Pancreatic Cancer Medscape

1/19/2020 https://emedicine.medscape.
com/article/280605-print
emedicine.medscape.com
Pancreatic Cancer
Updated: Jan 10, 2020
Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS
Overview
Practice Essentials
Pancreatic cancer is the tenth most common cancer in men and the ninth most common in women, but it is the fourth leading
cause of cancer deaths, being responsible for 8% of all cancer-related deaths. 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.
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
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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 Presentation for more detail.
Diagnosis
Pancreatic cancer is notoriously difficult to diagnose in its early stages.[1]
Testing
The laboratory findings in patients with pancreatic cancer are usually nonspecific. Patients with advanced pancreatic cancers
and weight loss may have general laboratory evidence of malnutrition (eg, low serum albumin or cholesterol level).
Potentially useful tests in patients with suspected pancreatic cancer include the following:
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[2]
GTX regimen (gemcitabine, docetaxel, capecitabine)[2]
Gemcitabine and albumin-bound paclitaxel[2]

FOLFIRINOX (LV5-FU [leucovorin/5-fluorouracil] plus oxaliplatin plus irinotecan): the National Comprehensive Cancer
Network (NCCN) recommends this as first-line treatment for patients with metastatic or locally advanced unresectable
disease with good performance status[2, 3]
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[4, 5]
5-FU
Erlotinib plus gemcitabine
Capecitabine monotherapy or capecitabine plus erlotinib: May provide second-line therapy benefit in patient's refractory
to gemcitabine[6]
Adjuvant therapy with gemcitabine is accepted as standard therapy for surgically resected pancreatic cancer.[7] However, a
study demonstrating markedly superior survival with modified FOLFIRINOX compared with gemcitabine in this setting promises
to be practice changing.[8, 9] On the basis of this study, NCCN guidelines added modified FOLFIRINOX as a category 1,
preferred adjuvant therapy regimen for patients with good performance status.[2]
Neoadjuvant therapy
The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy, but increasing
evidence supports its use in patients with resectable disease. Neoadjuvant regimen options include the following[2] :
FOLFIRINOX/modified FOLFIRINOX, with or without subsequent chemoradiation

Gemcitabine + albumin-bound paclitaxel, with or without subsequent chemoradiation
Gemcitabine + cisplatin (2–6 cycles) followed by chemoradiation (only for known BRCA1/2 mutations)
Maintenance therapy
Olaparib is approved for maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated
metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based
chemotherapy regimen.
.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.[10] (See Epidemiology.)
Pancreatic cancer is notoriously difficult to diagnose in its early stages. At the time of diagnosis, 52% of all patients have distant
disease and 26% have regional spread. The relative 1-year survival rate for pancreatic cancer is only 28%, and the overall 5-
year survival is 7%.[11] (See Prognosis and Workup.)
Types of pancreatic cancer
Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of the exocrine pancreas are
benign. (See Etiology and Histologic Findings.)
Less common histologic appearances of exocrine pancreatic cancers include giant cell carcinoma, adenosquamous carcinoma,
microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar
cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary connective tissue cancers of the pancreas can
occur. The most common of these is primary pancreatic lymphoma.
An adenocarcinoma of the pancreas is seen below. (See Histologic Findings.)
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 93% of them develop from the
exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Approximately 75% of all
pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% occur in the body of the pancreas, and 5-10%
occur in the tail.
Tobacco smoking is the most common recognized risk factors for pancreatic cancer. Others include obesity, high alcohol
consumption, history of pancreatitis and diabetes, family history of pancreatic cancer, and possibly selected dietary factors.[12]
Only 5-10% are hereditary in nature.[13]
Because excess risk for pancreatic cancer is greater in patients recently diagnosed with diabetes mellitus, it has been
suggested that diabetes may be at least in part a consequence or an early manifestation of pancreatic cancer. However, the
International Pancreatic Cancer Case-Control Consortium reported that a 30% excess risk for pancreatic cancer persists for
more than 2 decades after diabetes diagnosis, which supports the hypothesis that diabetes has a causal role in pancreatic
cancer.[14]
Less than 5% of all pancreatic cancers are related to underlying chronic pancreatitis. Alcohol consumption does not appear to
be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis.
The risk factors for pancreatic cancer are discussed in more detail below.
Smoking
Smoking is the most common environmental risk factor for pancreatic carcinoma. Estimates indicate that smoking accounts for
up to 30% of cases of pancreatic cancer.
People who smoke have at least a 2-fold greater risk for pancreatic cancer than do nonsmokers. Current smokers with over a 40
pack-year history of smoking may have up to a 5-fold risk greater risk for the disease. Smokeless tobacco also increases the
risk of pancreatic cancer.
It takes 5-10 years of discontinued smoking to reduce the increased risk of smoking to approximately that of nonsmokers.
Obesity and dietary factors
In a number of studies, obesity, especially central, has been associated with a higher incidence of pancreatic cancer. For
example, Li et al found that being overweight or obese during early adulthood was associated with a greater risk of pancreatic
cancer and a younger age of disease onset, while obesity at an older age was associated with lower overall survival.[15]
Several other studies have supported a link between early obesity and the risk of pancreatic cancer.[16, 17]
The incidence of pancreatic cancer is lower in persons with a diet rich in fresh fruits and vegetables. Fruits and vegetables rich
in folate and lycopenes (such as tomatoes) may be especially good at reducing the risk of pancreatic cancer.[18, 19]
Consumption of red meat, especially of the processed kinds, is associated with a higher risk of pancreatic cancer. Poultry and
dairy product consumption does not increase the risk of this disease.[20]
Despite early reports to the contrary, coffee consumption is not associated with an increased risk of pancreatic cancer.[21]
Diabetes mellitus
Numerous studies have examined the relative risk of pancreatic cancer in persons with diabetes mellitus. A systematic review of
30 studies concluded that patients with diabetes mellitus of at least 5-years' duration have a 2-fold increased risk of developing
pancreatic carcinoma. Pancreatic cancer may follow 18-36 months after a diagnosis of diabetes mellitus in elderly patients with
no family history of diabetes mellitus.
The National Comprehensive Cancer Network (NCCN) acknowledges long-standing diabetes mellitus as a risk factor for
pancreatic cancer. The NCCN also notes an association between sudden onset of type II diabetes mellitus in an adult older than
50 years and a new diagnosis of pancreatic cancer, although in those cases the diabetes is thought to be caused by the cancer.
[2]
Chronic pancreatitis
Long-standing, chronic pancreatitis is a substantial risk factor for the development of pancreatic cancer. A multicenter study of
more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer. This
risk increased linearly with time, with 4% of patients who had chronic pancreatitis for 20 years' duration developing pancreatic
cancer.[22]
The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. The mean age of development of pancreatic
cancer in these patients is approximately 57 years. The relative risk of pancreatic cancer in hereditary pancreatitis is increased
more than 50-fold, and the cumulative risk rate of pancreatic cancer by age 70 years is 40%.
This cumulative risk increases to 75% in persons whose family has a paternal inheritance pattern.[23]
Chronic pancreatitis from alcohol consumption is also associated a much higher incidence and an earlier age of onset of
pancreatic carcinoma.[24]
Genetic factors
Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease.[25]
The molecular genetics of pancreatic adenocarcinoma have been well studied.[26, 27, 28] Of these tumors, 80-95% have
mutations in the KRAS2 gene; 85-98% have mutations, deletions, or hypermethylation in the CDKN2 gene; 50% have mutations
in p53; and about 55% have homozygous deletions or mutations in Smad4. Some of these mutations can also be found in high-
risk precursors of pancreatic cancer. For example, in chronic pancreatitis, 30% of patients have detectable mutations in p16 and
10% have K-ras mutations.
Families with BRCA-2 mutations, which are associated with a high risk of breast cancer, also have an excess of pancreatic
cancer.[29]
Assaying pancreatic juice for the genetic mutations associated with pancreatic adenocarcinoma is invasive, but it may be useful
for the early diagnosis of the disease.[30] However, this approach is problematic, because genetic mutations in the pancreatic
juice may be found in patients with inflammatory pancreatic disease.
Certain precursor lesions have been associated with pancreatic tumors arising from the ductal epithelium of the pancreas. The
main morphologic form associated with ductal adenocarcinoma of the pancreas is pancreatic intraepithelial neoplasia (PIN).
These lesions arise from specific genetic mutations and cellular alterations that contribute to the development of invasive ductal
adenocarcinoma.[31]
The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening. Thereafter, p16/CDKN2A is
inactivated. Finally, the inactivation of TP53 and MAD4/DPC4 occur. These mutations have been correlated with increasing
development of dysplasia and thus with the development of ductal carcinoma of the exocrine pancreas.
Based on more recent data from sequencing of human tumors, pancreatic cancer is a genetically complex and heterogeneous
disease.[32] This is confounded by considerable variability in terms of the genetic malformations and pathways involved
between individual tumors. In addition, the long time from early to clinically manifested disease (21.2 y on average) allows for an
accumulation of complex genetic changes, which probably explains the fact that it is often resistant to chemotherapy and
radiation therapy.[33, 34]
The inherited disorders that increase the risk of pancreatic cancer include hereditary pancreatitis, multiple endocrine neoplasia
(MEN), hereditary nonpolyposis rectal cancer (HNPCC), familial adenomatous polyposis (FAP) and Gardner syndrome, familial
atypical multiple mole melanoma (FAMMM) syndrome, von Hippel-Lindau syndrome (VHL), and germline mutations in the
BRCA1 and BRCA2 genes.
Hereditary pancreatitis has been associated with a 40% cumulative risk of developing pancreatic cancer at 40%.[23] MEN-1 and
VHL are other genetic syndromes associated with pancreatic endocrine tumor development.
Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the time, and these pancreatic tumors are
noted to be the leading cause of disease-specific mortality.[35] Von Hippel-Lindau syndrome has been associated with
malignancy in 17% of masses found in the pancreas in people with this syndrome.[36]
Syndromes associated with an increased risk of the development of colon cancer, such as HNPCC and FAP (and Gardner
syndrome), have also shown an increased correlation with existence of pancreatic cancer, but the statistics have not been
impressive.
In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma. No statistics are available to show
the incidence of pancreatic cancer in patients with HNPCC.[37]
FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and the incidence in
sporadic cases to be 98%.[38]
The above disorders have specific genetic abnormalities associated with the noted increased risk of pancreatic cancer.
Pancreatic cancer in hereditary pancreatitis is associated with a mutation in the PRSS1 gene. Pancreatic cancer appearing in
FAP and HNPCC has been associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively. FAMMM and
pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine tumors of the pancreas associated with VHL are
thought to develop by way of the inactivation of the VHL tumor suppressor gene.[25]
Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the risk of developing pancreatic cancer by
2.3- to 3.6-fold, but BRCA2 has been associated more commonly with pancreatic cancer, at an incidence of 7%.[25]
Race-related factors
Black males in the United States have the highest incidence rate of pancreatic cancer.[39] (See Epidemiology, below.) The
reasons for the higher incidence of pancreatic cancer in African Americans are unclear. Certainly, differences in risk factors for
pancreatic cancer, such as dietary habits, obesity, and the frequency of cigarette smoking, are recognized among different
population groups and may contribute to the higher incidence of this disease among blacks.
However, Arnold et al found that excess pancreatic cancer in blacks cannot be attributed to currently known risk factors,
suggesting that as-yet undetermined factors play a role in the disease process.[40] One possibility is a difference in the
underlying frequency of predisposing genetic mutations for pancreatic cancer.
Epidemiology
Incidence in the United States
The American Cancer Society estimates that in the United States in 2020, about 57,600 new cases of pancreatic cancer (30,400
in men and 27,200 in women) will be diagnosed. The overall incidence rate of pancreatic cancer increased by 0.7% per year in
whites and 0.3% per year in blacks from 2007 to 2016.[11]
International incidence
Worldwide, pancreatic cancer ranks 11th in incidence but 7th as a cause of cancer death.[41] The age-standardized rate (ASR)
incidence ranges widely, from 7.7 per 100,000 population in Europe to 2.2 per 100,000 population in Africa. Among individual
countries, ASRs range from 0.81 per 100,000 in males in India to 15.3 per 100,000 in males in Latvia and the Republic of
Moldova.[41]
Race predilection
From 2011 to 2015, the highest incidence rate of pancreatic cancer in the United States was 16.9 cases per 100,000 persons
per year, in black men. The incidences in men in other racial/ethnic groups were as follows[10] :
Non-Hispanic: 14.7
White: 14.4
Hispanic: 12.0
American Indian/Alaska Native: 11.3
Asian/Pacific Islander: 11.0
The incidences in US women during that period were as follows[10] :
Black: 14.3
Non-Hispanic: 11.3
White: 11.1
Hispanic: 10.5
Asian/Pacific Islander: 9.2
American Indian/Alaska Native: 7.8
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 8% of all cancer-related deaths.The American Cancer Society estimates
that in the United States in 2020, about 47,050 people (24,640 men and 22,410 women) will die of pancreatic cancer. During
2008 to 2017, the death rate for pancreatic cancer increased slightly (by 0.4% per year) in whites and decreased slightly (by
0.5% per year) in blacks.[11]
Prognosis
Pancreatic carcinoma is unfortunately usually a fatal disease. The collective median survival time for all patients is 4-6 months.
The relative 1-year survival rate for patients with pancreatic cancer is only 28%, and the overall 5-year survival rate is 9%,
having increased from 3% between 1975 and 1977.[10] By stage, 5-year relative survival is 34.3% for localized disease, 11.5%
for regional disease, and 2.7% for distant disease.[10] At the time of diagnosis, 52% of patients have distant disease.[11]
(However, patients with neuroendocrine and cystic neoplasms of the pancreas, such as mucinous cystadenocarcinomas or
intraductal papillary mucinous neoplasms [IPMN], have much better survival rates than do patients with pancreatic
adenocarcinoma).
A 5-year survival in pancreatic cancer is no guarantee of cure; patients who survive for 5 years after successful surgery may still
die of recurrent disease years after the 5-year survival point. The occasional patient with metastatic disease or locally advanced
disease who survives beyond 2-3 years may die of complications of local spread, such as bleeding esophageal varices.
In patients able to undergo a successful curative resection (about 20% of patients), median survival time ranges from 12-19
months, and the 5-year survival rate is 15-20%. The best predictors of long-term survival after surgery are a tumor diameter of
less than 3 cm, no nodal involvement, negative resection margins, and diploid tumor deoxyribonucleic acid (DNA) content.
The median survival for patients who undergo successful resection (only 20% of patients) is approximately 12-19 months, with a
5-year survival rate of 15-20%.
Tingle et al reported that in patients with unresectable pancreatic ductal adenocarcinoma, the combination of the neutrophil-
albumin ratio (NAR) and the Ca19-9 level allows stratification into three groups with significantly different overall survival, as
follows[42] :
NAR ≤ 0.13 and Ca19-9 ≤ 770 U/mL - Median survival 20.5 months

NAR > 0.13 or Ca19-9 >770 - Median survival 9.7 months
NAR > 0.13 and Ca19-9 > 770 - Median survival 4.1 months
Patient Education
Smoking is the most significant reversible risk factor for pancreatic cancer.
Alcohol consumption does not increase the risk of pancreatic cancer unless it leads to chronic pancreatitis. A multicenter study
of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer.[22]
For patient education information, see the Pancreatic Cancer Health Center.
Presentation
History
The early clinical diagnosis of pancreatic cancer is fraught with difficulty. Unfortunately, the initial symptoms of the disease are
often quite nonspecific and subtle in onset. Consequently, these symptoms can be easily attributed to other processes unless
the physician has a high index of suspicion for the possibility of underlying pancreatic carcinoma.
Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise, nausea, fatigue, and
midepigastric or back pain.
Significant weight loss is a characteristic feature of pancreatic cancer.
Midepigastric pain is a common symptom of pancreatic cancer, with radiation of the pain to the midback or lower-back region
sometimes occurring. Radiation of the pain to the back is worrisome, as it indicates retroperitoneal invasion of the splanchnic
nerve plexus by the tumor.
Often, the pain is unrelenting in nature, with nighttime pain often being a predominant complaint. Some patients may note
increased discomfort after eating. The pain may be worse when the patient is lying flat.
Weight loss may be related to cancer-associated anorexia and/or subclinical malabsorption from pancreatic exocrine
insufficiency caused by pancreatic duct obstruction by the cancer. Patients with malabsorption usually complain about diarrhea
and malodorous, greasy stools. Nausea and early satiety from gastric outlet obstruction and delayed gastric emptying from the
tumor may also contribute to weight loss.
The onset of diabetes mellitus within the previous year is sometimes associated with pancreatic carcinoma. Even so, only about
1% of cases of new-onset diabetes mellitus in adults are related to occult pancreatic cancer.[14] Nevertheless, pancreatic
cancer should be at least thought of in a patient older than 70 years with a new diagnosis of diabetes and without any other
diabetic risk factors.
The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless obstructive jaundice. Patients with
this sign may come to medical attention before their tumor grows large enough to cause abdominal pain. These patients usually
notice a darkening of their urine and lightening of their stools before they or their families notice the change in skin pigmentation.
Physicians can usually recognize clinical jaundice when the total bilirubin reaches 2.5-3 mg%. Patients and their families do not
usually notice clinical jaundice until the total bilirubin reaches 6-8 mg%. Urine darkening, stool changes, and pruritus are often
noticed by patients before clinical jaundice.
Pruritus may accompany and often precedes clinical obstructive jaundice. Pruritus can often be the patient's most distressing
symptom.
Depression is reported to be more common in patients with pancreatic cancer than in patients with other abdominal tumors. In
some patients, depression may be the most prominent presenting symptom. This may in part be secondary to the high
frequency of delayed diagnosis with this disease. In addition, although patients may not communicate it to their families, they
are often aware that a serious illness of some kind is occurring in them.
A study by Turaga et al determined that male patients with pancreatic adenocarcinoma have a risk of suicide that is almost 11
times higher than the remainder of the population.[43] Patients who undergo surgery are more likely to commit suicide,
specifically in the early postoperative period.
Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis also occur with higher frequency in patients with
pancreatic cancer and may be the first presentation. Marantic endocarditis may develop in pancreatic cancer, occasionally being
confused with subacute bacterial endocarditis.
Physical Examination
Pain is the most common presenting symptom in patients with pancreatic cancer. As previously mentioned, the pain typically
takes the form of mild to moderate midepigastric tenderness. In some cases, radiation of the pain to the midback or lower-back
region occurs. Such radiation is worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve plexus by the tumor.
However, at the time of initial presentation, about one third of patients may not have pain, one third have moderate pain, and
one third have severe pain. All patients experience pain at some point in their clinical course.
Patients with clinical jaundice may also have a palpable gallbladder (ie, Courvoisier sign) and may have skin excoriations from
unrelenting pruritus.
Patients presenting with or developing advanced intra-abdominal disease may have ascites, a palpable abdominal mass,
hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction.
Subcutaneous metastases (referred to as a Sister Mary Joseph nodule or nodules) in the paraumbilical area signify advanced
disease.
A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer's shelf).
A metastatic node may be palpable behind the medial end of the left clavicle (Virchow's node). However, other nodes in the
cervical area may also be involved. Indeed, prior to the advent of computed tomography (CT) scanners to assess intra-
abdominal disease, pancreatic cancer accounted for some 25% of adenocarcinomas of the cervical nodes, primary site
unknown.
DDx
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.[2]
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
Workup
Workup
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.[44] It
is also normally present within the cells of the biliary tract and can be elevated in acute or chronic biliary disease. Some 5-10%
of patients lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of CA 19-9, monitoring
disease with this tumor marker will not be possible.
The reference range of CA 19-9 is less than 33-37 U/mL in most laboratories. Of patients with pancreatic carcinoma, 75-85%
have elevated CA 19-9 levels. In the absence of biliary obstruction, intrinsic liver disease, or benign pancreatic disease, a CA
19-9 value of greater than 100 U/mL is highly specific for malignancy, usually pancreatic.
Evaluation of CA 19-9 levels has been used as an adjunct to imaging studies for helping to determine the resectability potential
of pancreatic carcinoma. Fewer than 4% of patients with a CA 19-9 level of more than 300 U/mL have been found to have
resectable tumors.
Unfortunately, CA 19-9 is least sensitive for small, early stage pancreatic carcinomas and thus has not proven to be effective for
the early detection of pancreatic cancer or as a screening tool.[44]
An elevated CA 19-9 level is found in 0.2% of an asymptomatic population older than 40 years. Of these elevations, 80% are
false-positive results. If only symptomatic patients are studied, 4.3% have elevated CA 19-9 levels. Two thirds of these results
are false positive.
Although no standardized role has been set for CA 19-9 in the diagnosis of pancreatic carcinoma, it has growing importance in
the staging and follow-up of patients with this disease. Patients presenting with low levels of CA 19-9 (< 100 IU) are unlikely to
have occult metastatic disease and therefore may not need a staging laparoscopy prior to resection if other imaging shows no
advanced disease.
Additionally, during surgical, chemotherapeutic, and/or radiotherapeutic treatment for pancreatic cancer, a falling CA 19-9 seems
to be a useful surrogate finding for clinical response to the therapy. If biliary obstruction is not present, a rising CA 19-9 suggests
progressive disease.
Preoperative CA 19-9 levels may be of prognostic value, with high levels indicating poorer outcome and less chance of
resectability.[45, 46] Preoperative values above 50 U/mL have been shown to be associated with higher chances of recurrence.
Carcinoembryonic antigen
Carcinoembryonic antigen (CEA) is a high–molecular weight glycoprotein found normally in fetal tissues. The reference range is
2.5 mg/mL or less. CEA has commonly been used as a tumor marker in other gastrointestinal malignancies, but only 40-45% of
patients with pancreatic carcinoma have elevated CEA levels. In addition, benign and malignant conditions other than
pancreatic cancer can lead to elevated CEA levels. Thus, 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.
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).
The quality of CT scanners has been rapidly evolving. The speed of image acquisition, 3D imaging, and slices as thin as 2-3
mm have revolutionized the technology.
Newer scanner models, using spiral (ie, helical) CT scanning with multiple detectors and dual or triple-phase contrast
enhancement, have significantly improved the sensitivity and specificity of abdominal CT-scan findings in patients with
pancreatic carcinoma.
Multidetector CT scanning (MDCT) using a pancreas protocol is at least as accurate as EUS in the overall determination of the
resectability of pancreatic carcinoma. In fact, CT scanning may be more accurate than EUS in predicting involvement of the
superior mesenteric artery.[47]
National Comprehensive Cancer Network (NCCN) guidelines recommend MDCT angiography as the preferred imaging tool for
dedicated pancreatic imaging. Thin (preferably sub-millimeter) axial sections should be acquired using a dual-phase pancreatic
protocol, with images obtained in the pancreatic and portal venous phase of contrast enhancement. Coverage may be extended
to cover the chest and pelvis for complete staging, depending on institutional preferences.[2]
Other features of CT imaging include the following:
Because of a higher rate of enhancement by the normal pancreas, malignant tumors appear as lower-density lesions [48]
; 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.
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.
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.
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.
Additionally, because of the proximity of the pancreas to the EUS transducer, high-frequency ultrasonography (7.5-12 MHz) can
be used to produce very high-resolution (submillimeter) images. Where expert EUS is available, it has proven to be the most
sensitive and specific diagnostic test for pancreatic cancer. A negative endoscopic ultrasonogram is nearly 100% specific at
ruling out the presence of a pancreatic neoplasm.
In numerous series, EUS has been found to have detection rates of 99-100% for all pancreatic carcinomas, including those
smaller than 3 cm. EUS is as accurate as ERCP or MRCP for assessing the etiology of obstructive jaundice.
An additional significant diagnostic advantage is EUS-guided fine-needle aspiration, which allows for the simultaneous cytologic
confirmation of pancreatic carcinoma at the time of EUS diagnosis.
EUS appears to be equivalent to dual-phase, spiral CT scanning for assessing tumor-resectability potential. It is probably
superior to CT scanning as a means of assessing the T stage of the tumor, especially when the clinician is looking for portal vein
involvement in pancreatic head lesions.
EUS is probably inferior to CT scanning in assessing arterial involvement and distant metastases.[47] EUS and CT scanning are
poor at detecting occult nodal involvement.
On the whole, the NCCN guidelines recommend EUS as complementary to CT. However, if no mass is evident in the pancreas
on CT protocol imaging, the NCCN recommends EUS before other evaluation options. EUS is also valuable if there is possible
involvement of blood vessels or lymph nodes.[2]
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.
Magnetic Resonance Imaging

Interest in using MRI for abdominal imaging continues to grow. The role of MRI in pancreatic cancer has been less well studied
than has the role of CT scanning, although the modality does not appear to be superior to spiral CT scanning. Dynamic,
gadolinium-enhanced, 3D, gradient-echo MRI may offer enhanced sensitivity in the detection of small pancreatic lesions.
However, in patients with jaundice, MRCP can be used as a noninvasive method for imaging the biliary tree and pancreatic duct.
Whether MRCP is as sensitive and specific for pancreaticobiliary pathology as other procedures is still being investigated.
Because of the difficulty of working within intense magnetic fields, MRI is limited in performing MRI-directed needle aspirations;
however, this technology is undergoing rapid change.
The NCCN notes that MRI is most often used as a problem-solving tool, particularly for characterization of liver lesions that are
indeterminate on CT; when pancreatic tumors are suspected, but are not visible on CT; or when contrast-enhanced CT cannot
be obtained (eg, because of severe allergy to iodinated intravenous contrast material).
[2]
PET Scanning
PET scanning uses 18F-fluorodeoxyglucose (FDG) to image the primary tumor and metastatic disease.
PET scanning appears to be especially useful in detecting occult metastatic disease. Its role in pancreatic cancer evaluation
management is still under investigation. False-positive PET scans have been reported in pancreatitis.
By itself, PET scanning does not seem to offer additional benefits to high-quality CT scanning. However, studies in which PET
scanning was combined with simultaneous CT scanning (PET-CT) suggested that PET-CT scanning is more sensitive than
conventional imaging for the detection of pancreatic cancer and that PET-CT–scan findings sometimes change clinical
management.[49, 50]
The NCCN guidelines consider PET-CT an evolving technology; its role in the diagnosis of pancreatic cancer is not yet
established.[2]
Needle Aspiration
The necessity of obtaining a cytologic or tissue diagnosis of pancreatic cancer prior to surgery remains controversial and is
highly dependent on the institution.[51]
Arguments in favor of preoperative biopsy include its ability to provide proof of pathology prior to surgery, exclude unusual
pathology, and provide evidence of disease before the initiation of multidisciplinary treatment, such as neoadjuvant
chemotherapy.
Arguments against preoperative biopsy of pancreatic lesions are that the biopsy results will not alter therapy, that biopsy may
result in seeding and interfere with definitive surgery, and that the procedure increases the cost of care.
Studies of the risk of peritoneal contamination with CT-guided biopsy have suggested that this risk is actually very low. EUS-
guided fine-needle aspiration provides the additional advantage of aspiration through tissue that would ultimately be included in
the operative field should the patient undergo resection.
EUS-guided fine-needle aspiration has proven to be the most effective means for making a definitive cytologic diagnosis of
pancreatic carcinoma.
Using EUS-guided fine-needle aspirations, a cytologic diagnosis can be made in 85-95% of patients. For example, a
retrospective study by Turner et al found that EUS-guided fine needle aspiration was 80% accurate for the detection of
pancreatic carcinoma and was 94% accurate when atypical and suspicious samples are considered positive.[52]
A study by Micames et al suggested that percutaneous aspiration may be associated with a higher risk of peritoneal tumor
spread than is aspiration with EUS.[53]
Thus, for potentially resectable tumors, EUS-guided fine-needle aspiration is the preferred biopsy technique, if it is available and
if a biopsy needs to be obtained. Cost-benefit analyses have also confirmed that it is the most cost-effective mode of tissue
acquisition in suspected pancreatic cancer.
In a presentation delivered at the 2013 annual meeting of the American Society for Clinical Pathology, Huffman et al described a
new risk-stratification system for EUS–guided fine-needle aspiration cytology results that can help determine when pancreatic
lesions are malignant.[54] The researchers identified the following 3 morphologic characteristics as being significantly
associated with pancreatic malignancy:
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.[54]
The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT
scanning.
Histologic Findings
As previously mentioned, of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of
the exocrine pancreas are benign. Less common histologic appearances of exocrine pancreatic cancers include giant cell
carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary
cystic carcinoma, acinar cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary connective tissue
cancers of the pancreas can occur. The most common of these is primary pancreatic lymphoma. (See the images below.)
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.[55]
Islet cell tumors in patients with inherited syndromes such as multiple endocrine neoplasia are less likely to occur singly than in
patients without these syndromes, and in the case of multiple endocrine neoplasia type 1, are more frequently gastrinomas than
insulinomas. These variations of tumor function affect diagnosis and treatment strategies.[55]
Germline Testing and Molecular Analysis

Pancreatic cancer is associated with numerous hereditary syndromes and the results of germline testing can help guide
treatment selection. Whole-exome sequencing has been shown to find genomic lesions that are theoretically actionable in
almost 50% of tumors and to result in a change in clinical management in up to 30% of cases. Although the main driver mutation
is KRAS, molecular profiling can identify numerous other potentially actionable mutations.[56]
The NCCN guidelines recommend that clinicians consider germline testing in any patient diagnosed with pancreatic cancer and
consider a molecular analysis of tumors in those with metastatic disease. The NCCN panel has also strongly recommended
somatic profiling of tumor tissue.[2]
Molecular profiling can detect mismatch repair deficiency (dMMR) and microsatellite instability–high (MSI-H) status. Across
tumor types, patients with this phenotype may respond to pembrolizumab, which is now approved for patients with metastatic
cancer of any type and dMMR/MSI-H status. Although dMMR/MSI-H is present in only 1% of patients with pancreatic cancer, in
the pivotal trial of pembrolizumab, 83% of patients with dMMR pancreatic cancer showed a response.[57]
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.
AJCC staging of pancreatic tumors is as follows[58] :
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.[2] This technique is especially good for assessing major
arterial involvement or distant metastases.
EUS is better than CT scanning for detection of abnormal lymph nodes around the pancreas and celiac axis. Furthermore, with
the addition of EUS-guided fine-needle aspiration, EUS can help cytologically document metastatic disease in suggestive lymph
nodes.
The image below visually demonstrates the stages of pancreatic cancer.
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.
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[59, 60, 61, 2] :
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.
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.
Treatment
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.[62] These veins can be resected partially with as
much as 50% narrowing of the lumen. In addition, complete reconstruction is possible, especially using native veins as
replacement (ie, internal jugular, greater saphenous, or splenic).
Nonetheless, invasion of the superior mesenteric, celiac, and hepatic arteries still presents a barrier to resection. No evidence
indicates that a vascular reconstruction, which permits an attempt at surgical resection, improves or contributes to survival.
After a thorough preoperative workup, the surgical approach can be tailored to the location, size, and locally invasive
characteristics of the tumor. Curative resection options include pancreaticoduodenectomy, with or without sparing of the pylorus;
total pancreatectomy; and distal pancreatectomy. Each procedure is associated with its own set of perioperative complications
and risks, and these points should be taken into consideration by the surgical team and discussed with the patient when
considering the goal of resection.
Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that decisions about resectability involve
input from a multidisciplinary group of specialists at a high-volume center. The NCCN panel also agreed that selecting patients
for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities,
overall performance, and age.[2]
Guidelines on pancreatic cancer from the European Society for Medical Oncology (ESMO) advise that complete surgical
resection is the only potentially curative treatment available; however, 5-yr overall survival is only 10-20%, and long-term
survival in patients with node-positive disease is rare. ESMO recommendations include the following[63] :
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[64] :
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.[64]
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.[65] 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.[66]
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.[67]
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.[68]
Results of the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) show that the addition of nanoparticle
albumin-bound (nab)-paclitaxel to gemcitabine significantly improves overall survival in treatment-naive patients with metastatic
pancreatic cancer compared with gemcitabine alone.[4] Overall survival was approximately 2 months longer in patients treated
with combination therapy (8.5 vs 6.7 months). One-year and 2-year survival rates were also higher in the combination therapy
group (35% vs 22% and 9% vs 4%, respectively).
The results of a European phase III trial (ACCORD/PRODIGE) that compared the nongemcitabine regimen FOLFIRINOX
(leucovorin plus 5-fluorouracil [LV5-FU] plus oxaliplatin plus irinotecan) to gemcitabine in patients with metastatic pancreatic
cancer were reported in May 2011.[3] The median survival on the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the
gemcitabine arm. Of note, the incidence of adverse events and febrile neutropenia was significantly higher on the FOLFIRINOX
arm, despite the fact that only patients with ECOG performance status of 0-1 were included in this trial.
It remains to be seen how well this regimen will be integrated into the care of patients with pancreatic cancer and good
performance status worldwide.
The phase III PRODIGE 24/CCTG PA.6 trial demonstrated that modified FOLFIRINOX (mFOLFIRINOX) also provides
significantly longer survival than gemcitabine in patients with pancreatic ductal adenocarcinomas who have undergone R0 or R1
resection.[8] This study is potentially practice changing.[9] The NCCN now recommends FOLFIRINOX/modified FOLFIRINOX
as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance
status.[2]
At a median follow-up of 33.6 months, the median disease-free survival in PRODIGE 24/CCTG PA.6 was 21.6 months in the
mFOLFIRINOX group versus 12.8 months in the gemcitabine group; median overall survival was 54.4 vs 35.0 months,
respectively. Time until the appearance of metastases was a median of 30.4 months with mFOLFIRINOX versus 17.0 months
with gemcitabine). Overall, more patients experienced severe side effects (mainly hematologic) in the mFOLFIRINOX group
than in the gemcitabine group (76% vs 53%), but the side effects were manageable.[8]
Paclitaxel protein bound was approved by the FDA in September 2013 for metastatic pancreatic cancer.[5] The treatment
regimen includes paclitaxel protein bound 125 mg/m2 plus gemcitabine 1000 mg/m2 IV over 30-40 min on days 1, 8, and 15 of
each 28-day cycle. The NCCN also recommends the combination as a preferred first-line treatment for patients with metastatic
or locally advanced unresectable disease with good performance status.[2] This regimen may be considered instead of
FOLFIRINOX in patients unlikely to tolerate toxicities associated with FOLIRINOX.[4]
For patients with metastatic or locally advanced unresectable disease who have poor performance status, the NCCN
recommends gemcitabine monotherapy.[2]
Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patient's refractory to gemcitabine.
[6] There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m² over 30 minutes
intravenously.
Combinations of gemcitabine with cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not shown superior
benefit over gemcitabine alone.
A new encapsulated form of irinotecan in a long-circulating nanoliposome (Onivyde) was approved by the FDA in October 2015
for patients with advanced pancreatic cancer who have been previously treatment with gemcitabine-based chemotherapy.
Irinotecan liposomal is indicated for use in combination with fluorouracil and leucovorin.
Approval of irinotecan liposomal was based on a 3-arm, randomized, open-label study (NAPOLI-1 trial), which was conducted in
417 patients with metastatic pancreatic adenocarcinoma whose cancer had progressed after treatment with gemcitabine alone
or in combination with other agents. The regimen used in the trial was a combination of liposomal irinotecan (70 mg/m² IV
infused over 90 min [dosage for free-base irinotecan]) administered prior to fluorouracil (2400 mg/m² infused over 46 h) and
racemic leucovorin (400 mg/m² infused over 30 min) every 2 weeks.
Patients treated with this combination of liposomal irinotecan plus fluorouracil/leucovorin lived for an average of 6.1 months,
compared with 4.2 months for those treated with only fluorouracil/leucovorin or 4.2 months for patients treated with irinotecan
liposomal alone. Improvement in progression-free survival was also observed, to a median of 3.1 months with irinotecan
liposomal plus fluorouracil/leucovorin compared with 1.5 months for fluorouracil/leucovorin alone.[69]
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.[70, 71] 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.[72] In 2011, the NCCN panel recommended the measurement of serum CA 19-9
levels after surgery and before adjuvant therapy.[2]
A study by Neuhaus et al in 368 patients with resected pancreatic cancer found that adjuvant gemcitabine prolongs survival
when compared with surgery alone.[73] The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery-only
arms of the study, respectively. The 5-year survival rates were 21% and 9% for the gemcitabine and surgery-only arms,
respectively.
This trial was definitive and transformative. Adjuvant therapy with gemcitabine is now accepted as standard therapy for
surgically resected pancreatic cancer.[7] However, the superior survival demonstrated with modified FOLFIRINOX
(mFOLFIRINOX) may well make that regimen the standard of care for nonmetastatic pancreatic ductal adenocarcinoma in
patients who have undergone surgical resection and have a good performance status (see Chemotherapy).[9, 2]
A systematic review and meta-analysis by Wan et al found that adjuvant therapy with metformin signficantly reduced the risk of
death in Asian patients with pancreatic cancer (hazard ratio [HR]=0.74]), but not in whites. Mortality risk was reduced in patients
with stage I-II disease treated with metformin (HR=0.76, 95% CI=0.68-0.86) as well as in those with stage I-IV disease
(HR=0.88, 95% CI=0.79-0.99), but not in those with stage III-IV disease.[74]
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.[75, 76] 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 finds there is limited evidence to recommend specific neoadjuvant regimens off-study for patients with resectable or
borderline resectable tumor, and practices vary with regard to the use of chemotherapy and radiation. The guidelines prefer
consultation at a high-volume center when considering neoadjuvant therapy. If recommended, treatment should be at or
coordinated through a high-volume center when possible. Participation in a clinical trial is encouraged.[2]
Possible regimens include the following[2] :

Gemcitabine + cisplatin (≥2–6 cycles) followed by chemoradiation (only for known BRCA1/2 mutations)
A study by Dhir et al in 193 patients with resectable or borderline resectable pancreatic ductal carcinoma concluded that
FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel are viable options for neoadjuvant treatment. After adusting for
covariates, however, overall survival was found to be 4.9 months longer with FOLFIRINOX than with gemcitabine-paclitaxel.[77]
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.[78, 79] 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.[80]
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%.[81] 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.[82] 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.[83]
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.[84]
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.[85] This was even more
significant than margin positivity.[86]
Guidelines on pancreatic cancer from the European Society for Medical Oncology include the following treatment
recommendations[63] :
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.[81] 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.[87] 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.[81]
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.[88]
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
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.[89] The AAFP
guidelines concur with the USPSTF recommendation.[90]
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[91] :
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[44] :
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.[63, 2]
Diabetes Mellitus as Risk Factor
The NCCN guideline for pancreatic adenocarcinoma acknowledges long-standing diabetes mellitus as a risk factor for
pancreatic cancer. The guideline also notes an association between sudden onset of type 2 diabetes mellitus in an adult older
than 50 years and a new diagnosis of pancreatic cancer. NCCN guidelines states that clinicians should consider pancreatic
cancer in patients with diabetes who have unusual symptoms such as continuous weight loss and abdominal problems.[2]
Diagnosis
The European Society of Medical Oncology (ESMO) recommendations for diagnosis of pancreatic cancer include the
following[63] :
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[2] :
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[2] :
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.
The NCCN guidelines recommend that clinicians consider germline testing in any patient diagnosed with pancreatic cancer and
consider a molecular analysis of tumors in those with metastatic disease. The NCCN panel has also strongly recommended
somatic profiling of tumor tissue.[2]
Localized Disease Management

Defining Resectability Status
The National Comprehensive Cancer Network (NCCN) has adopted criteria for defining resectability status, which the European
Society of Medical Oncology (ESMO) also recommends. For tumors to be considered localized and clearly resectable, they
must demonstrate the following[2] :
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[92] :
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[92] :
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[92] :
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.
Postoperative recommendations include the following[92] :
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[63] :
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[63] :
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[2] :
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 therapy for patients with resectable or borderline
resectable tumors, but notes that "there is limited evidence to recommend specific neoadjuvant regimens off-study, and
practices vary with regard to the use of chemotherapy and radiation." NCCN recommendations on neoadjuvant therapy in
pancreatic carcinoma are as follows[2] :
Consult with a high-volume center when neoadjuvant therapy is being considered\.
If neoadjuvant therapy is recommended, treat at or coordinate through a high-volume center, when feasible.
Participation in a clinical trial is encouraged.
Subsequent chemoradiation is sometimes included.
Neoadjuvant regimen options include the following[2] :

Gemcitabine + cisplatin (≥2–6 cycles) followed by chemoradiation (only for known BRCA1/2 mutations)
Locally Advanced Disease

The 2016 ASCO guidelines include the following recommendations for treatment of locally advanced, unresectable disease[93] :
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.[93]
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.[93]
In patients with locally advanced (unresectable) tumors, ESMO recommendations are as follows[63] :
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[2] :
FOLFIRINOX/modified 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[94] :
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, 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[63] :
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[2] :
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/modified 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
Palliative Care
The National Comprehensive Cancer Network (NCCN) guidelines for palliative care include the following[2] :
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.
[63]
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[95] :
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
Medication
Medication Summary
The most active single agents for pancreatic cancer have been 5-fluorouracil (5-FU) and gemcitabine. Gemcitabine appears to
be slightly more active than 5-FU. Objective responses, meaning actual regression of tumor, have been 20% or less.
In December 2019, olaparib gained FDA approval for adults with germline BRCA-mutated metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.
Clinical trial results showed a statistically significant increase of progression-free survival in these patients compared with
placebo (7.4 months vs 3.8 months; P = 0.004).[96]
Antineoplastic agents
Class Summary
These agents inhibit cell growth and proliferation. They are used for chemotherapy.
Gemcitabine (Gemzar)
A frequently quoted trial showed a small, but statistically significant, improvement in overall survival with gemcitabine versus 5-
FU (5.7 vs 4.4 mo). Additionally, gemcitabine improved the quality of life in approximately 25% of patients. It is a pyrimidine
antimetabolite that nhibits DNA polymerase and ribonucleotide reductase, which in turn inhibit DNA synthesis.
Fluorouracil (Adrucil)
This is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with ribonucleic acid
(RNA) synthesis and function. Fluorouracil has some effect on DNA and is useful in symptom palliation for patients with
progressive disease. It is commonly used in patients with gastrointestinal malignancies. Response rates are typically less than
20% in pancreatic cancer.
Erlotinib (Tarceva)
This agent is pharmacologically classified as a human epidermal growth factor receptor type 1/epidermal growth factor receptor
(HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Erlotinib has
been approved by the FDA for use, in combination with gemcitabine, as a first-line treatment for locally advanced, unresectable,
or metastatic pancreatic cancer.
Capecitabine (Xeloda)
Capecitabine is a prodrug of fluorouracil that undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil),
inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes
with DNA, and to a lesser degree with RNA synthesis.
Paclitaxel protein bound (Abraxane)

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

Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the
single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Irinotecan liposomal is
used in combination with fluorouracil and leucovorin for metastatic adenocarcinoma of the pancreas after disease progression
following gemcitabine-based therapy.
Olaparib (Lynparza)
Olaparib is a poly (DP-ribose) polymerase (PARP) inhibitor. PARP enzymes are involved in normal cellular function (eg, DNA
transcription and repair). It is indicated for maintenance treatment of adults with deleterious or suspected deleterious gBRCAm
metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based
chemotherapy regimen.
Questions & Answers

Overview
How common is pancreatic cancer?
What are the signs and symptoms of pancreatic cancer?
What is the role of lab testing in the diagnosis of pancreatic cancer?
Which imaging studies are performed in the workup of pancreatic cancer?

How is pancreatic cancer treated?
Which surgical interventions are used in the treatment of pancreatic cancer?
Which chemotherapy agents are used in the treatment of pancreatic cancer?
Which neoadjuvant therapy regimens are used in the treatment of pancreatic cancer?
Which medications are used in maintenance therapy for pancreatic cancer?
What is the role of palliative therapy in the treatment of pancreatic cancer?
What are the life-time risk and survival rates for pancreatic cancer?
What are the types of pancreatic cancer?
What is the pathophysiology of pancreatic cancer?
What causes pancreatic cancer?
What is the role of smoking in the etiology of pancreatic cancer?
What is the role of obesity in the etiology of pancreatic cancer?
What is the role of diet in the etiology of pancreatic cancer?
What is the risk of diabetes mellitus (DM) in the etiology of pancreatic cancer?
What is the role of chronic pancreatitis in the etiology of pancreatic cancer?
What is the role of genetics in the etiology of pancreatic cancer?
Which patient groups are at highest risk for pancreatic cancer?
What is the incidence of pancreatic cancer in the US?
What is the global incidence of pancreatic cancer?
What is the racial predilection of pancreatic cancer?
Which age groups have the highest prevalence of pancreatic cancer by age?
What are the mortality rates for pancreatic cancer?
What is the prognosis of pancreatic cancer?
What is included in patient education about pancreatic cancer?
Presentation
Which clinical history findings are characteristic of pancreatic cancer?
What are the signs and symptoms of pancreatic cancer?
Which physical findings are characteristic of pancreatic cancer?
DDX
In which patients should a diagnosis of pancreatic cancer be considered?
How prevalent is regional spread or distant disease at diagnosis of pancreatic cancer?
Which disorders should be considered in the differential diagnoses of pancreatic cancer?
What are the differential diagnoses for Pancreatic Cancer?
Workup
Which tests are performed in the workup of pancreatic cancer?
How is chronic pancreatitis differentiated from pancreatic cancer?
What is the role of lab testing in the workup of pancreatic cancer?
What is the role of carbohydrate antigen 19-9 testing in the evaluation of pancreatic cancer?
What is the role of carcinoembryonic antigen testing in the evaluation of pancreatic cancer?
What is the role of tumor markers in the diagnosis of pancreatic cancer?
What is the role of CT scanning in the workup of pancreatic cancer?
What is the role of transcutaneous ultrasonography (TUS) in the workup of pancreatic cancer?
What is the role of endoscopic ultrasonography (EUS) in the workup of pancreatic cancer?
What is the role of endoscopic retrograde cholangiopancreatography in the workup of pancreatic cancer?
What is the role of MRI in the workup of pancreatic cancer?
What is the role of PET scanning in the workup of pancreatic cancer?
What is the role of fine needle aspiration (FNA) in the workup of pancreatic cancer?
Which morphologic characteristics are associated with pancreatic cancer?
Which histologic findings are characteristic of pancreatic cancer?
What is the role of germline testing in the diagnosis of pancreatic cancer?
What is the role of molecular profiling in the diagnosis of pancreatic cancer?
How are pancreatic masses characterized by surgeons?
How is pancreatic cancer staged?
Which imaging studies are used for staging of pancreatic cancer?
What is the role of preoperative staging laparoscopy in the management of pancreatic cancer?
What are the indications of staging laparoscopy in the management of pancreatic cancer?
What is the evaluation and treatment algorithm for pancreatic cancer?
Treatment
How is pancreatic cancer treated?
What are the NCCN guidelines for treatment selection in pancreatic cancer?
What are the ESMO treatment guidelines for pancreatic cancer?
What is the role of local ablation in the treatment of pancreatic cancer?
What is the role of chemotherapy in the treatment of pancreatic cancer?
What is the role of adjuvant therapy in the treatment of pancreatic cancer?
What is the role of neoadjuvant therapy in the treatment of pancreatic cancer?
What are the NCCN guidelines for neoadjuvant therapy for pancreatic cancer?
What is the efficacy of neoadjuvant therapy for the treatment of pancreatic cancer?
What is the role of pancreaticoduodenectomy (Whipple procedure) in the treatment of pancreatic cancer?
What are the ESMO guidelines for the use of pancreaticoduodenectomy (Whipple procedure) for the treatment of pancreatic
cancer?
What is the role of distal pancreatectomy in the treatment of pancreatic cancer?

What is the role of total pancreatectomy in the treatment of pancreatic cancer?
How is pain managed in pancreatic cancer?
How is jaundice treated in pancreatic cancer?
How is duodenal obstruction treated in pancreatic cancer?
Which dietary modifications are used in the treatment of pancreatic cancer?
Which specialist consultations are beneficial to patients with pancreatic cancer?
Guidelines
Which organizations provide guidelines on pancreatic cancer screening?
What are the USPSTF and AAFP guidelines for pancreatic cancer screening?
What are international CAPS consortium guidelines for pancreatic cancer screening?
What are the guidelines for the use of tumor markers in pancreatic cancer?
According to NCCN guidelines, when should pancreatic cancer be considered in patients with diabetes mellitus?
What are the ESMO diagnostic guidelines for pancreatic cancer?
What are the NCCN diagnostic guidelines for pancreatic cancer?
What are the NCCN guidelines for staging laparoscopy in patients with pancreatic cancer?
What are the NCCN guidelines for germline testing in patients with pancreatic cancer?
What are the criteria for defining resectability status in pancreatic cancer?
What are the criteria for borderline resectable tumors in pancreatic cancer?
What are the ASCO recommendations for primary surgical resection in pancreatic cancer?
What are ASCO treatment guidelines for potentially curable pancreatic cancer?
What are the ASCO criteria for preoperative therapy of pancreatic cancer?
What are the ASCO guidelines for postoperative treatment of pancreatic cancer?
What are the ESMO treatment guidelines for pancreatic cancer?
What are the ESMO treatment guidelines for resectable pancreatic cancer?
What are the NCCN treatment guidelines for localized pancreatic cancer?
What are the NCCN guidelines for neoadjuvant therapy for pancreatic cancer?
What are the NCCN recommended neoadjuvant regimens for pancreatic cancer?
What are the ASCO treatment guidelines for locally advanced, unresectable pancreatic cancer?
What are the ESMO recommendations for treatment of locally advanced pancreatic cancer?
What are the NCCN treatment guidelines for locally advanced pancreatic cancer?
What are the ASCO treatment guidelines for metastatic pancreatic cancer?
What are the ESMO treatment guidelines for metastatic pancreatic cancer?
What are the NCCN treatment guidelines for metastatic pancreatic cancer?
What are the NCCN guidelines for the palliative care in pancreatic cancer?
What are the ACS guidelines for nutrition and physical activity in the treatment of pancreatic cancer?
Medications
Which medications are the most active against pancreatic cancer?
What is the role of olaparib in the treatment of pancreatic cancer?
Which medications in the drug class Antineoplastic agents are used in the treatment of Pancreatic Cancer?
Contributor Information and Disclosures
Author
Tomislav Dragovich, MD, PhD Chief, Section of Hematology and Oncology, Banner MD Anderson Cancer Center
Tomislav Dragovich, MD, PhD is a member of the following medical societies: American Association for Cancer Research,
SWOG, American Society of Clinical Oncology
Disclosure: Nothing to disclose.
Coauthor(s)
Richard A Erickson, MD, FACP, FACG Professor of Medicine, Division of Gastroenterology, Department of Internal Medicine,
Texas A&M University Health Science Center; Director, Scott and White Clinic and Hospital
Richard A Erickson, MD, FACP, FACG is a member of the following medical societies: American College of Gastroenterology,
American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy
Claire R Larson, MD Resident Physician, Department of General Surgery, Scott and White Hospital, Texas A&M Health
Science Center College of Medicine
Claire R Larson, MD is a member of the following medical societies: American College of Surgeons, American Medical
Association
Mohsen Shabahang, MD, PhD, FACS Assistant Professor of Surgery, Division of Surgical Oncology, Director of Surgical
Residency, Texas A&M Health Science Center, Scott and White Clinic
Mohsen Shabahang, MD, PhD, FACS is a member of the following medical societies: American College of Surgeons, American
Medical Association, Association for Academic Surgery, Society of Surgical Oncology, Texas Medical Association, Western
Surgical Association
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University
School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center
N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for
Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral
Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic
Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas
Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal
and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress,
Southern Medical Association, Surgical Infection Society
Additional Contributors
Lodovico Balducci, MD Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology,
H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine
Lodovico Balducci, MD is a member of the following medical societies: American Association for the Advancement of Science,
American Association for Cancer Research, American College of Physicians, American Geriatrics Society, American Society of
Hematology, New York Academy of Sciences, American Society of Clinical Oncology, Southern Society for Clinical Investigation,
International Society for Experimental Hematology, American Federation for Clinical Research, American Society of Breast
Disease
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
Lewis J Rose, MD is a member of the following medical societies: American College of Physicians, American Medical
Association, American Society of Hematology, Pennsylvania Medical Society, Phi Beta Kappa, Philadelphia County Medical
Society
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Signs and symptoms

Significant weight loss: Characteristic feature of pancreatic cancer

See Presentation for more detail.

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

See Workup for more detail.

Curative resection options include the following:

Pancreaticoduodenectomy (Whipple procedure), with/without sparing of the pylorus

GTX regimen (gemcitabine, docetaxel, capecitabine)[2]

Gemcitabine and albumin-bound paclitaxel[2]

Erlotinib plus gemcitabine

FOLFIRINOX/modified FOLFIRINOX, with or without subsequent chemoradiation

See Treatment and Medication for more detail.

Types of pancreatic cancer

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

Obesity and dietary factors

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

NAR ≤ 0.13 and Ca19-9 ≤ 770 U/mL - Median survival 20.5 months

Significant weight loss is a characteristic feature of pancreatic cancer.

Abdominal aortic aneurysm

Hepatocellular carcinoma (hepatoma)

Bile duct strictures

Bile duct tumors

Neoplasms of the endocrine pancreas

Peptic Ulcer Disease

Computed tomography (CT)

Magnetic resonance imaging (MRI)

Accuracy for providing staging information

Thrombocytosis is also sometimes observed in patients with cancer.

Other features of CT imaging include the following:

Endoscopic Retrograde Cholangiopancreatography

Magnetic Resonance Imaging

Germline Testing and Molecular Analysis

AJCC staging of pancreatic tumors is as follows[58] :

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

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:

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

The image below visually demonstrates the stages of pancreatic cancer.

Preoperative staging laparoscopy

CA 19-9 level >150 U/mL