Pancreatic Adenocarcinoma: Current Problems in Surgery

Current Problems in Surgery 53 (2016) 107–154
Contents lists available at ScienceDirect
Current Problems in Surgery
journal homepage: www.elsevier.com/locate/cpsurg
Pancreatic adenocarcinoma
Mariam F. Eskander, MD, Lindsay A. Bliss, MD, MPH,
n
Jennifer F. Tseng, MD, MPH
Introduction
Pancreatic cancer is the ninth most common cancer in the United States, yet it is the fourth
leading cause of cancer death.1 Of the 42,000 cases diagnosed in 2014, approximately 35,000
will likely die in the next 5 years. By 2030, with a projected 55% increase in the incidence of the
disease, the number of new annual cases could be as high as 65,000.
The only potential cure for pancreatic cancer is surgery, although few patients undergo
surgery because of advanced stage, and almost all resected patients typically experience
recurrence within 10 years. Optimal treatment strategies are multimodal and should be
customized to the individual patient. Acquiring the skills to overcome this formidable disease
requires an understanding of its unique pathophysiology, risk factors, and precursors, as well as
current paradigms of therapy. Pancreatic adenocarcinoma, the most common type of pancreatic
cancer, will be referred to as pancreatic cancer in this review.
Historical considerations
Cancer of the pancreas has long fascinated and challenged the medical community. The
pathologist Giovanni Battista Morgagni first described the disease in 1769, although limited to
external examination of the specimen, he could not be sure whether it was cancer and not
chronic inflammation.2 The late 1800s ushered in a flurry of attempts at surgical removal (the
first operation for pancreatic cancer was performed in 1882) making risky surgery the only
therapeutic option and placing surgeons at the forefront of pancreatic cancer treatment. In
addition to gaps in knowledge, there were technical barriers to effective treatment. Reflecting on
these early difficulties facing surgeons, a textbook from 1902 states, “The treatment of malignant
From the Department of Surgery, Surgical Outcomes Analysis & Research, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA; n Address reprint requests to Jennifer F. Tseng, MD, MPH, Division of Surgical Oncology,
BIDMC Cancer Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Stoneman 9,
Boston, MA 02215. E-mail address: jftseng@bidmc.harvard.edu (J.F. Tseng)
http://dx.doi.org/10.1067/j.cpsurg.2016.01.001
0011-3840/& 2016 Elsevier Inc. All rights reserved.
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108 M.F. Eskander et al. / Current Problems in Surgery 53 (2016) 107–154
disease of the pancreas by the surgeon can hardly be said to exist…the mechanical difficulties of
the operation are well-nigh insuperable, and that if boldness and good fortune are the operator’s
gifts, the result to the patient hardly justifies the means.”3 With morbidity and mortality rates
still as high as 60% and 25%, respectively, into the 1960s, operative safety has only recently
radically improved.4,5 Although profound changes have occurred in the last 40 years in the way
we treat patients with the disease, which is now understood to be systemic, these changes
have not yet resulted in an improved overall life expectancy. Pancreatic cancer has just an 8%
5-year survival rate, only a 5% improvement since 1975.1,6,7 In the modern era of multimodal,
multidisciplinary treatment, the importance of surgery has not diminished, although it is now
seen as a tool in a larger toolbox of therapies.
Etiologic factors
Several risk factors for pancreatic cancer, some genetic and some acquired, have been
identified. Age is a substantial risk factor; as it is unusual to develop pancreatic cancer before the
age of 40, the risk increases 40-fold by the age of 80 years.8 Other basic demographic factors that
confer an increased (but less than 5-fold) risk for pancreatic cancer are male sex, Ashkenazi
Jewish descent, and black race.9
Hereditary
Family history has long been known to be a risk factor for pancreatic cancer; 10% of
pancreatic cancers are proposed to be hereditary. A case control study from Canada found that
7.8% of patients with pancreatic cancer had a positive family history compared with 0.6% of
controls.10 A similar study performed in the United states found that having a first-degree family
relative with pancreatic cancer increases the risk by 3.2-fold compared with the general
population.11 Although patients with one or more first-degree relatives with the disease have a
higher rate of pancreatic cancers outside the head of the pancreas, they show no difference in
survival after resection than do patients with sporadic pancreatic cancer.12
Up to 20% of hereditary pancreatic cancers are associated with a known cancer syndrome,
including familial breast and ovarian cancer syndrome (BRCA 2 mutations), Lynch syndrome
(mismatch repair gene mutations), atypical multiple mole melanoma (p16 mutations), Peutz-
Jeghers (STK11 mutations), and hereditary pancreatitis (PRSS1 mutations).13,14 Mutations in
PALB2, a partner and localizer of BRCA 2, also increased susceptibility.15 There is another large
group of patients with familial pancreatic cancer who have 2 or more first-degree relatives with
the disease but whose underlying genetic defect is unknown, although the mechanism of
inheritance is most likely autosomal dominant.16,17
Other risk factors
Smoking
The major modifiable risk factor for pancreatic cancer is cigarette smoking, which increases
the risk by 1.5 to 5.5-fold.18,19 Approximately a quarter of the 27,000 pancreatic cancer deaths
that occur annually could be avoided by cessation of smoking according to a 1996 prospective
study.18 If added to another established risk factor, smoking can be even more detrimental. It
increases the cancer risk of individuals with hereditary pancreatitis from 54-fold to 154-fold and
results in the diagnosis of cancer at a younger age.20 Furthermore, risk increases with longer
length of exposure and amount smoked.21 Nicotine has been shown to induce pancreatic
carcinogenesis in mice, but the exact mechanism is unknown.22
M.F. Eskander et al. / Current Problems in Surgery 53 (2016) 107–154 109
Obesity
There is also evidence of a weak association between obesity and pancreatic cancer. A recent
case control study identified a positive association between increasing body mass index (BMI)
and pancreatic cancer risk, and an earlier meta-analysis found a slightly increased relative risk of
1.19 per unit increase of BMI in obese people vs people of normal weight.23 There seems to be an
interaction between obesity and physical activity, with greatest risk in those with low physical
activity.24
Diabetes
Type II diabetes mellitus increases pancreatic cancer risk by 80% with higher relative risk if
the duration of diabetes is greater than 5 years; 25,26 hyperinsulinemia alone can increase risk by
up to 100%.27,28
Pancreatitis
Chronic pancreatitis, a progressive irreversible inflammatory condition most commonly
caused by chronic alcoholism affecting between 0.04% and 5% of the general population, confers
up to a 26-fold risk of development of pancreatic cancer, especially if the pancreatitis is
hereditary.29,30
Additional studies investigating everything from coffee to sugar have found that Helicobacter
pylori and cystic fibrosis are associated with an above-normal risk of pancreatic cancer, and
higher dietary selenium, folate, and methionine intake are associated with a lower risk.31-34 The
increased risk associated with a recent history of peptic ulcer disease is likely because of
increased surveillance.35
Pathology
Pancreatic cancer develops either from the endocrine (islet cell) or exocrine (ductal or acinar
cell) systems of the pancreas. Pancreatic adenocarcinoma, which accounts for more than 85% of
pancreatic neoplasms, primarily arises from the ductal epithelial cells of the exocrine pancreas,
yet ductal cells make up only 10% of pancreatic cells and 4% of pancreatic volume.36,37 New
evidence shows that adenocarcinoma might even arise from an alternate route, via trans-
differentiation from acinar cells in genetic mouse models.38
The genetics of pancreatic carcinogenesis is becoming more well understood. The earliest
mutations in pancreatic carcinogenesis appear to be k-ras mutations and telomeric short-
ening.39,40 The sheer number of acquired mutations is impressive; an average of 63 genetic
mutations per tumor were found in a genetic analysis of more than 20 pancreatic cancers.41 The
most commonly activated oncogene is k-ras, whereas inactivated tumor suppressors include
p16, p53, and MADH4.42 A total of 95% of tumors are k-ras positive, most of which have
mutations in k-ras2.43
Studies have shown that it takes at least 10 years between a mutation initiation and tumor
formation and another 5 years before metastatic potential.44 The Notch signaling pathway has
been implicated in neurovascular progression, the epidermal growth factor (EGF) in mitotic
activity and cell adhesion, the vascular EGF pathway in angiogenesis, and the hedgehog pathway
in cellular proliferation and fibroblast stimulation.45-48 Downregulation of e-cadherins may
contribute to the invasive tumor spread and early metastasis in pancreatic cancer and correlates
with poor survival after resection.49 Another cell adhesion molecule called Ep-CAM is an
independent prognostic factor for overall survival and could be related to suppression of
pancreatic cancer cell activity.50 The role of mast cells in angiogenesis and tumor growth has
also been described.51
Several reasons for the poor prognosis in pancreatic cancer have been postulated. In addition
to being a biologically aggressive tumor, there are many opportunities for local invasion as
follows: a rich vascular supply (allowing for vascular invasion) and nerve supply (for perineural
invasion), multidirectional lymph drainage (contributing to lymphatic invasion), and the
relationship of the pancreas to the retroperitoneum and peritoneum (allowing continuous local
spread).52 The venous drainage of the pancreas is via the portal vein (PV), so the liver is often the
first hematogenous metastatic site. The most common site of involved lymph nodes is the
retropancreatic region, with a prevalence of nodal metastases as high as 78.6% in one study.53
The prevalence of diabetes in patients with pancreatic cancer is approximately 40%, and it is
often newly diagnosed.54 This could be because of altered peripheral insulin resistance, the
increased risk for cancer in patients with preoperative diabetes, or possibly a paraneoplastic
phenomenon.55 A peptide called adrenomedullin that causes insulin resistance in beta cells in
mice has been found to be upregulated at the gene level and protein level as well as in the
plasma of patients with pancreatic cancer.56 Insulin resistance improves after pancreatic cancer
resection.
There have been some developments in the identification of pancreatic cancer stem cells, a
subset of cells resistant to traditional therapy that may mediate metastasis and could be a special
target for cancer treatment.57,58 Additional research to identify marker proteins for pancreatic
ductal adenocarcinoma utilizing cell lines is underway.59 For example, DPC4 immunolabeling for
genetic status at the time of autopsy for pancreatic cancer is correlated with the presence of
widespread metastasis but not with locally destructive tumors.60 Adenocarcinoma of the
exocrine pancreas is also carcinoembryonic antigen positive.61 Although tissue plasminogen
activator is absent from the normal human pancreas, it is expressed in 95% of pancreatic
cancers.62 A monoclonal antibody called PAM4 also shows high specificity for pancreatic cancer
and its precursors.63
Premalignant lesions
In this review, we describe 3 types of preinvasive neoplasias—2 that are clinically detectable
and another that is not. Although there is some overlap between them, especially on the
microscopic level, they are seen as distinct entities on different pathways to carcinogenesis.
Premalignant cystic lesions of the pancreas can manifest with concurrent cancer or transform
into malignancies over time. The key to effective management is balancing the risks of watchful
waiting with the morbidity of operative intervention.64 The 2 major premalignant cystic lesions
of the pancreas are intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic
neoplasms (MCNs).
First described in 1982 in Japan with an increase in relative frequency over time, IPMNs account
for up to 20% of pancreatic resections at some centers. They are premalignant lesions characterized
by the intraductal proliferation of neoplastic mucinous cells, leading to the formation of papillary
structures or cystic masses and often to mucin (MUC) production. They involve the native ducts by
definition (main, branch, or mixed), as opposed to MCNs, which are a different entity. More than
80% are located in the head of the pancreas with a mean diameter of 4.5 cm.65 Male to female
ratios tend to be higher in Asia; most are diagnosed during the seventh decade of life.66 Although
IPMNs have been associated with extrapancreatic neoplasms including gastric and colorectal
cancer, it is unknown how much of this is a result of surveillance bias.67,68 A recent multicenter
European study found no increase in frequency of extrapancreatic malignancies.69
IPMNs vary in level of aggressiveness and lie on a spectrum from benign adenoma to
carcinoma. They exhibit less genetic alterations than conventional ductal adenocarcinomas and
are less likely to exhibit k-ras, p16, or p53 genetic mutations, although one half of IPMNs are k-ras
positive.70 Invasive carcinoma may develop anywhere in the gland, although rates of malignancy
differ based on location, with main-branch IPMNs more likely than side-branch IPMNs to lead to
malignancy. The reported prevalence of malignancy for main-branch IPMNs ranges from 57%-
92% vs 6% to 46% in branch type, so smaller branch-type lesions without suspicious radiologic
features are usually watched.71-73 Studies have found that 3 cm marks the point of increased risk
of malignant change.74 Thus, per Sendai Consensus Guidelines, stable, asymptomatic side-
branch IPMNs less than 3 cm in diameter can be observed, and all main-branch IPMNs should be
resected.75,76 Recently, the criteria for branch-types have become controversial, as there are
reports of Sendai-negative IPMNs that have turned malignant.77 The literature reports that the
sensitivity of these criteria ranges from just 75%-97%, allowing for a potentially high false-
negative rate.78,79 More recently in 2012, a set of international consensus guidelines was
published that advocates for the resection of branch-type cysts that are symptomatic or have a
diameter 4 3 cm, have enhanced walls, mural nodules, main pancreatic duct dilation 45 mm,
an abrupt change in main pancreatic duct diameter with distal pancreatic atrophy, or positive
cytology or lymphadenopathy.80 Other investigators have identified the presence of a mural
nodule 4 5 mm and pancreatic juice carcinoembryonic antigen level of 4 30 ng/ML as clinical
factors that help identify high-risk malignant transformation in branch-duct type IPMN.81
The malignant potential of mixed-type IPMNs appears to be similar to that of main-duct.82,83
Levy and colleagues84 reported the risk of development of high-grade dysplasia or invasive
carcinoma at 2 years and 5 years for the branch-duct type at 9% and 15% respectively, and the
risks for the main-duct type and mixed-type at 58% and 63%, respectively. In patients who do
undergo surveillance for mixed-type IPMN, diffuse main pancreatic duct dilation, elevated
serum CA 19-9 levels, elevated serum alkaline phosphatase, and lack of extrapancreatic cysts
predict with 98% accuracy the likelihood of malignant progression over 5 years.
There are 4 subtypes of IPMN as follows: gastric, intestinal, pancreaticobiliary, and oncotic.
Intestinal type is the most common, and its invasive form is similar to colloid carcinoma, which
is notably less aggressive than conventional ductal adenocarcinoma.85 MUC staining of
pancreatic juice cytology has been used to differentiate the gastric (low malignant potential)
and intestinal (high malignant potential) subtypes.86
Ductal adenocarcinomas that do develop in the setting of IPMN appear to have a different
natural history—one with a better prognosis. In a study of patients who had surgery for invasive
adenocarcinoma arising in association with IPMN, patients presented at an earlier stage than
classical adenocarcinoma.87 The cancers may also differ on a molecular basis, which could be
related to better outcomes; there is near universal expression of a nuclear transcription factor
called DPC4 in IPMNs, which is only found in one half of ductal adenocarcinomas.88
Surgical resection for noninvasive IPMN has been associated with 5-year disease-free survival
rates of up to 100% compared with 40%-60% survival for the invasive type.74,89 However, IPMN
frequently recurs even after resection.90 A prospective cohort study with a median follow-up of
44.4 months found that an overall recurrence rate of 10.7%.91 Even after resection for
noninvasive IPMN, a study found that the risk of developing a new IPMN was 25%, of requiring
surgery was 14%, and of developing invasive pancreatic cancer of 7% (all at 5 years).92 Therefore,
close surveillance is recommended even after resection for noninvasive types.
MCNs, which occur predominantly in women and contain an ovarian-type stroma, are less
common and have been less genetically characterized.93 However, they too have malignant
potential and should be referred for surgical resection.94 These solitary lesions are typically
found in the body and tail of the pancreas and lack communication with the pancreatic
duct.95 Noninvasive lesions have minimal risk of recurrence and do not need surveillance
after resection, but those which are invasive have a recurrence rate between 37% and 83% at
5 years.96,97 Resected noninvasive MCN portends a 5-year survival rate of 94.7%-100% and
invasive MCN of 57%-62.5%.97,98 Imaging and pathology from a large MCN are shown in
Figure 1.
The microscopic form of dysplasia called pancreatic intraepithelial neoplasia (PanIN) is
considered the pancreatic counterpart to the epithelial dysplasia seen in other disease
systems.70 They represent stages in neoplastic growth, cyto-architectural changes, and
accumulation of genetic mutations from low grade (PanIN1A) to carcinoma in situ or PanIN3
(Fig 2).99,100 PanIN1 lesions are present in approximately one-third of the elderly population and
rarely become malignant, whereas PanIN3 lesions are direct precursors to cancer and are
commonly found in association with existing invasive carcinoma.101 Certain subpopulations of
PanINs are seen as morphologically distinct and may be able to provide molecular targets for
therapy.102 Assessment of pancreaticoduodenectomy (PD) specimens shows that adenocarcino-
mas more often arise in association with PanINs than from MCNs or IPMNs, possibly because of
higher likelihood of discovery of the latter lesions at a noninvasive stage.103
Fig. 1. (A) Axial CT scan image showing large infected mucinous cystic neoplasm of the pancreas causing diffuse
abdominal pain, fever, and hypotension. (B) Coronal CT scan image showing septations. (C) Pathology specimen after en
bloc distal pancreatectomy and splenectomy. (D) Pathology specimen of cystic componenents. Found to have high-grade
dysplasia. (Color version of figure is available online.)
There have been experimental attempts to interfere with the process of neoplastic
transformation in vivo. Fendrich and colleagues104 used genetically engineered mouse models
to show that aspirin and enalapril could delay the progression of PANIns. Interestingly, the
presence of PANINs at an R0 resection margin does not affect survival.105
Diagnosis
The early forefathers of pancreatic surgery recognized the importance of timely diagnosis.
William McCune, who performed the first of endoscopic retrograde cholangiopancreatography
(ERCP), acknowledged in 1968, “the notoriously poor results of surgical treatment of malignant
lesions of the pancreas and the extreme importance of early detection of cancer in this deep-
seated organ.”2 Early detection remains a challenge up to the present day.
Presentation
Symptoms of pancreatic cancer differ based on the location of the tumor (head, body, or tail)
as well as its size and stage. Most cancers result in obstruction of the pancreatic duct distal to the
tumor, often resulting in pancreatitis, and some in the head of the pancreas also result in
common bile duct obstruction and obstructive jaundice with corresponding elevations in
alkaline phosphatase and bilirubin levels. Approximately one half of patients with tumors in the
head of the pancreas present with upper abdominal pain or back pain.106 The abdominal pain is
caused by invasion of the celiac and superior mesenteric plexuses and becomes more localized
in later stages; radiation of pain to the back is associated with retroperitoneal invasion of the
Fig. 2. Progression of precursor PanIn stages to invasive cancer. (Reprinted with permission from Chang DK, Merrett ND,
Biankin AV, NSW Pancreatic Cancer Network. Improving outcomes for operable pancreatic cancer: is access to safer
surgery the problem? J Gastro Hepatol 2008;23:1036-45.) (Color version of figure is available online.)
splanchnic nerve plexus.107 Other symptoms include nausea, anorexia, weight loss, and new-
onset diabetes. Choluria (dark urine) and hypocholia (clay-colored stool) occur in 60% and 54% of
patients, respectively. Classic signs of pancreatic cancer, Courvoisier’s sign (palpable gallbladder)
and migratory thrombophlebitis, are only seen in 13% and 3% of patients with pancreatic
cancer, respectively.108 The ambiguity and absence of early symptoms contributes to delay in
diagnosis.
Screening
Owing to low lifetime risk of pancreatic cancer (1.3%), routine screening is not recommended
in an asymptomatic person in the general population.109 However, regular surveillance is
recommended for patients with at least a 5-fold increase in pancreatic risk; this includes
patients with a strong family history, patients with known genetic mutations, and combinations
of the 2. Patients with at least 3 first-degree family members with pancreatic cancer (who have
an estimated 32-fold increased risk) or 2 first-degree relatives (a 6.4-fold increased risk) should
be screened.110 An individual with 2 affected blood relatives, one of whom is a first-degree
relative, is also at increased risk and is a candidate for screening at the discretion of the provider.
Patients with Peutz-Jeghers syndrome have up to a 132-fold increased risk and should be
screened regardless of family history.111 BRCA2 carriers with at least 1 first-degree relative or 2
or more affected blood relatives should also be screened. Patients with PALB2/p16 mutations or
Lynch syndrome who have 1 or more affected first-degree relatives should be screened.9
Most experts agree that screening should start at the age of 50 years for most high-risk
individuals, except patients with hereditary pancreatitis who should begin at the age of
40 years.112 Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), or magnetic
resonance cholangiopancreatography (MRCP) are the most recommend imaging modalities. In a
Dutch prospective multicenter study of high-risk individuals undergoing first time screening,
EUS or MRI or both detected clinically relevant lesions in 6% of the population with 55%
agreement in detection of clinically relevant lesions.113 EUS was particularly sensitive to the
detection of small solid tumors and MRI to cystic lesions. The study implies that the modalities
are complementary rather than interchangeable in the screening setting. The optimal interval
for surveillance remains unknown, although 73.5% of participants in the International Cancer of
the Pancreas Screening Consortium in 2013 reported yearly surveillance.112 The reported rate of
cystic lesions in patients undergoing screening because of suspicion of hereditary pancreatic
cancer is as high as 40%.
Serum markers
As the only serum biomarker for pancreatic cancer approved by the Food and Drug
Administration, carbohydrate antigen 19-9 (CA 19-9, also known as sialyl Lewis-a) is useful for
detection of disease burden but is not utilized independently for diagnosis or screening because
of suboptimal sensitivity and specificity (approximately 80% and 73%, respectively.)114-116 First
identified in 1979, it is an aberrant glycoprotein expressed by cancer cells that contains 1 fewer
sialyl acid residues than its normal counterpart.
The prognostic value of CA 19-9 is widespread over the course of the disease. Its level is
associated with resectability—a median level of o100 U/mL has a positive predictive value (PPV)
of 60%-80% and 4100 U/mL a PPV for unresectability of 88%-91%.117,118 A low preoperative CA
19-9 has been linked with improved survival (levels o37 U/mL with a median survival of 22-40
months vs 7-30 months). Drops in postoperative levels and levels 437 U/mL after resection are
also associated with prolonged survival.119 Even a fall of 20% from baseline levels after 1 year in
unresectable cancer is an independent predictor for overall survival.120 Conversely, elevations in
the postoperative period are associated with likely recurrence.121
However, CA 19-9 has several limitations as a biomarker. It is only expressed in patients with
positive Lewis phenotypes and can therefore result in a false-negative in the 5%-10% of the
population who do not express the Lewis phenotype.122 It can also be falsely positive (10%-60%
of the time) in the setting of obstructive jaundice as well as in other gastrointestinal (GI) cancers
(colorectal, esophageal, and gastric) and benign hepato-pancreatico-biliary illnesses, including
pancreatitis, hepatitis, and cholangitis.118
Attempts to identify a superior serum biomarker for pancreatic cancer are underway. A 2015
study detected levels of a protein called Glypican-1 exclusively in exosomes derived from cancer
cell lines. Although it can also be elevated in breast cancer, this serum marker had a sensitivity
and specificity of 100% in detecting pancreatic cancer of all stages in humans and was able to
distinguish cancer from benign pancreatic disease. Furthermore, serum detection of the
biomarker occurred before detection of the cancerous lesion by MRI in genetically engineered
mouse models, presenting the prospect of early detection.123
Diagnostic imaging
Most pancreatic cancers are diagnosed via helical computed tomography (CT) scan, although
MRI has a near equal ability to detect tumors.124 Because the normal pancreas enhances better
than the cancer, tumors appear hypodense compared with the adjacent normal pancreas. The
pancreas distal to tumor can also appear atrophic.125 CT scans have increased difficulty detecting
lesions smaller than 2 cm, although a recent study found a sensitivity of 77% and specificity of
100% for the detection of pancreatic masses 2 cm in size by triple-phase helical CT.126
Endoscopy
The general need for a pretreatment tissue diagnosis is in general controversial but is
mandatory before the initiation of neoadjuvant therapy.125 EUS-guided fine-needle aspiration
(FNA) has the highest overall diagnostic accuracy of any modality, especially for smaller tumors,
and has a complication rate of only 2%.127,128 A meta-analysis of 33 studies assessing the
accuracy of EUS-guided FNA found a pooled sensitivity of 85% and specificity of 98% for
malignant cytology.129 When combined with a nondilated pancreatic duct, the negative
predictive value of FNA can be as high as 100%.130 The sensitivity and specificity of ERCP in the
diagnosis of pancreatic cancer are 70% and 94%, respectively.
Staging and resectability
The ultimate purpose of staging is to determine the surgical resectability of the cancer. Therefore,
it is critical to accurately assess the tumor’s size and location within the pancreas, potential vascular
involvement or the presence of any aberrant vascular anatomy, and the presence of metastasis. The
most commonly used staging system in the United States was developed by the American Joint
Committee on Cancer and utilizes a TNM-based classification (Table 1), most recently updated in
2010 with the seventh edition.131 These stages have been found to correlate with prognosis and
survival, although the addition of a grade component may improve prognostication.132
Resectability criteria for pancreatic cancer divide nonmetastatic resectability status into
3 groups as follows: (potentially) resectable, borderline resectable, and locally advanced. There is
still variable language and some controversy regarding the definition of borderline resectable
disease, but the level of disagreement has abated over time. In Table 2, we present the now
subtle differences between the 2015 National Comprehensive Cancer Network (NCCN)
Table 1
AJCC pancreatic cancer staging, 7th edition. (Adapted from AJCC Cancer Staging Manual, S.B. Edge, D.R. Byrd, C.C.
Compton, A.G. Fritz, F.L. Greene, A. Trotti (eds.) (7th ed) Springer, New York (2010).)
Primary tumor (T)
TX Primary tumor cannot be assessed

T0 No evidence of primary tumor
Tis Carcinoma in situ (including PanIN3)
T1 Tumor r2 cm in diameter
T2 4 2 cm in diameter
T3 Extends beyond pancreas without involvement of celiac axis or SMA
T4 Involves celiac axis or SMA
Regional lymph nodes (N)
NX Cannot be assessed
N0 No metastasis
N1 Metastasis
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Stage T N M
Stage 0 Tis N0 M0
Stage IA T1 M0 M0
Stage IB T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage III T4 Any N M0
Stage IV Any T Any N M1
Table 2
Comparison between National Comprehensive Cancer Network (NCCN) version 2.2015 and the Intergroup Trial
definitions of borderline resectable pancreatic adenocarcinoma in the head or uncinate process of the pancreas.
(Reprinted with permission from Katz et al.134)
National Comprehensive Cancer Network Intergroup Trial 2013

(NCCN) Version 2.2015
SMV-PV Solid tumor contact of 4 1801 or contact of Interface between tumor and vessel of Z1801
r 1801 with venous contour irregularity or around vessel circumference and/or
thrombosis but with suitable vessel proximal reconstructable occlusion
and distal, allowing for safe resection and vein
reconstruction
SMA Solid tumor contact of r1801 Interface between tumor and vessel of o1801
around vessel circumference
CHA Solid tumor contact without extension into Reconstructable, short-segment interface
celiac axis or hepatic artery bifurcation
allowing for safe/complete resection and
reconstruction
Celiac Trunk — Interface between tumor and vessel of o1801
around vessel circumference
IVC Solid tumor contact —
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guideliness) for Pancreatic
Adenocarcinoma V.2.2015. s 2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN
Guideliness and illustrations herein may not be reproduced in any form for any purpose without the express written
permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.
NATIONAL COMPREHENSIVE CANCER NETWORKs, NCCNs, NCCN GUIDELINESs, and all other NCCN Content are
trademarks owned by the National Comprehensive Cancer Network, Inc.
SMV, superior mesenteric vein; PV, portal vein; SMA, superior mesenteric artery; CHA, common hepatic artery; IVC,
inferior vena cava.
guidelines and the Intergroup trial guidelines (from 2013) for borderline resectable pancreatic
cancer.133,134 Although NCCN guidelines previously used subjective terms such as “abutment” and
“distortion,” the most recent guidelines specify the degree of contact between tumor and vessel.
Per the NCCN, in addition to no distant metastasis, clearly resectable tumors should have no
radiographic evidence of superior mesenteric vein (SMV) or PV distortion or less than 1801 of
contact without vein contour irregularity and have no contact with the celiac axis, common
hepatic artery (CHA), and superior mesenteric artery (SMA) (Fig 3). Similarly, the Intergroup
guidelines specify that the interface between tumor and veins should be less than 1801 around
the vessel to be considered resectable but make no specifications regarding venous contour.
According to the NCCN, borderline resectable tumors (Fig 4) can have solid tumor contact with
the SMV or PV of greater than 1801 or less than or equal to 1801 with contour irregularity or
thrombosis but with suitable remaining vessel for safe vein reconstruction. Inferior vena cava
contact is also considered borderline resectable. The Intergoup guidelines specify as borderline
resectable an SMV or PV interface of greater than 1801 between tumor and vessel or a
reconstructable occlusion. Both paradigms allow for solid tumor contact with the SMA of less
than 1801 or “short-segment” CHA contact that the NCCN specifies as not extending into the
celiac or hepatic artery bifurcation. An interface with the celiac axis of less than a 1801
circumference of the vessel wall is considered borderline resectable by the Intergroup guidelines;
this is not explicitly stated in the NCCN guidelines. Although the NCCN outlines criteria for
unresectability based on tumor location within the pancreas, these criteria align for the most part
with the Intergroup definitions of locally advanced disease: any solid tumor contact with the SMA
or celiac of 4 1801 makes the tumor unresectable. The NCCN notes that for tumors of the head or
uncinate process, tumor contact with the first jejunal branch of the SMA or the most proximal
jejunal branch to the SMV also makes tumors unresectable, as does tumor contact with the CA
and aortic involvment for tumors of the distal pancreas. Attainment of negative margins is rarely
feasible in the setting of locally advanced disease (Fig 5), so the great majority are unresectable
even after neoadjuvant treatment. Metastatic (stage IV) disease also precludes resection.
Fig. 3. CT scan demonstrating resectable pancreatic cancer with a clear fat plane between the tumor and the portal vein.
(Courtesy of Quyen D. Chu, MD, MBA.)
Radiologic
Staging is primarily accomplished by CT although centers vary in their algorithms and may
include positron emission tomography (PET), MRI, or MRCP in addition, although they have no
clear advantage over CT.135
Dedicated pancreas protocol multidetector CT (MDCT) with submillimeter section thickness
and image reconstruction is recommended and can assess the extent of vessel involvement, nodal
involvement, and distant metastasis.136 Nonionic iodinated contrast is used, and patients are
scanned both in the arterial phase (for opacification of celiac axis and SMA) and the venous phase
(for PV, SMV, and splenic vein) in which the cancerous lesion appears hypodense. In addition,
low-density oral contrast agent is given for adequate distension of the GI tract.125 Single-center
studies have estimated the sensitivity and specificity of MDCT for predicting resectability at 96%
and 33%, respectively.137 Although CT has a high predictive value of unresectability of 90%-100%,
Fig. 4. CT scans demonstrating borderline pancreatic cancer with reconstructable involvement of the porticomesenteric
axis. On the left, the tumor adheres to and partially occludes the portal vein. On the right, the tumor encases less than
1801 of the superior mesenteric vein. Both patients received a successful pancreaticoduodenectomy following
neoadjuvant therapy. (Courtesy of Quyen D. Chu, MD, MBA.)
Fig. 5. CT scans showing locally advanced pancreatic cancer encasing the common hepatic artery and the celiac trunk.
This patient was unresectable and received chemoradiation. (Courtesy of Quyen D. Chu, MD, MBA.)
it has a lower predictive value of resectability of 76%-90%, which is usually because of its inability
to detect tiny liver metastasis or minimal peritoneal spread.125 When compared with
intraoperative findings, CT has an accurate prediction of margin-negative resection rate 73% of
the time.138 Of note, CT only has an accuracy of 73% in the assessment of peripancreatic lymph
nodes in resectable pancreatic cancer compared to detailed histopathologic assessment.139
Does the accuracy of MDCT change after neoadjuvant therapy? A 2006 study from MD
Anderson assessed accuracy of MDCT for staging of pancreatic cancer in the setting of
neoadjuvant therapy and found that the negative predictive value (74%) for identifying
unresectable pancreatic cancer was comparable with previously reported data (45%-79%) in the
absence of neoadjuvant therapy.140
Additional imaging is of varying utility. Diffusion-weighted MRI was shown to change manage-
ment in 12.9% of patients and allowed for better detection of liver metastasis.141 Studies examining the
ability of fluorodeoxyglucose (FDG)-PET to enhance staging for patients deemed resectable by routine
methods have found that management was altered by the discovery of unsuspected distant disease in
13% to 16% of patients, respectively.142,143 However, the cost and benefit ratio of FDG-PET for pancreatic
cancer staging has been questioned, and the routine use of this modality remains controversial.144
Standardized reporting of radiology findings has been advocated by several professional
societies, with specific guidelines for terminology. A consensus statement released in 2014
suggested that radiologists specifically denote the presence of venous thrombosis, degree of
extension into the CHA, SMA, and SMV regarding branches, presence of attenuation in vessel
contact, and the presence of arterial variants.136
Surgical
Bernheim145 first performed an early “abdominal organoscopy” before an exploratory

laparotomy for a carcinoma in the head of the pancreas in a patient of William Halsted to
corroborate the absence of liver metastasis. As recent improvements in the quality of diagnostic
imaging have caught up with laparoscopic techniques, the role of diagnostic laparoscopy for
pancreatic cancer staging has been contentious.
We know that approximately 10%-25% of patients undergo unnecessary laparotomy owing to
the discovery of unresectable disease upon surgery.146 In a study performed at MGH, CT-occult
metastasis was discovered in almost 24% of patients undergoing laparoscopic staging, although
there were a substantial number of patients with locally advanced disease included.147 Another
study suggested that laparoscopic staging could change surgical management in up to 35% of
patients already assessed by high-resolution helical CT but also had a 14.3% false-negative
rate.148 Similar experiences have been reported at other centers, with laparoscopic examination
detecting approximately 82% of unsuspected distant metastasis.149 Some lesions are still missed
on laparoscopy, however, including those on the posterior liver surface, the paraduodenal
retroperitoneum, the jejunal mesentery, and the lesser sac.150 In one study, occult peritoneal
metastases were actually more likely to be detected in patients with potentially resectable
tumors that were explored via laparoscopy than via laparotomy (32% vs 10%, P ¼ 0.018).151
A Cochrane review of 15 studies published in 2013 found a 40% probability that a patient’s
pancreatic cancer would be unresectable after diagnostic laparoscopy and CT scan, compared
with a 17% probability for those receiving CT alone. The study estimates that on average, using
diagnostic laparoscopy with histological confirmation of suspicious lesions would avoid 23
unnecessary laparotomies for every 100 patients.152 In the case of staging laparoscopy after MRI,
given the low rate of missed metastases on imaging, the addition of laparoscopy has poor cost-
effectiveness and low marginal yield.153
Aside from the well-known risks of general anesthesia and laparoscopic surgery, staging
laparoscopy has no additional risks specific to the patient with cancer. It has not been found to
increase the occurrence of trocar-site disease or peritoneal disease progression of pancreatic
cancer.154 It is usually performed at the start of a planned resection, instead of as a separate
procedure. Routine use of peritoneal lavage is not currently recommended for determination of
resectability, as studies have found that patients with positive peritoneal cytology alone can still
achieve favorable long-term survival.155,156
Laparoscopic ultrasound has been suggested as a useful adjunct to laparoscopy. Without
significantly increasing morbidity or mortality, laparoscopic staging of pancreatic tumors with
the addition of ultrasound can reveal intraparenchymal hepatic metastases, small peritoneal
metastases, and critical retroperitoneal tumor-vessel relationships with an accuracy approach-
ing that of an open approach.157 However, much of the data on the utility of laparoscopic
ultrasound are derived from single-center studies in variable populations before the era before
high-quality MDCT.158 It is not currently recommended for routine use and should be limited to
cases with equivocal resectability or suspected but unconfirmed metastasis.
CA 19-9 can also be used as a guide. Levels below 100 U/mL predict low probability of
metastatic disease; in those patients, laparoscopy can be spared. In contrast, patients with
elevated CA 19-9 have an increased probability of metastatic disease and may benefit from
diagnostic laparoscopy.159 CA 19-9 levels have also been strongly associated with subradio-
graphic unresectable disease.
Summarized in an expert consensus statement written by Callery and colleagues in 2009,
staging laparoscopy should be used selectively. High-yield predictors include pancreatic head
tumors of at least 3 cm, tumors of the pancreatic body and tail, equivocal CT findings, and CA 19-
9 levels higher than 100 U/mL. Finally, staging laparoscopy may be used to rule out undetected
metastatic disease to optimize treatment selection for patients with locally advanced
unresectable cancer.125
Endoscopic
EUS can provide information to aid staging, including detection of involvement of mesenteric
vasculature, nearby organs, or lymph nodes.160 A 2013 meta-analysis of performance
characteristics for EUS found a 69% sensitivity and 81% specificity for nodal staging, 85%
sensitivity and 91% specificity for vascular invasion, and a 90% sensitivity and 86% specificity for
resectability.161 However, the sensitivity of EUS declines to 73% in the setting of chronic
pancreatitis.162
Primary therapies
Although surgical resection is the only management option leading to a potential cure, the
grim median survival of 11-20 months after resection alone demonstrates the necessity of
optimally sequenced multimodal treatment.163 The rates of multimodal treatment are still lower
than they should be, but they are rising. In Medicare patients, the use of multimodal therapy has
nearly doubled from 7% in the 1990s to 14% in the 2000s, with chemotherapy delivered
postoperatively in more than 90% of cases and preoperatively in less than 10%.164
Neoadjuvant therapy
As pancreatic cancer is believed to be a systemic disease with a narrow therapeutic window,

the prompt use of systemic therapy has theoretical benefits.165 Neoadjuvant (or preoperative)
therapy is increasingly being utilized to treat occult disease as early as possible, downstage
advanced tumors, and optimize patient selection for surgery.
Critics of the neoadjuvant strategy express concerns regarding tumor progression, given that
a decade ago only 45%-74% of initially resectable patients were subsequently resected after
induction chemoradiation and 38%-70% after induction chemotherapy.166 However, the
avoidance of ineffective surgical resection in patients with aggressive tumors who are at high
likelihood of early metastasis or recurrence can be seen as an advantage. A more recent meta-
analysis from 2010 showed that pooled resectability was 73.6% in initially resectable patients
after neoadjuvant therapy; a reasonable resectability rate of 33.2% was also achieved in initially
borderline or nonresectable patients.167
Chemoradiation delivered before surgery may be more effective than that delivered after. In a
recent report of 40 patients with borderline resectable disease receiving neoadjuvant therapy,
only 10% experienced local recurrence and 9% peritoneal recurrence.168 A prospective study in
locally advanced, unresectable patients showed that a neoadjuvant regimen of gemcitabine,
docetaxel, and capecitabine for those with venous involvement followed by gemcitabine and
capecitabine or radiation therapy (RT) in those with arterial involvement resulted in higher rates
of R0 resections and prolonged overall survival.169
There has been no reported increase in surgical complications following neoadjuvant
therapy.166,170,171 In a retrospective investigation of completion of multimodal therapy at a high-
volume center, although the rates of postoperative complications were similar for patients
receiving neoadjuvant therapy vs up-front surgery, these complications affected overall survival
only for the up-front surgery group.172
Neoadjuvant therapy is currently recommended for the treatment of borderline resectable
pancreatic cancer, but this strategy is not universally practiced; moreover, its benefit for
resectable patients remains a highly controversial question.173 Accordingly, most patients with
resectable disease who receive neoadjuvant therapy are enrolled in a clinical trial or are seen at a
number of specific cancer centers.
Only a randomized control trial (RCT) attempting to evaluate neoadjuvant vs up-front surgery
in resectable patients has been conducted thus far, and in addition to suffering from problems
with standardization of staging and surgery, it was underpowered to detect a difference in
survival.174 Therefore, the evidence in favor of neoadjuvant therapy is derived from
retrospective, prospective, and nonrandomized trials, as well as decision analysis models. A
summary of select nonrandomized phase II trials of neoadjuvant therapy is provided in Table 3.
Studies comparing survival between neoadjuvant treatment and up-front surgery are difficult
to interpret because of inherent selection bias, but patients (regardless of initial stage) receiving
Table 3
Selected nonrandomized phase II trials of neoadjuvant chemotherapy. (Adapted with permission from de Geus, et al.
Neoadjuvant therapy vs up-front surgical strategies in localized pancreatic cancer: a Markov decision analysis.
(unpublished).
Study Patients Inclusion Institution, Country Treatment regimen Median overall

period survival (months)
Talamonti et al450 20 2002-2003 Feinberg School of EBRT and 26 (Resected)

Medicine and gemcitabine
Northwestern University,
USA
Evans et al171 86 1998-2001 University of Texas M.D. EBRT and 34 (Resected)/
Anderson Cancer Center, gemcitabine 7 (unresected)
USA
Heinrich et al451 25n 2001-2007 Swiss Hepato-Pancreato- EBRT, gemcitabine 19.1 (Resected)
Biliary Center, Switzerland and cisplatin
Le Scodan et al452 41 1998-2003 Centre Hospitalier Lyon- EBRT, 5-FU, and 9.4 (all)/
Sud, France cisplatin 11.7 (surgery†)
Turrini et al453 34 2003-2005 Insitute Paoli-Calmettes EBRT and docetaxel 32 (Resected)/11
and Universite de la (unresected)
Mediterrannee, France
454
Pipas et al 33 2005-2008 Darmouth-Hitchcock IMRT, cetuximab, 24.3 (Resected)/10
Medical Center, USA and gemcitabine (unresected)
Takahashi et al455 110 2002-2009 Osaka Medical Center for EBRT and Overall 5-year
Cancer and Cardio- gemcitabine survival 56%
vascular Disease, Japan
Van Buren et al456 59 2007-2011 University of Pittsburg EBRT, gemcitabine 16.8 (All)/19.7
School of Medicine, USA and bevacizumab (resected)
457
Kim et al 68 2007-2010 University of Michigan, EBRT, gemcitabine, 27.1 (Resected)/
USA and oxaliplatin 10.9 (unresected)
Motoi et al458 35 2008-2010 Tohoku University, Japan Gemcitabine and S1 34.7 (Resected)/10
(unresected‡)
459
Hong et al 48§ 2007 - 2014 Massachusetts General EBRT and 17.3 (All)/27
Hospital, USA capacitabine (resected)
460
O'Reilly et al 38 2007-2011 Memorial Sloan-Kettering Gemcitabine and 27.2 (All)
Cancer Center, USA oxaliplatin
Takeda et al461 35 2002-2006 Kansai Rosai Hospital, EBRT ║ and 41.2 (Resected)/
Japan gemcitabine 10 (unresected)
n
25 with ductal adenocarcinoma of the pancreas of a total of 28.
†
Operated on with curative intent.
‡
Resected with distant metastasis.
§
A total of 48 with pancreatic cancer of a total of 50.
║
Accelerated hyperfractionated radiotherapy.
EBRT, external beam radiation therapy; FU, fluorouracil; IMRT, intensity modulated radiation therapy.
neoadjvuant treatment usually survive longer. For resectable patients, the median survival after
completion of neoadjuvant therapy before resection is approximately 3 years, compared with
2 years for patients who complete adjuvant therapy after resection, and 1 year for patients who
receive resection alone.170,171 A retrospective single-center analysis found longer disease-free
survival and lower rates of local and hepatic recurrence after neoadjuvant therapy compared
with up-front surgery but no difference in overall survival from date of surgery.175
Decision analyses models have consistently found a slight survival benefit for neoadjuvant
therapy over up-front surgery.176 Unpublished results from a decision analysis in 2016
(including only resectable patients) show that compared to up-front surgery, neoadjuvant
therapy offered an improved life expectancy of 32.2 vs 26.7 months and quality-adjusted life
expectancy (QALE) of 25.5 vs 20.8 quality-adjusted life months. The neoadjuvant approach
provided a benefit in LE and QALE when the probability of resectability at surgery after
neoadjuvant therapy exceeded 57% and 55%, a resectability rate that is becoming increasingly
likely with developments in the effectiveness of chemotherapy and radiation. Another decision
analysis from 2015 that used data from prospective studies of patients with resectable or
borderline resectable cancer also favored the neoadjuvant approach with a median overall
survival of 22 months vs 20 months and QALE of 19.8 vs 18.4 months, respectively.177
Neoadjuvant chemoradiation followed by surgery may also be more cost-effective than a
surgery-first approach with a net of $10,247 saved per patient.178
Lessons from centers that provide neoadjuvant therapy include the importance of durable
stents (especially if regimen is prolonged), attention to nutritional support and hydration,
management of diabetes, and supportive care.179 Metal stents are superior to plastic stents for
patients undergoing neoadjuvant therapy, with a complication rate almost 7 times lower.180 PET
may be more accurate than CT in detecting histopathologic response after neoadjuvant therapy
in tumors with prior vascular involvement.181
Adjuvant therapy
Adjuvant chemotherapy (after resection) provides a substantial survival benefit over surgery
only.182,183 Even for localized disease, studies have shown improved survival (hazard ratio ¼
o 0.5) after surgery and adjuvant therapy vs surgery alone.184 However, there is a discrepancy
between treatment recommendations and practice. Although adjuvant therapy is recommended
for pancreatic cancer at all stages, one-third to two-thirds of stage I and II patients who
underwent resection in 2010 did not get adjuvant therapy.185 Lower rates of adjuvant therapy
are also seen in elderly individuals.186
The addition of adjuvant chemoradiation (CRT) in adjuvant therapy is hotly debated. RCTs
have shown conflicting results. The GITSG trial (only 43 patients) found that 5-FU-based CRT
followed by maintenance 5-FU provided a significant survival benefit over observation after
surgery, whereas the EORTC trial found no difference in survival between 5-FU-based CRT and
observation after surgery.187,188 Finally, the ESPAC-1 trial reported no short-term survival benefit
and poorer long-term survival for CRT vs chemotherapy alone.189 These RCTs evaluating the role
of CRT in adjuvant therapy have been criticized for design and methodological flaws as well as
problems with accrual, standardization of therapy, and the use of inferior radiation treatment
schedules.190 Overall, the American experience has shown a benefit to CRT in certain
populations (such as those with lymph node involvement); in contrast, CRT is not widely used
in Europe.191,192 At this time, the benefit of adjuvant chemoradiation remains unclear, and
further studies are needed to further elucidate the populations in which CRT may be beneficial. A
summary of select randomized trials of adjuvant therapy are shown in Table 4.
Planned adjuvant therapy may not take place because of a myriad of barriers including
patient preference, the presence of comorbidities, poor performance status, surgical complica-
tions, and early recurrence. Postoperative complications have been reported to prevent or delay
the receipt of adjuvant therapy in 25%-30% of eligible patients.193
The exact timing of adjuvant therapy does not seem to matter; there was no difference in
survival when therapy was started within 8 weeks of surgery vs up to 12 weeks later, according
to ESPAC-3 data.194 However, completion of adjuvant therapy confers a substantial survival
benefit. The 68% of patients who completed the full 6 cycles of chemotherapy had the best
overall and recurrence-free survival. Current guidelines recommend that adjuvant therapy take
place within 4-8 weeks of surgery, and restaging is recommended after each treatment modality
Chemotherapy
Gemcitabine, a pyrimidine analog introduced in 1996, is the primary chemotherapeutic agent

used in both the neoadjuvant and adjuvant setting. The NCCN Practice Guidelines for adjuvant
treatment recommend systemic gemcitabine, continuous 5-FU, 5-FU/leucovorin, or capecitabine
after resection or gemcitabine, 5-FU, or 5-FU/leucovorin either preceded or followed by
fluoropyrimidine- or gemcitabine-based chemoradiation.133 The CRT route is endorsed
particularly for patients who are at high likelihood of local recurrence.195
Table 4
Randomized control trials of adjuvant therapy in pancreatic cancer. (Adapted with permission from de Geus, et al. Neoadjuvant therapy vs up-front surgical strategies in localized pancreatic
cancer: a Markov decision analysis. (unpublished).)
Study Patients Inclusion Institution, Country Phase Treatment arms Overall median Survival in
period months (P value)
Kalser et al187 43 1974-1982 Gastrointestinal Tumor Study Group (GITSG), III Obs. vs EBRT and 5-FU 10.9 vs 21 (0.03)
USA
M.F. Eskander et al. / Current Problems in Surgery 53 (2016) 107–154

Klinkenbijl 114n 1987-1995 European Organization for Research and III Obs. vs EBRT and 5-FU 12.6 vs 17.1 (NS)
et al188 Treatment of Cancer (EORTC)
Neoptolemos 541 1994-2000 European Study Group for Pancreatic Cancer III 5-FU and folinic acid vs EBRT and 5-FU 16.1 vs 15.5 (NS)
et al189 (ESPAC– 1), EU
Demols et al462 30 2001-2003 Erasme University Hospital, USA II EBRT and gemcitabine 19
Blackstock 47 1999-2003 Wake Forest University Comprehensive Cancer II EBRT and gemcitabine 18.3
et al463 Center, USA
Kosuge et al464 89 1992-2000 Japanese Study Group of Adjuvant Therapy for II Obs. vs Cisplatin and 5-FU 15.8 vs 12.5 (NS)
Pancreatic cancer (JSAP-1)
Regine et al182 388† 1998-2002 Radiation Therapy Oncology Group (RTOG-97-04) III EBRT and gemcitabine and 5-FU vs EBRT 20.5 vs 16.9 (NS)
and 5-FU
Yoshitomi 100 2002-2005 Chiba University Hospital, Japan II Gemcatabine vs Uracil/tegafur and 29.8 vs 21.2 (NS)
et al465 gemcitabine
Ueno et al466 118 2002-2005 Japanese Study Group of Adjuvant Therapy for II Obs vs gemcitabine 18.4 vs 22.3 (NS)
Pancreatic cancer (JSAP-2)
Van Laethem 90 2004-2007 EORTC-40013-22012/FFCD-9203/GERCOR, EU II Gemcitabine vs EBRT and gemcitabine 24.4 vs 24.3 (NS)
et al467
Neoptolemos 1088 2000-2007 European Study Group for Pancreatic Cancer III 5-FU and folinic acid vs gemcitabine 23.0 vs 23.6 (NS)
et al468 (ESPAC– 3), EU
Reni et al469 102 2003-2008 S. Raffaele Scientific Institute, Italy II Gemcitabine vs Cisplatin, Epirubicin, 5-FU 24.8 vs 28.9
and Gemcitabine
Schmidt 132 2004-2007 Ruprecht-Karls-University, Germany III 5-FU vs EBRT, 5-FU, cisplatin and 28.5 vs 26.5 (NS)
et al470 interferon-α-2B
Fenster et al471 73 2006-2008 Philipps—University of Marburg, Germany II Gemcitabine and cetuximab 22.4
Herman 48 2006-2012 Johns Hopkins University School of Medicine, USA II IMRT, erlontib, capecitabine 24.4
et al472
Oettle et al358 354 1998-2004 Charite Onkologie (CONKO–001), EU III Obs. vs gemcitabine 20.2 vs 22.8 (0.005)
Valle et al194 1088 2000-2007 European Study Group for Pancreatic Cancer III 5-FU and folinic acid vs gemcitabine 23.0 vs 23.6 (NS)
(ESPAC– 3), EU
5-FU, 5-fluorouracil; Obs, observation; NS, non-significant; EBRT, external beam radiation therapy; IMRT, intensity modulated radiation therapy.
n
114 patients with cancer of the pancreatic head of total 218 randomized.
123
†
388 patients with cancer of the pancreatic head of total 451 randomized.
No specific neoadjuvant regimens are recommended by the NCCN, but the most commonly
used agents are FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin), gemcitabine,
5-FU, mitomycin C, and platinum compounds. Almost one half of the neoadjuvant studies in a
recent meta-analysis used gemcitabine-based therapy, and radiotherapy with doses ranging from
24-63 Gy was applied in 93.7%.167 One strategy is the use of “induction chemotherapy” before
CRT, usually gemcitabine alone or in combination with other agents. Induction chemotherapy can
be used to “select” patients with no evidence of disease progression as suitable candidates for
subsequent CRT. 5-FU or gemcitabine are also often used as radiosensitizers, given at intervals
during radiotherapy.196
The efficacy of FOLFIRINOX in the setting of metastatic disease has led to its use as part of
neoadjuvant regimens for borderline resectable cases as well. For borderline resectable patients,
the period of induction neoadjuvant chemotherapy is longer (and is often followed by
chemoradiotherapy especially if vascular reconstruction is planned). In one high-volume center
experience, systemic therapy (FOLFIRINOX or nab-paclitaxel/gemcitabine) is initiated first (2
months) and is then followed by chemoradiation (gemcitabine-based, intensity-modulated RT)
in the setting of stable or responsive disease.197 At another center, systemic FOLFIRINOX therapy
can last up to 4 months.168 The median length of neoadjuvant therapy can be as long as
7 months at other centers.198,199 A meta-analysis of studies of FOLFIRINOX-based neoadjuvant
therapy in borderline resectable or unresectable patients found a 43% resectability rate and an
R0 resection rate of 39.4%. Particularly among the borderline resectable patients, a R0 resection
rate of 63.5% was achieved.200
Unfortunately, chemoresistance is often a problem. Although gemcitabine appears to be quite
effective as a cytotoxic agent in vitro, the same results are not seen in vivo; predictive models
have been created to enhance understanding of tumor cell behavior.201
Radiation therapy
RT is thought to promote locoregional control, as an association between RT and decreased

incidence of local recurrence has been observed.202 Radiation in various forms can be used both
in neoadjuvant and adjuvant regimens. The NCCN guidelines for radiation in adjuvant therapy
are 45-46 Gy in 1.8-2 Gy fractions to the tumor bed, anastomoses, and adjacent lymph nodes,
followed by another 5-9 Gy to the tumor bed and anastomoses. Recommended dose limitations
in the preoperative vs postoperative setting by organ are also provided.133
Recent studies have shown the safety of dose escalation of external beam RT (EBRT) up to
55 Gy, but several techniques have been developed that allow for the focused treatment of
diseased tissue with reduced dose exposure to normal tissue.203,204 Intraoperative radiotherapy
allows for the delivery of RT to the tumor bed under direct vision. This can be accomplished via
implantation of iodine-125 seeds, brachytherapy, or the more popular method of intraoperative
electron beam radiotherapy. Phase II trials of intraoperative electron beam radiotherapy in
locally advanced pancreatic cancer have shown median survivals between 9 and 13 months.
Intensity-modulated radiotherapy (IMRT) is a type of radiation delivered with varying intensities
within a field. A small study from Germany showed comparable outcomes for IMRT and
conventional 3D radiotherapy in the neoadjuvant setting.205 However, studies evaluating IMRT
in the adjuvant setting have shown varying levels of GI toxicity.206–208 Furthermore, IMRT
treatments are typically delivered daily for 6 weeks, and limits to the maximal dose may be
necessary because of tumor movement with respiration or intestinal distension.209 Stereotactic
body radiotherapy (SBRT) delivers intensified treatment to the tumor and surrounding
vasculature (in 1-5 high-dose fractions) with submillimeter precision and rapid falloff, thereby
sparing normal tissue.210 Because of the short treatment length (usually under a week), it is
convenient for patients and interferes minimally with timing of systemic therapy.211 It can be
used as a boost for conventional EBRT or IMRT or as primary radiation treatment. CyberKnife
(Accuray, Sunnyvale, CA) is a real-time image-guided robotic radiosurgery system used for
delivery of SBRT that tracks the tumor during respiration and movement using a combination of
previously implanted fiducial markers and an external camera. In sequence with induction
chemotherapy, SBRT facilitates negative resection margins in borderline resectable patients and
local control in unresectable patients.212 For resected patients, adjuvant SBRT can allow for
quicker initiation of chemotherapy.213
The toxicity for conventional photon-based radiotherapy is not trivial. The RTOG 9704 trial
reported a 59% incidence of grade 3 nonhematologic toxicity in patients receiving a dose of
50.40 Gy with 5-FU as adjuvant therapy.182 Similar rates were reported in the FFCD or SFRO trial
for unresectable patients receiving 60 Gy with 5-FU and cisplatin.214 Given these risks, the
potential risks vs benefits of chemoradiation must be weighed and decisions made for the
individual patient.
Some studies have suggested a reduction in normal tissue exposure for protons (ionizing
radiation) as opposed to photons.215 A phase I study demonstrated the feasibility of neoadjuvant
chemoradiation with 1 week of proton beam therapy and capecitabine followed by early surgery,
but a second series was halted because of unexpected intraoperative fibrosis.216,217
Targeted therapy and immunotherapy
On the horizon are new therapeutic strategies including “targeted therapy” aimed at specific
biologic pathways of tumor growth and immunotherapy, the stimulation of the immune system
to eradicate tumors.218 Several molecular targeted therapies, many in oral form, are being tested,
although their efficacy in pancreatic cancer is yet to be proven; cetuximab, an EGFR-targeted
therapy, as well as axitinib and bevacizumab, vascular EGFR inhibitors, and matrix metal-
loproteinase (MMP) inhibitors such as Marimastat have shown similar survival to Gem
monotherapy in advanced pancreatic cancer.219,220 Erlotibib, an EGFR inhibitor used in advanced
pancreatic cancer, is also being tested as a component of adjuvant therapy.221
Immunotherapy includes direct methods where immune-competent cells are stimulated to
attack cancer cells or indirect methods such as immunization where an immunogen stimulates
the body to inhibit the growth of tumors.222 Because many patients with pancreatic cancer have
known mutations, vaccines targeted against these tumor-specific mutations may provide a
benefit. Studies demonstrate that adjuvant vaccination with mutant K-ras, MUC1, or telomerase
peptides is safe and tolerable but their efficacy as immunogenic agents is not consistent in
human subjects.223-225 In particular, a combination of whole-cell vaccine-based immunotherapy
and chemotherapy shows promise.226 A single-center phase II study testing the efficacy of
granulocyte-macrophage colony-stimulating factor adjuvant immunotherapy with subsequent
chemoradiation in resected patients revealed a favorable median survival of 24.8 months.227 In a
Phase II RCT of an immunogen called Gastrimmune (G17DT) in patients with advanced
pancreatic cancer, responders to G17DT survived significantly longer.228 Other methods to
reverse immune suppression, including CD-40 antibodies, have shown tumoricidal properties
both in vitro and in vivo.229 The use of immunotherapy in cases of chemoresistance is also a
topic of increased interest.
Surgery
Preoperative considerations and preparation

Surgery is the cornerstone of therapy for pancreatic cancer and is the only hope for cure.
Efforts should be made to optimize patients for surgery to attain the best possible outcome, as
several preoperative factors such as malnutrition are independent risk factors for poor outcomes
following pancreatic surgery for cancer.230 Early identification and intervention is vital and
should be performed in a multidisciplinary setting. Screening tools including the subjective
global assessment and malnutrition screening, as well as preoperative measurement of albumin
and prealbumin, can help the provider identify patients who may benefit from additional
nutritional support.231
Evidence suggests that preoperative biliary drainage not be performed routinely and instead
be reserved for patients with coagulation disorders or those who would undergo neoadjuvant
therapy. Although the delay in surgery for preoperative biliary drainage makes no difference for
survival, there is also no discernable benefit to drainage seen on multiple studies.232 A
multicenter European trial (in which plastic stents were used) showed higher complication rates
with no improvement in perioperative outcomes, and a review showed no benefit (but increased
costs) with biliary drainage before surgery.233,234 However, another multicenter study found
increased odds of severe postoperative complications and decreased survival when preoperative
serum bilirubin levels exceeded 300 mmol/L, suggesting a benefit to biliary stenting in this
subset of patients with extreme jaundice.235
Finally, close attention to preoperative imaging also assists with operative planning. CT scans
can show the presence of anatomic anomalies, such as a replaced right hepatic artery. The need
for venous reconstruction should also be anticipated preoperatively to avoid the complications
associated with “technical misadventures” and delays in the operating room.236
Patient selection and risk calculators

Patient selection is paramount in surgery for pancreatic cancer, as patients are often elderly,
malnourished, and coagulopathic.237 Pancreatic resection in elderly adults can result in higher
rates of morbidity compared to younger individuals, but the survival benefit of resection does
not decrease with increasing age.238-241
Performance status can be described according to the Eastern Cooperative Oncology Group
scale as follows: 0 ¼ fully ambulatory, symptom free; 1 ¼ fully ambulatory but with symptoms;
2 ¼ in bed less than 50% of the day; 3 ¼ in bed more than 50% of the day; and 4 ¼ confined to
bed all day. Patients with poor performance status are typically not offered surgery because of
poor outcomes.242
Several prediction rules and risk calculators using preoperative characteristics have been
designed for pancreatic surgery. For stratifying risk of in-hospital mortality after pancreatic
resection for cancer, there is an integer-based risk score incorporating age group, Charlson score,
sex, type of pancreatectomy, and hospital volume status.243 Using the American College of
Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database, there is a
prediction tool for probability of 30-day morbidity and mortality for patients undergoing PD.244
Variables include age, sex, body mass index, functional health status, comorbidities, as well as
laboratory values such as creatinine, albumin, platelets, and white blood cell count. A similar
tool using NSQIP for distal pancreatectomy (DP) has also been created.245 These calculators can
be used for preoperative counseling and for the optimization of perioperative care in high-risk
patients. Other risk calculators such as the Physiologic and Operative Severity Score for the
Enumeration of Mortality and Morbidity (POSSUM) and the Surgical Apgar score involve
operative variables and therefore cannot be used for preoperative risk stratification.246,247
Technique
Surgical strategies
A classic PD, also known as the Whipple procedure, is typically performed for
adenocarcinoma located in the pancreatic head, neck, or uncinate process. In its original form
as described by Whipple and colleagues,248 it was a 2-stage procedure beginning with biliary
and gastric outlet decompression followed a few weeks later by resection of the second part of
the duodenum and head of the pancreas. Along with technical advancements, the operation has
undergone various modifications that have improved its safety and widened the boundaries of
resectability.
Exclusion of metastasis via thorough examination of the abdominal cavity is first performed,
often via laparoscopy. Special attention is paid to the liver, omentum, and peritoneum.
Suspicious lesions are sent for frozen section. Resectability is determined by examination of the
extent of local and nodal tumor involvement. A Kocher maneuver is performed to mobilize the
Fig. 6. Reconstructions in a standard pancreaticoduodenectomy (A) and pylorus-sparing pancreaticoduodenectomy (B).

(Courtesy of Douglas B. Evans, MD.) (Color version of figure is available online.)
duodenum and head of the pancreas, exposing the underlying inferior vena cava and aorta. The
surgeon can then palpate the relationship to the SMA.249 SMV and PV involvement is no longer
prohibitive for resection, and certain levels of arterial reconstruction can be attempted on an
individual basis. Many centers that perform surgery within the context of multimodal therapy
do not consider nodal involvement an absolute contraindication to surgery and do not routinely
perform frozen sections of nodes before PD.236
In the classic Whipple procedure, the organs removed en bloc are the gastric antrum, the
duodenum, the proximal 10 cm of the jejunum, the head of the pancreas, the gallbladder, and
the distal common bile duct. After reconstruction, 3 anastomoses are created as follows: a
pancreaticojejunostomy (PJ), hepaticojejunostomy (HJ), and gastrojejunostomy (GJ).250 Figure 6
shows the resections completed in a classic Whipple and Figure 7 a typical pathologic specimen.
Fig. 7. Pathologic specimen from a standard pancreaticoduodenectomy. (Courtesy of Douglas B. Evans, MD.) (Color
version of figure is available online.)
An open PD is typically performed via upper midline or bilateral subcostal incision. For a
classic Whipple, the antrum is transected, and the gastroduodenal artery is divided near its
origin. The pancreatic neck is transected from the body of the pancreas anterior to the level of
the SMV or portal confluence.251 The pancreatic head is then dissected from the retroperitoneal
soft tissue and from the vascular bed of the SMV or portal confluence and SMA. The proximal
jejunum approximately 5-10 cm distal to the Ligament of Treitz is divided and the end brought
through the transverse mesocolon in a retrocolic manner to form the PJ. The anastomosis can be
created via the duct to mucosa technique that entails an inner layer of absorbable monofilament
suture connecting the duct to a small enterotomy in the jejunal mucosa and an outer layer of silk
suture joining the pancreatic capsule to the jejunum. Alternatively, a running anastomosis can
be performed connecting the whole gland to a larger jejunal enterotomy; the neck can be
invaginated 1-2 cm into the lumen of the bowel.249 The distal one-third of the CBD is transected,
and the remaining proximal segment is anastomosed to the jejunum about 10 cm distal to the PJ
in an end-to-side orientation to form the HJ anastomosis. Fifteen centimeters distally to the HJ,
an end-to-side GJ is performed. The GJ can be performed more distally in an antecolic fashion
as well.
In the pylorus-preserving PD (PpPD), the entire stomach as well as 2-3 cm of the proximal
duodenum are preserved, resulting in the creation of a duodenojejunostomy. Reductions in
complications including delayed gastric emptying, dumping, and anastomotic ulcers have been
reported, although a meta-analysis showed no difference in morbidity or mortality.252,253 Some
studies have also found reduced operative time, blood loss, and hospital stay for the PpPD.253,254
A Japanese RCT comparing resection of the pylorus ring with no resection of the pylorus ring
and preservation of the entire stomach found higher rates of delayed gastric emptying with
preservation of the pylorus.255 A lower rate of delayed gastric emptying has been reported for
antecolic (as opposed to retrocolic) reconstruction of the duodenojejunostomy in the PpPD.256
Frozen sections of the pancreatic and bile duct margins are performed with further resection
until negative. The surgeon should clearly document in the operative report the presence or
absence of a grossly complete resection. Avoidance of a positive margin at the peripancreatic
retroperitoneal tissue near the origin of the SMA is important, and it is precisely this location
where an R1 margin is most likely.257 The SMV-PV confluence must be mobilized for maximum
visualization of the SMA, and although sharp, ultrasonic, or thermal means of skeletonization are
acceptable, the use of a stapler to divide the uncinate from the SMA is not recommended,
as it leaves behind too much tissue.258 The “uncinate process first” (retrograde dissection of
the pancreatic head) and the “hanging maneuver” are two methods to attain negative
retroperitoneal margins.259,260
Because of its location, cancer of the body or tail of the pancreas is less likely to be
symptomatic in its earlier stages and therefore less likely to be resectable at presentation.261 In a
DP, the spleen and distal pancreas are mobilized and removed en bloc; the remnant pancreas is
oversewn proximal to any evidence of gross disease.249
No survival benefit has been reported for routine total pancreatectomy (additional removal of
entire pancreas, spleen, and margin of peripancreatic tissue) over the classic Whipple operation,
and it should only be performed if oncologically indicated.262–264 Likewise, an extended PD
(which involves dissection of the retroperitoneal and aortocaval lymph nodes) increases
morbidity without providing a survival benefit and is also not recommended.265,266
Extent of lymphadenectomy
Lymph node involvement is an important negative prognosticator for survival. Because
lymph nodes are embedded in the retroperitoneal adipose tissue, the assessment of lymph
nodes in pancreatic cancer is a joint venture between surgeons and pathologists.
Although current American Joint Committee on Cancer guidelines recommend the
examination of 12 nodes, some studies suggested that 15 lymph nodes should be examined
during PD for accurate staging of node-negative pancreatic cancer.267 A study using the
Surveillance, Epidemiology, and End Results (SEER) database found that many patients had an
inadequate number of lymph nodes examined and could therefore have been understaged
following pancreatic surgery; the median number of lymph nodes examined was 7, and
approximately 10% of patients resected between 1988 and 2003 had no lymph nodes examined.
A subsequent study in the National Cancer Database (NCDB) from 2003-2004 found that only
16.4% of patients with pancreatic cancer had at least 15 nodes examined.268
Regional lymph nodes of interest for standard lymphadenectomy during PD are located along
the gallbladder or common bile duct, anterior CHA, PV, the head of the pancreas, the SMV, and
the right side of the SMA; celiac, splenic, and left gastric artery nodes should not be
included.131,269 For distal splenectomy, nodes from the splenic hilum, splenic artery, and
superior margins of the pancreas should be examined.
A total of 5 prospective, randomized trials of extended vs standard lymphadenectomy have
shown no long-term survival benefit for extended resection.270,271 Current evidence supports a
standard lymphadenectomy as opposed to an extended lymphadenectomy with retroperitoneal
soft tissue clearance.272
For DP, some have advocated for the use of a radical antegrade modular pancreatosplenec-
tomy (RAMPS) for more extensive lymph node dissection. A retrospective comparison of
conventional DP and RAMPS found that although RAMPS allowed for a greater number of
retrieved lymph nodes, it did not lead to improved overall survival.273
Operative techniques and outcomes

Several methods of pancreatic anastomosis have been promoted but evidence for the
superiority of any single method has so far been inconclusive. RCTs comparing end-to-side, end-
to-end, or duct to mucosa and invagination techniques reveal a range of rates of fistula and are
difficult to compare owing to different definitions. A randomized trial comparing a duct with
mucosa anastomotic technique with end-to-side for creation of the PJ found no significant
difference in complication rate, whereas a prospective randomized trial found fewer pancreatic
fistulas using the invagination technique compared with duct to mucosa.274,275 Pancreaticogas-
trostomy, as an alternative to PJ, is associated with a lower risk of postoperative pancreatic fistula
as well as decreased severity of fistula but no difference in overall morbidity or mortality.276 The
use of fibrin sealants or glues to high-risk PJ anastomoses has not proven beneficial.
A meta-analysis including both internal and external stents found no benefit to intra-
operative pancreatic duct stent placement; however, those with external pancreatic duct stents
were found to have reduced fistula rates in a subgroup analysis and a subsequent randomized
trial.277,278
Almost one-third of patients who receive a DP develop pancreatic fistula. The optimal
technique for closure of the pancreatic remnant remains unknown. Options include hand-sewn
vs stapled closure as well as the use of fibrin glue or a jejunal patch.279,280 Selective duct ligation
or prophylactic transpapillary pancreatic stent insertion or both can also be performed.281
Minimally invasive vs open

Minimally invasive techniques including laparoscopy and robotic surgery have the potential
to provide improved visualization, contribute to decreased postoperative narcotic use, and lead
to shorter hospital stays.282 The first laparoscopic pancreatectomy (a pylorus-preserving PD) was
performed in 1994 for chronic pancreatitis and since then, surgeon expertise in this technique
has rapidly improved.283 More recently, the draw of high-definition graphics, increased degrees
of freedom for movement, and ergonomic advantages have led to the rise of robotic systems.284
In particular, minimally invasive DP is emerging as a viable alternative to open DP.
Retrospective single-center series (mostly in benign or borderline tumors) have shown lower
morbidity rates and shorter hospital stays after receipt of laparoscopic surgery.285,286 A national
study found equivalent adjusted odds of complete resection, number of lymph nodes removed,
and 30-day readmission and a shorter length of stay for laparoscopic or robotic DP compared
with open pancreatectomy.287 Equivalent median survival has been reported among experi-
enced surgeons.288,289 A reduction in operative time, blood loss, and conversion rate is seen after
the completion of only 10 laparoscopic distal PDs.290 Adequate volume remains a challenge—
between 2010 and 2011, 85% of Committee on Cancer-accredited cancer centers performed
fewer than 10 cases.287
In comparison, the uptake of laparoscopic pancreaticoduodenecomy has been less wide-
spread: only a few surgeons perform purely laparoscopic PDs. Some centers have achieved
decreased blood loss, hospital stay, and complication rates compared to open PD using the Da
Vinci robotic system.291 National data on the topic of minimally invasive PD (MIPD) is lacking.
MIPD use for pancreatic cancer has increased by 45% between 2010 and 2011 but 92% of
hospitals performing MIPD during that time period had a 2-year volume of less than 10 cases.
A total of 2 articles examining perioperative outcomes after MIPD using the National Cancer
Database found that although 30-day mortality did not significantly differ (5.1-5.2% for MIPD vs
3.1-3.7% for open surgery), MIPD was associated with almost double the odds of perioperative
death on multivariate analysis.292,293 However, when limited to hospitals with high hospital
volume (more than 10 cases in 2 years), operative technique was no longer independently
associated with mortality.293 An investigation into the learning curve for robotic PD
demonstrated statistical improvements in estimated blood loss and conversion to open surgery
after 20 cases, the incidence of pancreatic fistula after 40 cases, and operative time after 80
cases.294
There are limited data on the cost-effectiveness of minimally invasive techniques. A small
single-center study found that although upfront operative cost is higher for robotic PDs, once
follow-up hospitalization costs are included, costs became equivalent.
Minimally invasive techniques for the resection of pancreatic cancer are feasible and safe if
performed by experienced surgeons in a high-volume setting. Larger series with longer follow-
up times are needed for perioperative and oncologic outcomes after minimally invasive
pancreatic surgery for cancer.
Vascular resections and extended pancreatectomy

Initially described in the 1970s, mesentericoportal vein resection with the goal of negative
margins is performed today at many high-volume centers. Indeed, the International Study Group
of Pancreatic Surgery (ISGPS) supports the up-front operative resection of “reconstructable” SMV
or PV involvement.295 To be reconstructable, these lesions should allow for adequate inflow and
outflow in the reconstructed veins and lack of involvement of the SMA and CHA.296
Vascular resection can be performed via direct anastomosis, patch, or interposition graft that
can be either prosthetic or autogenous in nature (Fig 8).297-300 The concern for infection has
restricted the use of prosthetic grafts although good results have been demonstrated at some
centers. A series of 33 patients (85% with pancreatic cancer) receiving segmental vein resection
via interposition PTFE graft reconstruction discovered no cases of graft infection over a median
survival of 12 months for the patients with cancer.301 Figure 9 illustrates the use of autogenous
vein patches and interposition grafts. Size matching for autogenous veins can be challenging,
and veins from various locations including the gonadal veins, superficial femoral vein, and left
renal vein have been harvested.302-304 A study of 34 patients receiving PV or SMV reconstruction
using lower extremity vein (saphenous for patching and femoral for replacement) found an
overall patency rate of 88% at a mean follow-up of 5 months.305 Another study (mostly using
vein patches) achieved an exceptional 97% patency rate within 6 months postoperatively,
attributed by the authors to the assistance of a vascular surgeon during vascular resection.306 For
tension-free anastomosis, bovine patch is also a reasonably priced option that is durable and
biocompatible with no need for vein harvesting, but little is known about its role in venous
repair.307
Because operative time and blood loss tend to be greater in PDs with vascular resection,
surgical candidates should be carefully selected.308,309 However, the overall safety of venous
vascular resection has been established. A total of 2 meta-analyses of retrospective studies have
found that morbidity, mortality, and survival outcomes do not differ between pancreatic
resections with and without venous vascular resection.310,311
Fig. 8. Techniques for reconstruction of the superior mesenteric vein/portal vein. (Reprinted with permission from
Tseng JF et al., Pancreaticoduodenectomy with vascular resection: margin status and survival duration. J Gastroint Surg
2004;8:935.)
In contrast, arterial resection during pancreatectomy is associated with a 5-fold increased

odds of perioperative mortality compared with no arterial resection during pancreatectomy but
improved survival compared with those who do not undergo resection.312 This may be because
of the theory that venous involvement is merely related to tumor location, whereas arterial
involvement is due to aggressive tumor biology.313 For celiac reconstruction, the common or
proper hepatic artery must be preserved and re-anastomosed to ensure hepatic perfusion.314
Fig. 9. Intraoperative examples of venous reconstruction include (A) a saphenous vein patch on the portal vein, (B) a
saphenous vein graft from the proximal to distal replaced right hepatic artery (RRHA), and (C) an IJ interposition graft of
the SMV. (Courtesy of the Medical College of Wisconsin Pancreas Program and Douglas B. Evans, MD.) LHA, left hepatic
artery; GDA, gastroduodenal artery; RRHA, replaced right hepatic artery; HA, hepatic artery. (Color version of figure is
available online.)
Table 5
Grades of delayed gastric emptying. (Adapted with permission from Wente MN, et al. Delayed gastric emptying (DGE)
after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery
2007;142(5):761-8.)
Grade NGT required Unable to tolerate solid Vomiting or gastric Use of

oral intake by POD distension prokinetics
A 4-7 Days or reinsertion 4 POD 3 7 Yes or no Yes or no

B 8-14 Days or reinsertion 4POD 7 14 Yes Yes
C 4 14 Days or reinsertion 4POD 14 21 Yes Yes
NGT, nasogastric tube; POD, postoperative day.
DP with celiac resection (DP-CAR, also called the modified Appleby procedure) for tumors of
the body and tail is also possible in select patients. Here, collateral flow through the
gastroduodenal artery provides perfusion to the liver.315 Compared to a DP with no celiac
resection, DP-CAR is associated with longer operative time, increased rates of postoperative
kidney injury, and a 30-day postoperative mortality rate of 10%.316 In a Japanese study, DP with en
bloc celiac axis resection for locally advanced cancer of the pancreatic body resulted in a 91% R0
resection rate and a 5-year survival of 42%.317 A case series from one high-volume center showed
favorable outcomes for patients with arterial encasement who responded to neoadjuvant therapy
and underwent planned arterial resection, most often an Appleby procedure.318
Multivisceral resections (involving colon, stomach, kidney, adrenals, liver, etc.) are associated
with increased short-term morbidity but still provide a survival benefit compared with palliative
procedures.319,320 One-fifth of patients receiving multivisceral resections also have a venous
resection.
Vascular resection is not without its risks. A population-based analysis found that the
frequency of vascular resection during PD has increased between 2000 and 2009 and that the
postoperative complication rate with vascular resection is higher than without, even at high-
volume hospitals.321 In a large multicenter retrospective cohort study from the UK comparing
PD with vein resection, PD only, and palliative bypass in patients with T3 borderline resectable
pancreatic cancer, higher complication rates were found in the PD groups but no difference
between PD and PD with vascular resection. Perioperative mortality was similar in all 3 groups;
no difference in overall survival between the PD only and PD with vascular resection groups was
identified.322
There are no guidelines regarding the need for type and length of anticoagulation after a
venous reconstruction during PD. This is based on studies showing no difference in thrombosis
rates after venous reconstruction between those receiving and not receiving anticoagulation
(aspirin, warfarin, or clopidogrel.)323
More well-designed studies are needed to compare survival for increasing degrees of
vascular resection in locally advanced pancreatic cancer with nonsurgical chemotherapy or
chemoradiation treatments.
Perioperative outcomes—Morbidity and mortality

Based on NSQIP data, the 30-day mortality rate is approximately 2.6% for PD, 1.2% for DP, and
5.4% for total pancreatectomy.244,245,324 Although mortality after pancreatic resection has
improved, morbidity remains high at 30%-40%.325,326 Postoperative complications delay the
receipt of adjuvant therapy.327 Furthermore, their effective management contributes to lower
overall mortality rates.328 Sepsis, surgical site infection, and respiratory complications are the
most common postoperative complications.244,245 Pancreas-specific complications include
bleeding, anastomotic leaks, intra-abdominal infection, and delayed gastric emptying. Grades
of delayed gastric emptying are presented in Table 5. Small pancreatic duct diameter and soft
pancreatic tissue are two risk factors for anastomotic leak.329 Every effort should be made to
prevent leaks from pancreaticoenteric anastomoses, as these increase the risk of abscess
formation, postpancreatectomy hemorrhage, and delayed gastric emptying.330 Late
Table 6
Grades of postoperative pancreatic fistula with main parameters. (Adapted with permission from Bassi et al.331)
Grade A Grade B Grade C
Clinical condition Well Often well Ill-Appearing

n
Specific treatment No Yes or no Yes
US or CT if obtained Negative Negative or positive Positive
Persistent drainage after 3 weeks No Usually yes Yes
Reoperation No No Yes
Cause-specific death No No Possibly yes
Signs of infection or sepsis No Yes Yes
Readmission No Yes or no Yes or no
US, ultrasound; CT, computed tomography.

n
Peripheral or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin analog and/or drainage.
complications include dumping and endocrine or exocrine insufficiency. An estimated 20%-30%

of all complications are life-threatening or require intervention (Clavien-Dindo grade III-IV.)235
Interventional drainage or stenting for leaks, fistulas, and abscesses, endoscopic dilation of
stenosis, and angiography or endovascular management of delayed hemorrhage are important
minimally invasive advances in the management of complications after PD that have reduced
the rate of reoperation.4
The International Study Group on Pancreatic Fistula published a standardized definition of
postoperative pancreatic fistula in 2005: “drain output of any measurable volume of fluid on or
after postoperative day 3 with an amylase content greater than 3 times the serum amylase
activity.” They created 3 grades (A, B, and C) of postoperative pancreatic fistula with increasing
severity (Table 6).331 A recent study highlighted the burden of Grade C fistulas; they develop in
approximately 2% of patients receiving PD.332 More than 85% have an additional complication.
Approximately 70% require reoperation and nearly two-thirds do not receive adjuvant therapy. A
10-point clinical risk score for pancreatic fistula (CS-POPF) is presented in Table 7.333
Somatostatin, an octreotide analog that inhibits pancreatic enzyme secretion, can be given as
prophylaxis postoperatively to decrease the rate of pancreatic fistulas, although there is no clear
evidence that somatostatin enhances closure for preexisting fistulas.334
As patients with cancer undergoing surgery, patients after PD are at above-average risk for
venous thromboembolic events. A study using data from NSQIP found an incidence of deep vein
thrombosis of 2.3% and pulmonary embolism of 1.5% within 30 days after pancreatectomy for
cancer.335
Approximately 1 of every 5 patients undergoing PD is readmitted. An analysis of 30-day
readmissions using SEER data found that more than 95% of the variation in readmissions was
attributable to patient-level factors such as comorbidity, 4% to hospital factors, and only 0.3% to
surgeon-level factors.336
Volume or outcome relationships

There is now widespread agreement that the experience and volume of a surgeon and
hospital are important features influencing successful pancreatic resections and long-term
results.337 Owing to advancements in anesthesia, operative selection, and surgical technique as
well as the regionalization of pancreatic cancer care to high-volume centers, mortality after PD
has dropped from approximately 25% in the 1960s to less than 3% at some high-volume
centers.338 In a study using Medicare data, higher hospital volume explained 67% of the decrease
in operative mortality for pancreatectomy from 1999-2008.339 High hospital volume has even
been linked to improved long-term survival.340
The effect of volume is seen on intermediate outcomes as well. Patients with localized
pancreatic cancer are more likely to receive multimodal treatment at high-volume centers.184 In
a study from the NCDB, patients undergoing PD at low-volume centers were more likely to have
margin-positive resections.341 They also had fewer lymph nodes examined during PD than at
Table 7
Risk score for prediction of postoperative pancreatic fistula. (Reprinted with permission from Callery et al.333)
Risk factor Points
Gland texture
Firm (6-10) 0
Soft (1-5) 2
Pathology
Pancreatic adenocarcinoma or chronic pancreatitis 0
All others 2
Pancreatic duct diameter (mm)

Z5 0
4-4.9 1
3-3.9 2
2-2.9 3
r1.9 4
Intraoperative blood loss (mL)

r400 0
401-700 1
701-1000 2
4 1000 3
Negligible risk, 0 points; low risk, 1-2 points; intermediate risk, 3-6 points; high risk, 7-10 points.
high-volume hospitals.342 High-volume centers are more equipped to deal with complications of
treatment and have the multidisciplinary teams necessary to manage multimodal therapy.330 As
an illustration, the presence of interventional radiology at a hospital is associated with lower
perioperative mortality after pancreatic surgery.343 In a landmark “failure to rescue” article,
Medicare patients receiving pancreatectomy at very-low-volume hospitals were 1.7 times more
likely to suffer a complication and 3.2 times more likely to die after that complication than
patients at very-high-volume hospitals.344
The belief that high-volume centers are safer locations for the performance of pancreatic
surgery has led to the regionalization of pancreatic cancer care. From 2007-2011, National Cancer
Institute-designated Cancer Centers (NCI-CCs) performed 53.5% of pancreatic operations for
cancer.345 A Dutch study in the Netherlands found improved survival after centralization of
pancreatic surgery.346
Oncological outcomes
Survival
Resection is critically important for survival—patients with unresected pancreatic cancer

have a 5-year survival of 8.7% if locally advanced and 1.8% if metastatic.7 In contrast, studies of
patients with resected pancreatic cancer (most of whom have adjuvant therapy) have shown 5-
year survival rates between 18% and 20%, a number that has not meaningfully changed in the last
25 years.347,348 Figure 10 shows Kaplan-Meier curves for adjusted cancer-specific survival by
stage and resection status.
Positive margins, lymph node metastasis, larger tumor size, and poor differentiation have all
been found to predict poor survival after resection.347,349 In total, 3 or more units of blood
transfused during pancreaticoduodenecomy is also predictive of poor survival as is perineural
invasion.348,350 Patients who develop a thromboembolism, especially early on in their illness,
have worsened survival.351
Although the prognostic value of microscopically negative (R0) resection margins has
differed in some studies, this can be attributed to pathology evaluation and the definition of R1
resection.352 When R1 resection is defined as cancer within 1 mm of the resection border, R0
Fig. 10. Cancer-specific survival for (A) resected and (B) unresected patients. Survival is adjusted for age, sex, race, tumor
site, tumor grade, and receipt of radiotherapy and stratified by disease stage for patients diagnosed with pancreatic
adenocarcinoma from 1998 to 2005 in the Surveillance Epidemiology End Results cancer registry. The survival curves for
patients with unresected stage II and III cancers are superimposed. Overall, 47% of people who underwent resection
received radiotherapy vs 19% among those who did not. The use of systemic chemotherapy was not available. (Adapted
with permission from Katz MH, Hu CY, Fleming JB, Pisters PW, Lee JE, Chang GJ. Clinical calculator of conditional survival
estimates for resected and unresected survivors of pancreatic cancer. Arch Surg 2012;147(6):513-9.) (Color version of
figure is available online.)
resection is superior.353,354 It remains a key objective in the resection of adenocarcinoma of the

pancreas, as it influences both local recurrence and survival.
In an analysis of patients with pancreatic cancer who received surgical resection between
1998 and 2002, 3.9% survived at least 10 years. Predictors of long-term survival included tumor
characteristics (lymph node positivity ratio, pathologic T or M stage, size, grade, and surgical
margin), treatment variables (receipt of adjuvant chemotherapy), and sociodemographic factors
(age, education level, and insurance status.)355
Recurrence
Early recurrence of invasive pancreatic cancer is common even after curative resection: 80%
of patients have a recurrence within 2 years.356 Most patients develop a recurrence, with highest
likelihood in the abdominal cavity, and subsequently die from metastatic disease. There is a
significant amount of drug resistance in pancreatic cancer, and the cause is not well
understood.357
Several studies have addressed patterns of recurrence. Extrapancreatic recurrence appears to
be more common than isolated local recurrence. One study found a 69.5% recurrence rate over a
mean follow-up time of 32.4 months. The first site of recurrence was local only in 23.7%
(estimated at 10%-35% in other studies), local plus distant in 21.2%, and only distant in 55.1%.358-360
In another study, 75.9% of patients experienced a recurrence over a median follow-up of 18.5
months. Extrapancreatic recurrence most commonly occurred in the liver.361 There is a vast
difference seen in postoperative survival between patients with isolated local recurrence (16.4
months) vs patients with metastasis (9.4 months.)356
The guidelines for postoperative surveillance from the NCCN call for a physical examination,
CA 19-9 level, and CT scan at 3-6 month intervals for the first 2 years and then annually.362
However, a study using a large administrative database of Medicare patients found that 23% of
patients did not receive a CT scan in the year following surgery, and that there was no temporal
pattern to CT use, suggesting that scans were obtained for symptoms rather than regular
surveillance.363
A total of 3 factors together have been found to predict local early recurrence with a 90.4%
accuracy: pre-op CA 19-9 level 4 228 U/mL, tumor diameter 4 3.1 cm, and pathologic lymph
nodes preoperatively.364 Positive surgical margins and an elevated postoperative CA19-9 predict
early development of distant metastases but not locoregional failure.365 Longer progression-free
survival has been independently associated with neoadjuvant chemoradiation, lower estimated
blood loss, lack of positive posterior margin, lack of nodal microinvolvement, and adjuvant
therapy.183,358,360,366,367 A study found that the accuracy of MDCT in detecting recurrence was
85%, for FDG-PET the accuracy was 85%, and for CA 19-9 the accuracy was 95%. The authors
conclude that a combination of CA 19-9 with either multidetector CT or FDG-PET CT is 100%
accurate.368
There does appear to be a response to chemoradiation in patients with recurrent pancreatic
cancer without distant metastasis.369 In a small Japanese study, 30 patients treated with
radiotherapy at a median dose of 54 Gy experienced encouraging local control and overall
survival.370 However, surgical reoperation for local recurrence may not be feasible because of
dense adhesions and the extent of tumor invasion. A study found that patients who had an
interval of greater than 9 months between resection and recurrence were more likely to benefit
from re-resection.371 Encouraging results were reported in Germany in a small study of patients
with local recurrence who were surgically explored (and some grossly resected or debulked),
then treated with both intraoperative RT and external beam radiation.372
Quality of life
The data on quality of life (QOL) in pancreatic cancer are lacking. Almost one half of the
number of patients with pancreatic cancer experience pain.373,374 Among newly diagnosed
patients, 29% reported severe pain and 37% moderate pain.373 Relief of pain is associated with
enhanced quality of life, including improved mood and decreased interference with activities.375
Methods for pain relief in unresectable patients range from nonsteroidal anti-inflammatory
drugs (NSAIDs) to narcotics to epidurals to celiac plexus blocks. Neurolytic celiac axis block
provides effective pain relief for 74% of patients and is especially effective for tumors in the head
of the pancreas.376 Multimodal pain control is recommended, as pain from pancreatic cancer is
multifocal, with visceral, somatic, and neuropathic components.377 Early symptom control for
anxiety, nausea, fatigue, and anorexia is also important.378
A diagnosis of pancreatic cancer can have severe psychological effects. A total of 38% of
patients were found to have elevated depression scores after a new diagnosis with pancreatic
cancer.373 Men with pancreatic cancer are 11 times more likely to commit suicide than the
general population.379 Fear of recurrence is also common: more than one-third of patients with
pancreatic cancer had a fear of cancer recurrence score that indicated “frequent fearful thoughts,
emotional disturbance, and functional impairment.”380
The receipt of surgery for pancreatic cancer appears to improve QOL in a small study from
Mexico.381 Another study evaluating quality of life in the elderly after PD in Israel found
improvement in functional, symptom-based, and global QOL scores in the months after
surgery.382 It takes 3-6 months after surgery for QOL to return to preoperative levels.383 The
receipt of adjuvant chemotherapy after macroscopically complete resection has been associated
with improved QOL in a prospective randomized study.384
Palliation
Given the 6-10 month median survival time for patients with advanced pancreatic cancer,
palliative efforts should focus on increasing comfort and improving quality of life.385,386 In
addition to addressing pain control and biliary or intestinal obstruction, palliation should also
manage malnutrition, thromboembolism, and depression.387 Currently, an RCT is underway to
evaluate the benefits of integration of early palliative care with standard oncologic care for
advanced lung and noncolorectal GI malignancies.388 Although hospice use at end of life has
increased over time for Medicare patients, there has been a decrease in early enrollment and
an increase in ICU admissions and chemotherapy use in the last month of life.389 This
suggests that hospice services may not be used optimally although they increase QOL and
lower cost.
Surgical
The need for surgical palliation is usually a result of obstructive jaundice, gastric outlet
obstruction, or pain unresponsive to other modalities. When proximal GI tract obstruction
(which is more commonly gastric than duodenal in patients with pancreatic cancer) cannot be
treated endoscopically, a bypass or double bypass operation can be undertaken.390 Roux-en-y HJ
is generally preferable to choledochoduodenostomy or cholecystojejunostomy owing to superior
outcomes.391,392 A meta-analysis from 2009 found that prophylactic gastroenterostomy during
surgical exploration of unresectable patients reduced the incidence of gastric outlet obstruction
without influencing morbidity and mortality.393 A total of 38% of patients with unresectable
cancer and biliary stents who receive chemoradiation, however, do develop a symptomatic
duodenal obstruction at a mean of 11.4 months after diagnosis requiring intervention, and that
rate has risen over time.394
Palliative bypass is preferable to planned palliative resection, as studies comparing the 2 have
found higher morbidity and mortality in the resection group as well as longer operating times
and longer hospital lengths of stay.395
There are several methods of surgical pain control, including celiac axis block and
splanchnicectomy. Neurolytic celiac axis plexus block (now done laparoscopically or endoscopi-
cally) is safe and decreases the need for pain medication.396,397 A study evaluating the efficacy of
laparoscopic celiac axis block in patients with unresectable cancer found that it resulted in
improved pain scores with minimal complications and short operative time.398 An RCT found
that celiac axis block even improves survival.375 Thoracoscopic splanchnicectomy is a minimally
invasive interruption of the fibers of the splanchnic nerve, allowing for relief of abdominal pain
while avoiding some of the potential side effects of a celiac plexus neurolysis. It has shown good
short-term pain relief and improved QOL for patients with unresectable cancer in single-center
studies.399,400
Endoscopic
The reality is that 80% of patients with pancreatic cancer who have progressed to biliary
obstruction are not operative candidates.401 In addition to being performed therapeutically for
symptomatic patients with obstructive jaundice who are awaiting surgery, ERCP can also be
performed for unresectable patients in need of biliary decompression. In the case of long-term
use (43 months), expandable metal stents are preferable to plastic stents, which occlude sooner
and at higher rates.402
Studies have shown mixed outcomes for biliary bypass vs stenting for palliation, likely
because of the variety of outcomes measured. Early RCTs found no difference in complication
rates.403 Other RCTs found more complications in the surgery group.404 However, these were
performed before advances in expandable metal stents. A meta-analysis from the year 2000
found that 3% (0%-16%) of patients required endoscopic re-intervention in the biliary (all
plastic) stent group vs 35% (28%-43%) requiring surgical re-intervention in the surgical bypass
group.405 The most recent meta-analysis on the topic, published in 2014, did not differentiate
between metal and plastic stents and found no difference in technical success rates or
morbidity or mortality but that recurrent biliary obstruction was 9 times more likely after
stent placement.406
Given that the short-term outcomes of surgical bypass may be inferior to stenting, current
recommendations call for endoscopic stenting in poor surgical candidates with a short life
expectancy and biliary bypass for patients with good performance status and longer life
expectancy.407,408 A recent study of palliative bypass for pancreatic cancer cites a 30-day
mortality rate of 6.5% and major complication rate of 20%.409 For some patients, these short-term
risks may be prohibitive. The decision of which path to pursue in cases of biliary obstruction
should be undertaken on an individual basis with the input of a multidisciplinary team and
should take into account life expectancy.410 This paradigm should be revisited as data on
minimally invasive bypass become available, which has the potential of changing the short-term
risk profile of surgical bypass.
Chemotherapy
Gemcitabine has been the preferred method of palliative chemotherapy, having been
shown to prolong survival and improve QOL for patients with unresectable pancreatic
cancer.386,411 Its side effects include nausea, vomiting, lethargy, and bone marrow suppression.
Recent phase III trials have supported the addition of second cytotoxic agents, although the
benefits are small.412 Albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine lead to
significantly improved progression-free and overall survival (by only 1.8 months for both), but
with increased rates of peripheral neuropathy and myelosuppression. Gemcitabine plus
capecitabine (GEM-CAP) vs gemcitabine alone shows a significant survival benefit on meta-
analysis.413
In 2011, the PRODIGE 11 study found that FOLFIRINOX (oxaliplatinin, irinotecan, fluorouracil,
and leucovorin) was superior to gemcitabine monotherapy for metastatic pancreatic cancer in
patients with good performance status, with a notable survival advantage over gemcitabine but
increased toxicity (neutropenia, thrombocytopenia, diarrhea, and neuropathy.)414 Notably,
locally advanced patients were excluded from this study. FOLFIRINOX is now preferentially used
for patients with high performance status and good hepatobiliary function. If gemcitabine or
FOLFIRINOX are unavailable, capecitabine with or without oxaliplatinin or 5-FU or leucovorin or
oxaliplatinin (OFF) are also viable options.415
Radiation therapy
The combination of radiotherapy with chemotherapy for palliation remains controversial.416

The LAP 07 study found no benefit to the addition of radiation to chemotherapy for locally
advanced pancreatic cancer; however, 2 efficacy trials have demonstrated the safety of
concurrent radiotherapy with fixed-dose gemcitabine, and another study found improved
survival with chemoradiotherapy vs radiation alone.208,385,417
Newer therapies have focused on reducing systemic toxicity and increasing local control.
Some hospitals have shown good results for unresectable locally advanced patients treated with
EBRT, chemotherapy, and intraoperative radiotherapy.418 SBRT using Cyberknife is also an
emerging technique for palliation.419 EUS-guided fiducial placement for SBRT can be performed
to minimize the need for surgery.420 SBRT has been reported to relieve pain and improve quality
of life in patients with unresectable and metastatic disease.421,422 Although earlier studies using
a single fraction of 25 Gy showed high rates of late GI toxicity, later studies have achieved over a
50% decrease in toxicity using 5 fractions of 6.6 Gy.423–425 Survival outcomes appear to be
improving over time; whereas early studies showed poor survival, more recent reports show
results comparable to conventional radiotherapy (ERBT.)426,427 Importantly, SBRT with or
without chemotherapy is safe and effective in patients older than 80 years age who are either
unresectable or cannot have surgery owing to comorbid conditions.428 More studies are needed
comparing EBRT and SBRT for unresectable pancreatic cancer.
Other therapies
Erlotinib, an EGFR tyrosine kinase inhibitor, is Food and Drug Administration-approved for
unresectable pancreatic cancer in combination with gemcitabine.429 The addition of other agents
is also being tested: an efficacy study of the addition of upamostat (a urokinase plasminogen
activator) to Gem showed tolerability but similar survival for nonresectable locally advanced
patients.430 Recent studies have demonstrated the safety of ablative therapies such as
radiofrequency ablation (RFA) for liver metastasis, microwave ablation, high-intensity–focused
ultrasound (HIFU), carbon ion radiotherapy, and photodynamic therapy for locally advanced
cancer.431–436
Future directions
Detection of the pancreatic cancer at earlier stages is critical. Translational research should
continue to identify biomarkers that can be used for early diagnosis and prognostic
prediction.437 A systematic review of 78 studies revealed 76 potential molecular markers, of
which only 11 were confirmed in 2 or more studies. None could yet be recommended for clinical
use. A total of 2 micro-RNA panels in whole blood as well as an exosomal protein have been
identified that distinguish patients with pancreatic cancer from healthy controls, but more
research is needed to understand their utility.438
We should focus on improving the modalities that we do have, including the application of
image-guided surgery and SBRT, as well as the development of new methods and paradigms for
effective treatment.204,439-441 Enhancing the sensitivity of pancreatic cancer cells to chemo-
therapy is an important undertaking—methods involving small interfering RNA (siRNA) have
been proposed. Novel methods for delivery of chemotherapeutic agents are also being
developed, including nanoparticle-mediated drug-eluding scaffolds.442 Gene transfer and
immunotherapy are quickly advancing fields that may allow for inhibition of tumor growth or
systemic antitumor immunity.443 A better understanding of genetics as well as medication
transport and metabolism would permit us to investigate variation in response to therapy and
allow for more personalized medicine. The optimal sequencing of evolving therapies with
surgery should also be examined.
The use of multiple therapeutic modalities has created a need for increasing coordination
between specialties, leading to a move toward multidisciplinary care. A single-day pancreatic
multidisciplinary clinic provided a comprehensive and co-ordinated evaluation of patients that
led to changes in therapeutic recommendations in close to a quarter, according to a 2008
study.444
Finally, numerous studies have pointed to the underuse of surgery, different referral patterns,
and overall inadequate care for certain populations.445-449 We must ensure that everyone
eligible for potentially life-saving treatment receives it.
Conclusions
Although pancreatic cancer remains a fatal disease, pancreatic surgery is rapidly evolving,
and therapeutic breakthroughs are on the horizon. Efforts to improve outcomes for pancreatic
cancer should focus on early diagnosis and referral, reducing and managing operative
complications, and the development of novel and optimally sequenced therapeutic techniques.
Funding
Howard Hughes Medical Institute Early Career Award, American Surgical Association
Foundation Fellowship, American Cancer Society MSRG 10-003-01 (to JFT).
Pyrtek Fund Research Fellowship (to LAB).
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Pancreatic Adenocarcinoma: Current Problems in Surgery

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Current Problems in Surgery 53 (2016) 107–154

Contents lists available at ScienceDirect

Current Problems in Surgery

journal homepage: www.elsevier.com/locate/cpsurg

Other risk factors

Staging and resectability

Primary tumor (T)

TX Primary tumor cannot be assessed

Regional lymph nodes (N)

Distant metastasis (M)

National Comprehensive Cancer Network Intergroup Trial 2013

Bernheim145 ﬁrst performed an early “abdominal organoscopy” before an exploratory

As pancreatic cancer is believed to be a systemic disease with a narrow therapeutic window,

Study Patients Inclusion Institution, Country Treatment regimen Median overall

Talamonti et al450 20 2002-2003 Feinberg School of EBRT and 26 (Resected)

Gemcitabine, a pyrimidine analog introduced in 1996, is the primary chemotherapeutic agent

M.F. Eskander et al. / Current Problems in Surgery 53 (2016) 107–154

RT is thought to promote locoregional control, as an association between RT and decreased

Targeted therapy and immunotherapy

Preoperative considerations and preparation

Patient selection and risk calculators

Fig. 6. Reconstructions in a standard pancreaticoduodenectomy (A) and pylorus-sparing pancreaticoduodenectomy (B).

Operative techniques and outcomes

Minimally invasive vs open

Vascular resections and extended pancreatectomy

In contrast, arterial resection during pancreatectomy is associated with a 5-fold increased

Grade NGT required Unable to tolerate solid Vomiting or gastric Use of

A 4-7 Days or reinsertion 4 POD 3 7 Yes or no Yes or no

NGT, nasogastric tube; POD, postoperative day.

Perioperative outcomes—Morbidity and mortality

Grade A Grade B Grade C

Clinical condition Well Often well Ill-Appearing

US, ultrasound; CT, computed tomography.

complications include dumping and endocrine or exocrine insufﬁciency. An estimated 20%-30%

Volume or outcome relationships

Risk factor Points

Pancreatic duct diameter (mm)

Intraoperative blood loss (mL)

Resection is critically important for survival—patients with unresected pancreatic cancer

resection is superior.353,354 It remains a key objective in the resection of adenocarcinoma of the

The combination of radiotherapy with chemotherapy for palliation remains controversial.416

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