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Chapter 16
Pancreatic Ductal Adenocarcinoma
RicardoJ.Bello andCallisiaN.Clarke
Introduction
It is estimated that over 62,000 people were diagnosed with pancreatic cancer in the
United States in 2022. Pancreatic cancer is now the third leading cause of cancer
deaths in the United States [1], rising in the mortality ranks as prognosis improves
for other cancers. Similarly, the burden of disease caused by pancreatic cancer has
signicantly increased worldwide over the past three decades [2]. Most pancreatic
cancers arise from the exocrine pancreas and are characterized as pancreatic ductal
adenocarcinoma (PDAC). Neuroendocrine tumors of the pancreas, the next most
prevalent type of pancreatic cancer, represent about 3% of pancreatic cancers. This
chapter focuses on work-up and treatment sequencing for PDAC.
Pathophysiology
PDAC most often originates from pancreatic intraepithelial neoplasia (PanIN)
lesions. These premalignant lesions gain genetic alterations in a somewhat uniform
pattern to ultimately transform into PDAC.Most PanIN lesions will develop early
in the KRAS oncogene, with subsequent acquired mutations in CDKN1A and
CDKN2A, while TP53 and SMAD4 tend to occur at later stages of malignant transformation. Fewer PDAC cases arise in the setting of intraductal papillary mucinous
neoplasms (IPMN) [2]. This limited subset of premalignant lesions arises from proliferation of mucin-secreting neoplastic epithelium and generally carries favorable
prognosis at early stages. IPMN offer an opportunity for prophylactic pancreatic
R. J. Bello · C. N. Clarke (*)
Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
e-mail: rbello@mcw.edu; cnclarke@mcw.edu
Switzerland AG 2025
E. P. Ceppa et al. (eds.), The SAGES Manual of Evolving Techniques in
Pancreatic Surgery, https://doi.org/10.1007/978-3-031-78409-5_16
275© The Author(s), under exclusive license to Springer Nature
276
resection as determined with clinical and radiological surveillance. However, current risk stratication systems imprecisely estimate IPMN malignant potential,
resulting in resource-intensive surveillance and overtreatment for some patients
with IPMN [3].
Advances in molecular and genomic analyses have led to multiple classications
of PDAC based on molecular signatures of tumor samples. Of these, the classication system that appears to be most clinically relevant distinguishes between basallike and classical (i.e., pancreatic progenitor) types of PDAC.The basal-like subset
has been linked with worse prognosis and decreased response rates to chemotherapy
when compared to the classical subset [2].
R. J. Bello and C. N. Clarke
Work-Up
Computed tomography (CT) is the most frequently used imaging tool for pancreatic
cancer diagnosis and staging. Our institutional CT protocol for pancreatic tumors
includes multidetector-row CT imaging with thin sections over the upper abdomen
and dual phase contrast (late arterial pancreatic and portovenous phases) providing
high-resolution images of the primary tumor and its relation to surrounding vascular
structures. It also allows detection of metastatic lesions in the lung, liver, and
regional lymph nodes and is therefore critical when determining clinical stage
[4–6]. From these images, it is possible to render advanced 3D imaging for additional detail on the primary tumor’s relationship with surrounding vessels.
There is >90% correlation between high-quality preoperative pancreas protocol
CT and intraoperative ndings at high-volume pancreas centers [7–9]. It is therefore
critical to obtain high-resolution pancreas protocol CT prior to any invasive procedures (e.g., ERCP) which can obscure tissue planes and limit the ability to accurately stage patients due to bleeding, inammation, or artifact from biliary stents.
Similarly, it is critical to obtain updated imaging after completing neoadjuvant treatment and prior to pancreatectomy.
Tissue Diagnosis
A pancreatic mass that is suspicious for PDAC will prompt tissue biopsy to conrm
the diagnosis. This is particularly necessary in patients undergoing a neoadjuvant
approach to pancreas cancer treatment. Endoscopic ultrasonography (EUS) with
ne needle aspiration (FNA) is the preferred approach to obtain tissue samples for
diagnosis. Additionally, EUS provides additional information regarding the relationship between the tumor and its surrounding vessels as well as the extent of disease in the regional nodes [10]. EUS needle biopsy avoids the theoretical risk of
16 Pancreatic Ductal Adenocarcinoma
277
intra-peritoneal seeding that is described with percutaneous CT-guided biopsies.
Moreover, EUS can be done as part of the same anesthesia event as endoscopic
retrograde cholangiopancreatography (ERCP), with the option of stenting the bile
duct in the common setting of biliary obstruction, to ensure sustainable biliary
drainage. The downside of EUS is that it is operator dependent and therefore
requires centers to have experienced endoscopists available for reliable, accurate,
and safe tissue diagnosis.
Serum Tumor Markers
Serum carbohydrate antigen (CA19-9) should be obtained in all patients with PDAC
after serum bilirubin has normalized and before starting any treatment modality.
This sialylated Lewis antigen is the most widely validated biomarker for PDAC, and
its trends can be informative in more than 70% of patients. However, serum CA19-9
will be non-informative in up to 30% of patients with PDAC.This is because about
5–10% of the population will be CA19-9 “non-producers” because they lack the
enzyme to synthesize any level of the antigen. Roughly 20% of patients with PDAC
will be CA19-9 non-responders, because their tumor never produces the antigen
above the normal range. In these patients, a low CA19-9 does not add any data to
inform management. For this reason, it is important to state that a normal CA19-9in
the setting of clinical or imaging ndings suggestive of a pancreatic mass does not
preclude pancreatic cancer.
For patients who do produce CA19-9, serial measurements of serum levels
throughout receipt of multimodal therapies and during surveillance are helpful for
prognostic purposes and to guide treatment decisions. Very elevated levels correlate
with higher disease burden, lower potential for R0 resection, lower response to therapy, and worse overall survival [11]. After completing neoadjuvant therapy, normalization or CA19-9 or at least a decrease to half of the pre-treatment level is
signicantly associated with higher rates of surgical resectability and improved survival outcomes [12]. After pancreatectomy, normalization of CA19-9 is also associated with improved survival outcomes, [13] especially for patients with localized
PDAC undergoing neoadjuvant treatment who may harbor micrometastatic disease
not evident in CT imaging [14]. Sustained elevations of CA19-9 on the other hand
will signal tumor recurrence, many times preceding CT or clinical evidence of
recurrence for up to 6months [13, 15–17]. The second most documented tumor
marker for PDAC is carcinoembryonic antigen (CEA). Although levels of this glycoprotein have been traditionally associated with colorectal cancer, it is also elevated in other cancer types, including 30–60% of PDAC cases. In patients with
PDAC, CEA has been shown to be an independent predictor of worse overall survival and its addition to CA19-9 is more informative than measuring CA19-9
alone [18].
278
R. J. Bello and C. N. Clarke
Staging andClassication
Patients with PDAC are classied into four separate categories based on CT ndings: resectable, borderline resectable, locally advanced, and metastatic (Table16.1).
This classication allows patients to be stratied on the probability of achieving an
R0 (margin-negative) resection while preserving critical visceral blood ow, and
guides decision-making on multimodal treatment sequencing. Naturally, oncologic
outcomes are signicantly superior when R0 resection is achieved compared to R1
(microscopically positive margin) resection. Overall survival ranges between 11
and 15months for R1 resection achieved in upfront surgery cohorts, compared to
18–23months among patients with R0 resection [20–22]. Pancreatectomy achieving only a R2 resection offers no survival benet over systemic therapy alone, demonstrated by similar overall survival when comparing these patients to those
undergoing nonoperative treatment for unresectable locally advanced disease or
Table 16.1 Classication of resectable, borderline resectable, and locally advanced pancreatic
cancer as determined by the Multidisciplinary Pancreatic Cancer Working Group at the Medical
College of Wisconsin
Locally advanced ALocally
Resectable Borderline resectable
Tumor–
arterial
interface
Tumor–
venous
interface
Likely candidate for
surgical resection
after neoadjuvant
therapy
Modied from Tsai etal. [19]
SMA superior mesenteric artery, CA celiac artery, HA hepatic artery, PV portal vein
SMA None ≤180° abutment >180° but ≤270°
encasement
CA None ≤180° abutment >180° without
extension to aorta
with possibility for
celiac resection
with or without
reconstruction
HA None Short segment
abutment or
encasement without
extension to CA or
HA bifurcation
PV-SMV None Tumor-induced
narrowing >50% of
the SMV, PV or
portal conuence
with suitable targets
above (PV) and below
(SMV) for
reconstruction
Yes Ye s Yes No
>180° with
extension to CA
but not HA
bifurcation and
amenable to
reconstruction
Occlusion of PV/SMV conuence
with no targets for reconstruction
advanced B
>270°
>180°
encasement
with extension
to aorta
>180°
encasement
with extension
beyond HA
bifurcation
16 Pancreatic Ductal Adenocarcinoma
279
metastatic disease [20, 22, 23]. There is no role for surgical debulking in pancreatic
cancer. Resection should only be attempted with the goal of achieving complete
tumor extirpation with regional lymphadenectomy or for specic palliative purposes.
Most patients diagnosed with pancreatic cancer will have evidence of metastatic
disease on presentation; another 25% will have locally advanced disease with the
primary tumor involving surrounding vascular structures. Only about 20% will have
truly resectable disease [24]. A subset of patients with limited involvement of surrounding vascular structures will become operable after responding to neoadjuvant
multimodality treatment, allowing pancreatectomy with curative intent and with a
high probability of R0 resection. These patients are categorized as borderline resectable and they derive signicant oncologic benet from additional treatment modalities such as cytotoxic chemotherapy and external beam radiation prior to
pancreatectomy [25, 26]. The classication between resectable and borderline
resectable pancreatic cancer is important as it has signicant implications for management and prognosis. When compared with patients with resectable pancreatic
cancer, patients with borderline resectable disease carry higher risk of occult metastatic disease. They also usually require complex surgical resections with possible
vascular reconstruction and have a higher probability of margin-positive resection.
These patients benet the most from neoadjuvant chemotherapy and chemoradiation, increasing rates of R0 resection by tumor downstaging and margin sterilization, as well as from helping to select and only operate on patients who will benet
from pancreatectomy.
Recent improvements in systemic therapy for PDAC with the use of modied
FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound paclitaxel have
resulted in improved response rates and survival outcomes across all stages of disease. These chemotherapy regimens can be used in the neoadjuvant setting, signicantly increasing the proportion of patients who are eligible for resection [26–28],
highlighting the importance of accurate staging and early stratication for
resectability.
There is a lower likelihood of a margin-negative resection with increasing tumorvasculature interface [29]. It is now well established that high rates of R0 resection
are achievable with acceptable outcomes with resection of the superior mesenteric
vein (SMV), portal vein (PV), or portal conuence when there is venous involvement with PDAC primary tumors [30–32]. This is not true for superior mesenteric
artery (SMA) and celiac artery involvement. The reason behind this difference is the
potential for tumor extension along the periarterial autonomic neural tissue, which
acts as a conduit for the tumor along the involved vessel [33]. Patients with PDAC
and arterial involvement will often have microscopically positive arterial margins,
even away from gross tumor, unless they undergo neoadjuvant treatment with chemotherapy and/or chemoradiation. Logically, there are lower rates of R0 resection
as the tumor-artery interface progresses from abutment of the vessel to encasement.
Distinguishing between borderline resectable and locally advanced PDAC
depends on careful examination of the relationship between the tumor and arteries
(i.e., SMA, celiac trunk, hepatic arteries) to determine abutment (≤180° tumor contact) or encasement (>180° tumor contact) of these structures. Further attention is
280
R. J. Bello and C. N. Clarke
focused on the tumor’s relationship with the SMV or PV, with specic care to identify a proximal and distal target for any reconstruction required for venous involvement with narrowing or occlusion. At our institution, we dene borderline resectable
disease as that which is limited to tumor abutment at the SMA or celiac axis, or
short segment encasement of the hepatic artery. Tumor-associated narrowing of
over 50% of the SMV, PV or portal conuence, or occlusion with suitable proximal
and distal targets for vascular reconstruction also represents borderline resectable
disease (Table16.1). Locally advanced disease is dened by either encasement of
the SMA, celiac artery or long segment of hepatic artery, or SMV-PV occlusion
without an option for venous reconstruction.
Most patients with borderline resectable pancreatic cancer can undergo resection
with curative intent if there is careful management of multimodal sequencing of
neoadjuvant therapy paired with prehabilitation and good patient selection. Katz
etal. [25, 26] reported on 160 consecutive patients with borderline resectable pancreatic cancer treated at a single tertiary cancer center over 7years. All patients
underwent neoadjuvant chemotherapy and/or chemoradiation. Chemotherapy
included either single-agent gemcitabine or gemcitabine in combination.
Chemoradiation included a radio-sensitizing agent such as 5-uorouracil (FU),
paclitaxel, gemcitabine, or capecitabine alongside external beam radiation (most
frequently to 50.4Gy in 28 fractions). Of these 160 patients, 125 (78%) completed
neoadjuvant therapy and 66 (41%) proceeded to pancreatectomy, achieving negative margins for 94% of these patients. Median survival for patients who completed
all intended therapy was 40months, compared to 13months in patients who did not
undergo resection (p<0.001).
Contemporary chemotherapy regimens have increased the rates for surgical
resectability in patients with locally advanced PDAC.Chatzizacharias et al. [34]
described their experience with 96 consecutive patients with locally advanced
PDAC treated at a single high-volume tertiary cancer center over a 9-year period.
They divided locally advanced disease into two subtypes based on tumor-vascular
anatomy (Table16.1.) In this cohort, 45 patients (47%) had locally advanced type A
disease at time of diagnosis while 51 (53%) had locally advanced type B disease.
All patients were treated with neoadjuvant induction chemotherapy (FOLFIRINOX
and/or Gemcitabine plus nab-paclitaxel) for a minimum of 4months followed by
chemoradiation. Fifty-six patients were not candidates for resection following neoadjuvant therapy due to progression, no improvement, or development of metastasis. Forty patients (42%) underwent pancreatectomy with 80% achieving R0
resection; 28 of these patients were locally advanced type A accounting for 62% of
patients initially evaluated, while only 12 patients (24%) of locally advanced type B
patients became candidates for resection. These patients underwent complex resections with a major morbidity of 15% (Clavien-Dindo Grade 3 or greater), median
length of stay of 9 days, and no perioperative mortality. Patients with locally
advanced pancreas cancer who underwent resection had a median overall survival
16 Pancreatic Ductal Adenocarcinoma
281
of 37.5months compared to 15.8months in those that were not resected. This study
demonstrated that with appropriate patient selection and neoadjuvant multimodality
sequencing incorporating contemporary chemotherapy regimens, a subset of locally
advanced pancreas cancer patients, traditionally deemed unresectable, may undergo
complex resections with high probability of complete resection and associated survival benet when performed at high-volume centers. For this reason, in order to
best identify patients at diagnosis with a reasonable chance of proceeding to surgical resection with a survival benet, our institution has further divided locally
advanced pancreas cancer into two subtypes, type A and B, each with an associated
probability for resectability of 62% and 24%, respectively. Locally advanced pancreas cancer type A is considered potentially resectable after extensive neoadjuvant
treatment while locally advanced type B is generally deemed unresectable.
Multidisciplinary Decision-Making
At the time of diagnosis, there should be consideration of surgical resection for
patients with favorable anatomy and good performance status. Treatment plans and
appropriate sequencing should be made as part of a multidisciplinary discussion
with input from medical oncology, surgery, diagnostic radiology, radiation oncology, and interventional gastroenterology. The decision to approach a patient with
the intent to perform curative pancreatectomy should be determined near diagnosis
based on patient factors and cross-sectional imaging.
Even in patients with resectable disease at the time of diagnosis, there are signicant advantages of pursuing total neoadjuvant therapy (TNT) as the routine
approach for PDAC.First, TNT ensures that all intended therapies are completed
prior to undergoing pancreatectomy. This increases the proportion of patients
receiving all the necessary modalities for optimal survival outcomes after pancreatectomy for PDAC.It is widely accepted that even in the most experienced hand,
only about 50–60% of patients will go on to receive adjuvant chemotherapy after
pancreatectomy for PDAC. Second, neoadjuvant therapy will often downstage
tumors, increasing the likelihood of a margin-negative resection. Finally, a TNT
approach helps to identify patients who will develop early distant metastatic disease or tumor progression despite the best available systemic therapy, and who are
then spared of the morbidity of a pancreatectomy that would be unlikely to offer
any survival benet.
There has been rapid uptake in the past decade of neoadjuvant chemotherapy for
resectable and borderline resectable PDAC.The shift toward neoadjuvant therapies
is founded on improved response rates with chemotherapeutic regimens in the adjuvant settings. We will therefore summarize the evidence for adjuvant chemotherapy
and radiation therapy before focusing on neoadjuvant therapies.
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R. J. Bello and C. N. Clarke
Adjuvant Trials
Systemic Chemotherapy
Chemotherapy is a key component of treatment for PDAC since it is mainly a systemic disease. The rst drug that was studied for advanced pancreatic cancer was
uorouracil (5-FU). Monotherapy with 5-FU produced negligible response rates
and did not offer signicant palliative or survival benet [35, 36]. Burris etal. [37]
then studied patients with advanced pancreatic cancer treated with gemcitabine,
comparing this to patients treated with 5-FU, both as single therapies in a randomized controlled clinical trial. Patients treated with gemcitabine had higher clinical
response rates (23.8%) compared to 5-FU (4.8%, p=0.002). Burris etal. also demonstrated a signicant increase in median survival by 1month for these patients
(5.7months vs. 4.4months, p=0.003). Although these survival outcomes are much
lower than those achieved with contemporary chemotherapy regimens, this promising nding led the way to gemcitabine being approved for PDAC as rst-line
therapy.
Compared to 5-FU, capecitabine (an oral uoropyrimidine converted in the gastrointestinal tract into 5-FU) results in higher drug concentration in tumor tissue
[38]. Capecitabine as monotherapy has been shown to be more efcacious than
5-FU and to have similar response rates (24%) to gemcitabine [39]. Demonstrating
effectiveness of both gemcitabine and capecitabine as single agents for PDAC was
a key step before developing combination chemotherapy regimens that would later
improve response rates and survival outcomes in patients with advanced
PDAC. Newer chemotherapy combinations achieved median overall survival
approaching 1year in the setting of unresectable disease [27].
Conroy etal. studied combination chemotherapy using 5-FU/leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) in a phase II/III randomized controlled clinical trial involving 342 patients with advanced pancreatic cancer and good
performance status. Comparing FOLFIRINOX to single-agent gemcitabine, they
demonstrated longer overall survival (11.1months vs. 6.8months, p<0.001), longer progression-free survival (6.4months vs. 3.3 months, p <0.001), and higher
response rates (31.6% vs. 9.4%, p<0.001) among patients treated with FOLFIRINOX
[27]. This study therefore established FOLFIRINOX as rst-line therapy for
advanced pancreatic cancer in patients with good performance status who can tolerate treatment. Building on this experience, Conroy etal. conducted a more recent
randomized controlled, clinical trial using modied FOLFIRINOX (without bolus
uorouracil to decrease toxicity) among patients with PDAC who underwent pancreatectomy with R0 or R1 resection and no evidence of metastatic disease. The
PRODIGE-24 trial reported a median follow-up of 33.6months and established
superiority of modied FOLFIRINOX over gemcitabine with longer disease-free
survival (21.6 months vs 12.8 months, p < 0.001) and longer overall survival
(54.4months vs 35months, p=0.003). However, there was a higher incidence of
toxicity events for patients on the modied FOLFIRINOX arm, as 75.9% of patients