paclitaxel can be considered for best chance of response
 In patients with performance status 2 and/or bilirubin level higher than 1.5 times the
upper limit of normal, monotherapy with gemcitabine should be considered
 In patients with performance status 0 or 1 and bilirubin level less than 1.5 times the
upper limit of normal, combination chemotherapy with either FOLFIRINOX or the
combination of gemcitabine and nab-paclitaxel should be considered
 The efficacy of treatment has to be evaluated every 2 months with a comparative CT
scan
NCCN treatment guidelines include the following recommendations [1] :
 Decisions about treatment and resectability should involve input from a
multidisciplinary group of specialists
 Selection of patients for surgery should be based on the probability of cure, as
determined by resection margins; other factors include comorbidities, overall
performance status, and age
 FOLFIRINOX or gemcitabine plus nab-paclitaxel is recommended as a first-line
treatment for patients with metastatic or locally advanced unresectable disease who
have good performance status
  Gemcitabine monotherapy, or palliative therapy and best supportive care, is
recommended for metastatic or locally advanced unresectable disease in symptomatic
patients with poor performance status
No form of neoadjuvant therapy in pancreatic carcinoma should be regarded as standard; this
remains an area for clinical trial study.
Palliative Care
The National Comprehensive Cancer Network (NCCN) guidelines for palliative care include
the following [1] :
 Endoscopic biliary metal stent is preferred for biliary obstruction
 Enteral stent for gastric outlet obstruction
 Consider radiation therapy with or without chemotherapy to palliate pain
 Pancreatic enzyme replacement for pancreatic insufficiency
 Low-molecular-weight heparin is preferred over warfarin for management of
thromboembolic disease
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. [56]
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 [92] :
 Supplementation with omega-3 fatty acids
 Pancreatic enzyme replacement therapy, along with diet modification, to manage
disease symptoms and treatment side effects
 Consultation and close follow-up with a registered dietitian for an individualized dietary
prescription