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20 Management of Primary Pancreatic
https://t.me/medicina_free
Cancer
Omali Pitiyarachchi1, John Kokkinos1, George Sharbeen1, Phoebe A. Phillips1,
2,3
Robert C. Gandy
3,6
Thompson
1
Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, New South Wales, Australia
2
Department of General Surgery, Prince of Wales Hospital, Randwick, New South Wales, Australia
3
School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, New South Wales, Australia
4
Medical Imaging Department, Prince of Wales Hospital, Randwick, New South Wales, Australia
5
Graduate School of Biomedical Engineering, Faculty of Engineering, UNSW Sydney, New South Wales, Australia
6
Department of Radiation Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia
7
Department of Palliative Medicine, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia
8
Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia
, Jessica A.L. Borbasi7, Rebecca Strutt
, Koroush S. Haghighi
2,3
, Daniel A. Moses
3,7
& David Goldstein
4,5
, Stephen R.
3,8
Introduction
Omali Pitiyarachchi & David Goldstein
Globally, primary pancreatic cancer is the seventh most
common cause of cancer deaths (Bray et al. 2018). In Australia
this has now become the third commonest cause of cancer
deaths (AIHW 2021), and it is projected to move to second
most common cause of cancer deaths by 2030 (Rahib et al.
2014; Siegel et al. 2022). The most common subtype is
pancreatic ductal adenocarcinoma (PDAC) which comprises
85% of all pancreatic carcinomas. The five-year overall survival
rate for PDAC is 11% for all stages combined and has improved
modestly from 6.5% in 2007–2019, attributed to both earlier
diagnosis and new treatments (AIHW 2021). Survival correlates with stage and surgical resectability. Surgical resection is
considered feasible if systemic dissemination is absent, and
local invasion of adjacent structures such as major vessels is not
evident; discussed further in the Surgery section of this chapter.
Only 20% of patients have resectable disease at diagnosis
(Butturini et al. 2008), and approximately 15% can undergo
complete surgical resection (Burmeister et al. 2015). The
majority of patients have metastatic or locally advanced disease
at diagnosis (80–85%) with a poor outcome of 3% overall
survival at five years (Siegel et al. 2022). A major contributing
factor to the poor prognosis is chemoresistance and the negative role of tumor stroma which is further discussed in the
Biology section.
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
Biology
John Kokkinos, George Sharbeen & Phoebe A. Phillips
PDAC originates from ductal epithelial cells in the pancreas
and evolves from pre-malignant lesions (pancreatic intraepithelial neoplasia, PanIN) (Hidalgo 2010). Genomic and transcriptomic data have identified distinct subtypes of PDAC that
correlate with varying degrees of patient outcome and chemotherapy response (Bailey et al. 2016; Collisson et al. 2011;
Moffitt et al. 2015; Waddell et al. 2015). However, actionable
molecular targets in PDAC patients are infrequent at 20–30%
(Bailey et al. 2016; Waddell et al. 2015), and overlaid with access
and clinical barriers – with two key studies showing that only
2–3% of PDAC patients who were referred to a precision medicine program received personalized targeted therapy (Ding
et al. 2021; Pishvaian et al. 2020). The bigger opportunity for
precision medicine in PDAC may instead lie in the microenvironment of PDAC (Kokkinos et al. 2021a).
Early in PDAC development, a marked desmoplastic reaction
occupies up to 90% of the PDAC tumor and is composed of extracellular matrix (ECM) and stromal cells, mainly consisting of
cancer-associated fibroblasts (CAFs) (Erkan et al. 2012; Li et al.
2010; Phillips 2012). CAFs produce the dense fibrosis in PDAC
which compresses tumor vasculature and increases intratumoral
fluid pressure, creating a physical barrier to drug delivery and
immune cell penetration (Diop-Frimpong et al. 2011; Olive et al.
2009b; Provenzano et al. 2012). Importantly, certain stromal features in PDAC, including high cross-linked collagen or hyaluronan content for example, correlate with poor patient outcome
(Cheng et al. 2013; Erkan et al. 2008; Miller et al. 2015; Whatcott
et al. 2015). High levels of hypoxia, nutrient deprivation, and
oxidative stress created by the tumor microenvironment
(Kamphorst et al. 2015; Martinez-Useros et al. 2017; Pan et al.
2016; Tao et al. 2021) also drive the selection of aggressive and
386
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heterogeneous clones of PDAC and CAF cells with a more
chemoresistant and metastatic phenotype (Chaika et al. 2012; Cheng
et al. 2014; Qin et al. 2020; Shukla et al. 2017; Tréhoux et al. 2015).
Additionally, CAFs directly exert pro-tumorigenic effects on
surrounding PDAC cells through the release of cytokines,
growth factors, and nutrients, and the formation of an immunesuppressive landscape (Huber et al. 2020; Karamitopoulou
2019). For example, a recent study showed that PDAC CAFs are
highly reliant on the cystine transporter SLC7A11 and dual-cell
therapeutic targeting of SLC7A11 in both PDAC cells and
CAFs reduced fibrosis and tumor progression in vivo (Sharbeen
et al. 2021). Furthermore, CAFs are capable of promoting
metastasis of PDAC cells (Hwang et al. 2012; Pan et al. 2021;
Vonlaufen et al. 2008; Xu et al. 2010). This process can be stimulated by CAF secretions such as TGF-β (Ligorio et al. 2019).
Additionally, evidence has shown that CAFs are capable of
metastasizing together with PDAC cells to promote the
formation of a pro-metastatic niche in distant organ sites (Xu
et al. 2010).
The above evidence suggests the therapeutic potential of
targeting pro-tumor functions of CAFs and the stroma for
PDAC treatment. However, clinical trials targeting the
PDAC stroma have failed to show survival advantage to
PDAC patients. The sonic hedgehog inhibitor vismodegib,
which showed promise in preclinical studies (Olive et al.
2009a), showed no treatment benefit in phase I and II
clinical trials (Catenacci et al. 2015; Kim et al. 2014). An
enzymatic approach to degrade the PDAC stroma using the
drug PEGPH20 showed encouraging preclinical activity
(Provenzano et al. 2012), but a phase III trial in metastatic
PDAC patients showed no survival benefit (Van Cutsem et
al. 2020). These failed clinical trials show that targeting the
stroma alone as a “one-size-fits-all” approach is unlikely to
be effective. Recent research has shifted towards an approach
of understanding the inter-patient and intra-patient cellular
heterogeneity of the PDAC stroma to design more personalized therapeutic strategies.
Recent advances in single cell transcriptomics have identified subtypes of CAFs with proposed distinct functions within
the PDAC microenvironment (Elyada et al. 2019; Öhlund et al.
2017). This is further complicated by the observation that
stromal transcriptomic signatures within the spatial architecture
of PDAC show distinct associations with patient outcomes
(Ligorio et al. 2019); although the functional role of these
stromal signatures need to be validated to allow for therapeutic
exploitation.
To facilitate translation of therapeutics that target the
PDAC stroma, preclinical models need to accurately mimic
the complexity and heterogeneity of human PDAC. The
PDAC tumor explant model, which maintains the viability,
3D tumor and stromal architecture, and genetic drivers of
surgical patient PDAC tissue for 12 days, carries potential to
guide the translation of stromal targeting strategies
(Kokkinos et al. 2021b; Sharbeen et al. 2021). These explants
can be utilized in a precision medicine setting based on
stromal and/or tumor signatures of each patient as a
functional tool to inform patient treatment in real-time
(Kokkinos et al. 2021a).
To maximize the translation of recent scientific advances, an
active collaboration is required between researchers and clinicians so that researchers gain a clinically relevant perspective,
while clinicians can facilitate the clinical translation of promising new therapeutic strategies.
Areas for Further Research
• It remains unknown how the high degree of transcriptional
and spatial heterogeneity of the PDAC stroma influences
patient response to chemotherapy and whether distinct CAF
subtypes can be therapeutically exploited.
• Pre-clinical models that accurately mimic the complexity
and heterogeneity of human PDAC are needed to guide the
translation of novel therapeutic strategies that target tumor and
stromal cells.
• Need for understanding the basis of response and failure to
targeted tumor and stromal therapies, and development of
novel therapeutic strategies for future evaluation. This can
involve embedding deep correlative science on pre- and posttreatment specimens in mice and humans.
Incorporating Translational Scientists
in the Clinic to Maximize Translation
John Kokkinos, George Sharbeen & Phoebe A. Phillips
The inclusion of translational research teams in cancer MDT
meetings can bridge the gap between research lab and clinic.
These meetings provide opportunities for researchers to follow
the whole cycle of patient management and appreciate the
clinical challenges faced by PDAC patients. Key issues we now
appreciate are that patient treatment selection is often based
on performance status and comorbidity profile rather than
tumor biology alone – reinforcing the need for functional
precision medicine tools to guide treatment selection.
Furthermore, disease progression is often rapid, so precision
medicine tools must have fast turnaround times to be clinically
meaningful. Another unmet clinical challenge is that most
patients present with metastatic disease yet most research
involves cell lines or tissue samples obtained from surgically
resectable disease, which represent a minority of PDAC
patients with better prognosis. Future collaborative research
should focus on obtaining metastatic tissue samples for
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research purposes and integrating scientists in trial design to
allow integrated scientific evaluation of clinical trial samples
pre- and post-treatment to understand the biological basis
behind success or failure of new therapeutics as well as basic
scientific discoveries (Figure 1).
To allow for seamless integration of translational scientists
into cancer MDT meetings, educational programs should be
available for researchers to upskill their clinical expertise to be
able to follow the fast-paced nature of an MDT meeting. This
will enable scientists to contribute to MDT meetings – while
they may not be able to directly influence patient management,
they can educate the MDT on the latest advancements in
research and how the present clinical challenge can be potentially solved by future developments in the field.
Multidisciplinary Team
Omali Pitiyarachchi & David Goldstein
Multidisciplinary care has become the gold standard in the
management of patients with pancreatic cancer (Maharaj et al.
2021). The purpose of the MDT includes establishing the diagnosis by evaluating the patient’s history, tumor pathology, biomarkers, and imaging. It also encompasses staging, a decision
about tumor resectability, and overall management plan. In cases
where upfront resection is not possible, or metastatic disease is
present, then a discussion regarding optimum radiation and/or
systemic therapy is recommended. There may also be cases where
the best recommendation for the patient is for no intervention.
Figure 1 A new model of translational research using the power of deep correlative science to inform patient treatment and guide future research goals.
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The discussion is led by a clinician who has taken responsibility for that patient, advocating for their wishes, and ensures
MDT recommendations are followed through (Taylor et al.
2014). The MDT required to discuss a patient with pancreatic
cancer should include representatives from upper gastrointestinal surgery, gastroenterologists, medical oncologists, radiation oncologists, radiologists, nuclear medicine physicians,
pathologists, as well as palliative/supportive care, nursing staff,
allied health (dietician, social work), genetics, and General
Practitioners. The presenting clinician should be able to provide sufficient and timely information for the MDT so that
treatment recommendations are well informed and more likely
to be actioned (Jalil et al. 2013; Stairmand et al. 2015).
The increasing complexity of pancreatic cancer care and the
implementation of multi-modality treatment highlights the
value of an MDT (Maharaj et al. 2021). Despite the lack of conclusive evidence of increased survival, specialized MDT should
result in increases in optimal personalized management, appropriate surgical treatment and increased clinical trial enrolment.
Improved guideline adherence and patient satisfaction, reduced
waiting times, and measurable changes in cancer management
in up to 52% of cases are reported (Croke and El-Sayed 2012;
Lamb et al. 2013).
Although all patients with pancreatic cancer should be formally presented, due to large numbers and meeting frequency,
this may not be possible. More complex cases requiring multidisciplinary input should be prioritized, but registering all
patients does enable monitoring of local outcomes over time as
part of benchmarking of quality and safety. To ensure that no
patient is disadvantaged due to geography, networked MDTs
can allow access for patients and their clinicians in centers with
potential lack of expertise. This can result in changes in disease
stage assessment and access to multimodality (Pawlik et al.
2008) therapy by enabling greater access to these services.
Which Patients should be discussed at a
Pancreatic Cancer MDT?
Ideally all patients diagnosed with pancreatic cancer should be discussed, but if resources are limited, prioritize discussion of:
• Patients with a new diagnosis of non-metastatic disease
• Recurrence with oligometastatic disease and/or unusual site of
recurrence
The Role of Imaging in the Work-up
of a Patient with Pancreatic Cancer
Daniel A. Moses
Medical imaging is the primary means by which the stage of
pancreatic adenocarcinoma is determined. It is performed at
presentation and following neo-adjuvant treatment to provide
adequate staging and assessment of tumor resectability.
Staging for pancreatic adenocarcinoma is based on the TNM
classification system described by eighth edition of the
American Joint Committee on Cancer (AJCC) and the
International Union of Cancer Control guidelines (Chun et al.
2018). Non-invasive imaging methods that can be used for
diagnosis include computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography
(PET). Endoscopic ultrasound (EUS) can also be used, but is
more invasive.
CT is the modality of choice for diagnosis and staging due to
its speed of acquisition, availability, excellent spatial resolution,
and ease of standardization of scanning protocols across different vendors and institutions. It outperforms EUS and is
equivalent to MRI in terms of accuracy of staging (Shrikhande
et al. 2012). In respect to assessing resectability, CT has high
sensitivity (87%), moderate specificity (63–75%) and highlights pancreatic lesions and vascular anatomy, in particular
involvement of vascular structures around the tumor (Hong
et al. 2018).
CTs’ high spatial resolution allows detection and accurate
measurement of lymph nodes. Unfortunately, the low soft
tissue contrast is not accurate at detecting micrometastatic
deposits within lymph nodes. Therefore, the nodal staging
of CT is limited, and usually related to size criteria. At a cutoff of 5mm short axis diameter the accuracy for the detection of nodal metastatic disease is 55–60% (Shrikhande et al.
2012).
Liver metastases from pancreatic adenocarcinoma are typically hypoenhancing on the portal venous phase and CT has
been shown to have a good sensitivity (70–76%) in their detection (Motosugi et al. 2011; Zhang et al. 2012). Early metastatic
disease often involves the peritoneum, but is often subtle and difficult to detect on CT. This is especially true if there is background
pancreatitis, for example from ERCP and stent insertion.
For the assessment of resectability and local staging of
pancreatic cancer, the American College of Radiology (ACR)
guidelines (Jones et al. 2017; Qayyum et al. 2017) recommend
a biphasic acquisition with:
1 a late arterial phase timed to peak enhancement of the
pancreatic parenchyma to maximize visualization of the
primary tumor (typically 45–50 sec after the start of the IV
injection).
2 a portal venous phase to optimize visualization of venous
structures and detectability of hepatic metastases (typically 70
seconds after the start of the IV injection).
The sensitivity and accuracy of contrast enhanced CT for
staging pancreatic adenocarcinoma is high and does not appear
to vary between the different types of CT scanners (Zamboni et
al. 2007). However, imaging and interpretation at high-volume
centers may be more accurate (Walters et al. 2011). Without
intravenous contrast CT has poor soft tissue contrast and is not
useful in staging (Shrikhande et al. 2012).
EUS has variable sensitivity and accuracy for staging of pancreatic adenocarcinoma (<60% sensitivity). It is operator-dependent
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andtherefore unable to be standardized across institutes. However,
it is the most sensitive test for detecting small periampullary lesions
which are undetectable on CT or MRI (Wang et al. 2013), and is
best used as an adjunct or complementary modality to CT. EUS
plays a larger role in diagnosis and tissue acquisition.
Advances in MRI technology over the last few years have
improved spatial resolution and speed of acquisition but
staging using MRI still requires an acquisition time that may
extend up to 45 minutes, compared to CT of less than three
minutes. MRI also has the ability to look at functional aspects
of physiology and molecular processes. An important
functional sequence is diffusion weighted imaging which looks
at the motion of water molecules. It can detect when the diffusion of water molecules is restricted, such as in highly cellular
tumors, where the intra- and extracellular spaces are small. The
protocol of choice in the MRI staging of pancreatic cancer is
Magnetic Resonance Cholangiopancreatography (MRCP).
Contraindication to MRI include patients that have electronic
or metal implants, and those that are claustrophobic. In
comparison to CT, greater soft-tissue contrast can be appreciated on MRI and it is therefore far superior to staging CT when
IV contrast cannot be administered, for example in the setting
of renal failure. Overall, in respect to determining resectability,
contrast enhanced MRCP has a sensitivity of 93% and specificity of 50% to 75% (Hong et al. 2018), MRI has greater sensitivity (up to 90%) for detecting and characterizing liver
metastases when compared to contrast enhanced CT, especially
when combined with hepatospecific paramagnetic gadolinium
based contrast (Motosugi et al. 2011; Zhang et al. 2012).
The role of PET in staging for pancreatic adenocarcinoma is
unclear (Wang et al. 2014b). It is not useful in the local staging.
A recent Australian study (Burge et al. 2015) observed that PET
may change management for fluorodeoxyglucose (FDG)-avid
lesions; however, only about 75% of pancreatic tumors are
FDG-avid. When combined with CT, PET shows increased
sensitivity and changed management in 11% (Farma et al.
2008) and 16% (Burge et al. 2015) of patients.
Recommendations
• Dual phase contrast enhanced computed tomography within four
weeks of diagnosis should be performed for tumor-node-metastases
staging and assessing resectability before presentation to the multidisciplinary team.
• If no metastatic disease is detected the decision about whether a
tumor is resectable, borderline or nonresectable should be made by
consensus at a multi-disciplinary team meeting.
• If imaging shows metastases, no further scanning is required and a
biopsy should be conducted to confirm diagnosis (in this circumstance
a non-dual phase CT may be acceptable).
• Staging investigations should be conducted prior to biopsy or
stenting, as the presence of hematoma, stent artefact or pancreatitis
reduces the ability to accurately define resectability.
• When lesions are small (<1 cm), the sensitivity of the pancreatic protocol computed tomography is reduced and the endoscopic ultrasound
method should be considered to complement computed tomography
results for enhanced diagnosis. Endoscopic ultrasound plays a role
more so in diagnosis and tissue acquisition than in staging.
• If tissue resolution with the pancreatic protocol computed tomography is not clear (isodense pancreatic tissue or cystic lesions), or no mass
is visible but the patient is jaundiced (potential liver involvement), then
contrast enhanced MRCP should be performed to improve visual acuity
to increase diagnostic capability for malignancy.
• MRCP and PET, if available, may be considered prior to resection or
neoadjuvant therapy, to reduce risk of occult malignancy in patients
with atypical radiological findings or who are biologically borderline
(CA 19.9 ~500 U/ml).
Pre-operative Management
Robert C. Gandy & Koroush S. Haghighi
In the presence of a solid, resectable mass suspicious for adenocarcinoma, biopsy proof is not required before proceeding with
upfront resection. Initial tissue diagnosis (using EUS biopsy) is
advisable when it can be safely performed, as it may alter
treatment decisions in a small number of patients, such as those
with autoimmune pancreatitis (Gandy et al. 2016).
In contrast, confirmation of malignancy with biopsy is required
for patients with metastatic disease, locally advanced tumors, and
borderline resectable disease prior to commencing neoadjuvant
therapy. Biopsy is also recommended if a neuroendocrine tumor
is suspected, although Dotatate PET scan can provide an
alternative approach to biopsy to confirm grade 1/2 disease.
Tissue can be taken by passing a fine-needle under EUS
guidance (EUS-FNA or EUS-FNB) or under CT guidance. EUS
guided tissue acquisition has a lower risk of tumor seeding and
is preferred (Chen et al. 2012).
Successful predictors of diagnostic yield of EUS-guided
biopsy in pancreatic cancer include:
• experience of endoscopist
• number of passes of needle through tumor
• type of needle used (fine needle biopsy (FNB) vs fine needle
aspiration)
• presence of onsite cytologist/cytopathologist.
Ongoing research to improve the diagnostic accuracy of
EUS-FNA is ongoing. The presence of a cytologist during the
biopsy procedure improves diagnostic yield (Iglesias-Garcia
etal. 2011; Khan et al. 2017).
Pre-operative Biliary Stenting
• Patients considered for upfront surgery
Preoperative decompression of the biliary system should be
performed selectively on a case-by-case basis, factoring in
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surgical timing and preferably endoscopically. Considerations
include biliary sepsis or active coagulopathy, total bilirubin
levels of 20mg/dl or 340Umol/l, or when there is a need for
pre-surgical optimization or extended evaluation that may
delay surgery beyond two weeks. Multiple randomized trials
have been conducted in patients with potentially resectable
pancreatic cancer and malignant obstructive jaundice, with
one suggesting benefit for preoperative biliary drainage, but
the remaining eight concluding potential harm from sepsis
related morbidity or no benefit (Bonin and Baron 2011).
• Patients considered for neoadjuvant therapy
When neoadjuvant treatment is considered, preoperative stenting is mandatory to reduce the risk of interruption of systemic
therapy (Seo et al. 2019). Biliary stenting also restores GI continuity and improves nutrition over an extended treatment
period. Short uncovered or partially covered metal stents outperform plastic stents and can be removed at subsequent
surgery.
Laparoscopy
Staging Laparoscopy
Small hepatic or peritoneal metastases, which are not evident
from the preoperative studies, may be found at surgical exploration in 8–15% of cases. As an example, 117 of 1423 pancreatectomies (8%) intended for resection of pancreatic ductal
adenocarcinoma were aborted, most often due to occult liver
(79%) or peritoneal metastasis (16%) (Gemenetzis et al. 2019).
For this reason, many surgeons prefer to begin cancer operations with laparoscopy, which permits examination of the
liver and peritoneal surfaces and biopsy of any suspicious
areas, avoiding inappropriate laparotomy. A drawback is the
inability to determine whether any vascular invasion has
occurred that precludes resection, accordingly we restrict the
use of laparoscopy to cases with a high likelihood of unresectability, including the suspicion of lymph node metastasis not
proven on biopsy, indeterminate liver lesions, the presence of
peritoneal fluid or raised ca 19–9 above 250 U/ml (Gemenetzis
et al. 2019).
Pancreatic body and tail tumors have higher rates of occult
peritoneal metastasis and may warrant laparoscopy prior to
laparotomy. Timing of diagnostic laparoscopy can be prior to
trial of dissection and peritoneal washings may be performed
then or immediately prior to laparotomy.
Laparoscopy Prior to Neoadjuvant Therapy
In contrast to resectable disease, borderline resectable
pancreatic cancer (BRPC) is associated with higher rates of
occult metastatic disease (up to 25% of cases). In this setting,
laparoscopy to perform peritoneal washings and biopsy of suspicious lesions may be beneficial. Following neoadjuvant
therapy, laparoscopy prior to laparotomy in BRPC and locally
advanced pancreatic cancer (LAPC) can also reduce the
non-therapeutic laparotomy rate in between 20 and 36%
respectively and can fail to detect metastatic disease in only 5%
of cases (Peng et al. 2017; Ta et al. 2019).
Perioperative Care
Robert C. Gandy & Koroush S. Haghighi
A surgical treatment pathway is currently considered to be the
only potentially curative option for pancreatic adenocarcinoma.
At a minimum this includes surgery and adjuvant chemotherapy,
and confers both high morbidity and the risk of perioperative
mortality. Given the potential adverse impact, a surgical pathway
should be reviewed by a specialist multi-disciplinary team whose
role is to reduce rates of futile or non-therapeutic surgery.
Assessment
Referral pathways to pancreatic surgeons differ between healthcare systems around the world. In our own setting, patients
with suspected pancreatic malignancy are often referred to surgical teams for diagnosis, work-up, and therapy, whereas in
other regions referral to a pancreatic surgeon may take place
only after work-up is complete or even following induction
therapy. However, it is important for pancreatic surgeons to
make a complete assessment prior to initial MDT meeting and
therapy. Decision-making regarding the surgical pathway
chosen depends on clinician’s assessment of the resectability of
the disease and whether localized disease is determined to be:
Definitions
Resectable: These are tumors in which a successful pancreatectomy could be completed with clear margins and lower risk of
early recurrence.
Borderline resectable: These are tumors with substantial risk of
positive margins or lymph node metastasis if surgery was considered upfront.
Locally advanced: These are tumors that have not metastasized
but are initially inoperable but may be down staged or downsized, allowing successful surgery with clear margins.
A patient may be borderline resectable based upon anatomical (A), biological (B), or conditional (C) elements alone, or in
combination, as initially proposed by MD Anderson Cancer
Center (Isaji et al. 2018).
Clinical Assessment, Pre-optimization and
Preparation for Multidisciplinary Presentation
Clinical assessment plays a critical role, minimum information required includes the duration of illness, important
red flag symptoms, and signs for advanced disease such as
back pain or extensive weight loss. Clinicians should also have
had extensive discussion with patients and family members
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regarding their treatment wishes, so they may advocate on
their behalf at an MDT. It is important for clinicians to arrange
a pancreatic protocol computed tomography (PPCT) scan of
the chest and abdomen, tissue biopsy and bile duct stenting,
when appropriate (see below) and preoperative blood tests
should include liver function, renal function, diabetic function,
and tumor markers, prior to initial MDT (Gandy et al. 2016).
Patients being assessed for pancreatic surgery often have
significant medical comorbidities. Since most resections are
performed electively, adequate time is available to assess risk
factors and optimize the patient’s medical status. Early
assessment in a pre-anesthetic clinic gives the opportunity to
mitigate any risk factors, through specialist optimization of
known organ dysfunction. Formal nutritional assessment
and early dietetics intervention may help prevent weight loss
in the peri-operative period (early intervention in the form
of stenting, enteral, or even parenteral feeding, may be
required). Functional assessment with a specialist physiotherapist and pre-habilitation may improve outcomes of pancreatectomy but given time constraints may be most suited to
patients undergoing neoadjuvant therapy. Patients who are
considered borderline resectable on conditional grounds
may become resectable following medical optimization
(Bundred et al. 2020).
The median age of diagnosis of pancreatic cancer patients
is 70 years and with life expectancy increasing, a considerable proportion of patients will experience frailty syndrome.
Frailty has a significant impact on outcomes of pancreatic
surgical pathways and patients’ ability to undergo adjuvant
or neoadjuvant therapy. The clinical frailty score (CFS) is a
simple and easy-to-use screening tool for patients undergoing surgical pathways such as pancreatectomy for
pancreatic adenocarcinoma (Mcisaac et al. 2020). High CFS
scores correlate with survival as well as being a predictor of
peri-operative morbidity and new disability following surgery (Yamada et al. 2021).
However, the implementation of integrated surgical care of
older patients with surgeons and geriatricians mitigates the
effects of perioperative delirium and reduces complications
(Norris and Close 2020).
Initial Multidisciplinary Meeting (Non-metastatic
Pancreatic Adenocarcinoma)
In comparison to other tumor streams, where the TNM staging
system is estimated clinically and radiologically, non-metastatic pancreatic cancer is preoperatively staged by its resectability status. The treatment pathway may vary greatly on this
assessment. Of key significance is the appreciation and
agreement on what constitutes borderline resectability based
on the anatomical dimension of tumor-vessel relationship,
including elements related to biological factors of the tumor,
and conditional factors of the host.
Assessment of Resectability
Operable/resectable Pancreatic Cancer
Anatomically resectable disease under the international consensus is characterized by no tumor contact with arterial structures and up to 180 degree contacts with the superior mesenteric
vein (SMV)/portal vein (PV) confluence or unilateral narrowing of the SMV/PV confluence only. Limited vein contact on
imaging is not an independent risk factor for survival but is
associated with higher margin positivity (up to 35%) and the
need for venous resection and reconstruction (Tran Cao et al.
2014; Yamada et al. 2013).
Borderline Resectable Pancreatic Cancer
In 2016 the international consensus definition of borderline
resectable pancreatic cancer defined three distinct areas for the
assessment of non-metastatic disease (Isaji et al. 2018).
Anatomical factors of the disease: the tumor in relation to the
A
loss of fat planes between adjacent organs and major blood vessels.
B Biological: suspicion for metastatic disease despite appearing resectable based on anatomic criteria.
Conditional: patients with poor performance or comorbid-
C
ity, but otherwise resectable disease based on Anatomic and
Biological criteria.
Biological Factors
Patients were considered to have BRPC (low probability to achieve
resection with 1mm clear margin but possible) based on pancreatic
protocol CT scan. The BRPC classification is supported by the
overall survival difference between the groups observed, when
compared to clearly resectable tumours, of 27.8 to 44.5 months
(Tran Cao et al. 2014). For the purposes of classification and
benchmarking borderline resectable disease is further subdivided
into BR-PV, or BR-A based on involvement of SMV/PV and/or
arterial structures, respectively (Gandy et al. 2016; Isaji et al. 2018).
In addition to standard axial measurement of degree, a
formal longitudinal or cephalocaudal assessment of extent,
specifically in relation to the inferior margin of the duodenum.
This is employed to address the issue whether safe and successful portal vein reconstruction can be performed. Venous
involvement below this level is classified unresectable and
locally advanced and is now widely adopted.
The next element in consideration of vascular involvement (in addition to circumference and length) is the resultant effect of such involvement on venous flow or arterial
anatomy. Bilateral narrowing of the SMV/PV, or occlusion of
these veins equates to BR-PV disease (in the absence of
extension beyond the inferior border of the duodenum)
(Tempero et al. 2021).
Similarly, stenosis or deformity of arterial structures upstages
contact with the coeliac axis or SMA of less than 180° (BR-A) to
locally advanced. Arterial involvement of the common hepatic
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artery may be considered borderline resectable (so long as
there is no tumor contact with the proper hepatic artery and/or
the coeliac axis).
Biological Factors Includes a High Degree of
Suspicion for Metastatic Disease despite
Appearing Resectable Based on Anatomic Criteria
In this context, “borderline” may be referring to an individual
patient’s likelihood of benefit from upfront surgery and indicate
a preference for systemic therapy as first line treatment, followed
by restaging prior to proceeding to surgery where appropriate.
Such factors include – clinical findings suspicious (but unproven)
of distant metastases, regional lymph nodes metastases (Ozaki et
al. 1999) diagnosed by EUS biopsy, or positron emission tomography-computed tomography 24, or high CA 19.9 level (in the
absence of hyperbilirubinemia). International consensus agreed
on a threshold value of 500 IU/mL as the level above which a
patient may be categorized as BR-Type B based on a study demonstrating lower resection rate and lower median survival time
after resection at that cut-point (Khorana et al. 2019). Such
patients may be at most of “borderline-benefit” from upfront
surgery without preoperative systemic therapy.
Conditional Factors Includes Patients that May
Require Initial Optimization
The final element by which a patient with anatomical clear
resectability, and no suspicion of micro metastatic disease may
be considered to be at risk of borderline benefit is in their ability
to withstand the surgical rigor of pancreaticoduodenectomy
(borderline resectable on conditional grounds – BR-Type C).
Based on Eastern Co-operative Group (ECOG) performance
status (PS), with data showing PS of 2 associated with significantly shorter median survival for all resectable stages of
pancreatic cancer (Tas et al. 2013) compared with ECOG 0 or 1
as does major co-morbidity .
However, some patients with BR-Type C disease may be rendered fit for surgery with appropriate medical optimization,
nutritional support, or pre-habilitation (Tzeng et al. 2014).
We have found this “A, B, C” framework useful for use in
multidisciplinary meetings when assessing cases of non-metastatic pancreatic cancer, as borderline resectability has a large
bearing on choice of surgical pathway; with such patients often
being considered for neoadjuvant therapy.
Locally Advanced Pancreatic Cancer
Disease considered inoperable (unable to achieve R0, without
downstaging) due to proven extensive (including macroscopic
para-aortic and non-regional) lymph node metastasis or tumor
involvement with veins and arteries beyond that defined as borderline resectable. Around 25% of patients may become resectable with extensive neoadjuvant chemotherapy (Kunzmann et al.
2019).
Limitations of Conventional Imaging
Pancreatic tumors are often poorly visualized on conventional
imaging such as MRI and CT imaging. PET scan and endoscopic ultrasound may give additional information in respect
to the nature of enlarged or suspicious lymph nodes or the
interface of major vasculature (Luz et al. 2014; Wang et al.
2014b). Contrast enhanced MRI with liver specific contrast
may also provide more information of suspicious lymph nodes
(Motosugi et al. 2011). Small volume peritoneal deposits are
difficult to determine on preoperative imaging and are one of
three primary reasons for non-therapeutic laparotomy. Staging
laparoscopy may be beneficial to reduce the risk of non-therapeutic laparotomy as described above.
Re-imaging after Neoadjuvant Therapy
The primary purpose of repeat imaging prior to surgery is to rule
out metastatic disease, multiple studies have shown that while
response to treatment (using the resist criteria) is a good predictor
of future resectability, lack of response using conventional imaging
does not predict non-resectability in borderline cases (Beleù et al.
2019; Katz et al. 2012; Xia et al. 2017). In the setting of locally
advanced disease lack of response again does not predict unresectable disease, but attention should be paid to feasibility of vascular
reconstruction. To date the best predictor of response and complete
pathological response is the normalization of tumor marker Ca
19–9, notwithstanding its own limitation (Boone et al. 2014;
Ferrone et al. 2015; Truty et al. 2021).
Pancreaticoduodenectomy Technique
Minimally invasive pancreaticoduodenectomy has acceptable
outcomes in selected patients. In expert high-volume centers, it
may be associated with reduced length of stay and earlier time
to adjuvant therapy (Sharpe et al. 2015; Stauffer et al. 2017).
Extended Pancreatectomy
Extended pancreatectomy remains an area of controversy and
the evidence supporting the utility of extended resection has
many confounding factors. Despite the potential for increased
peri-operative morbidity (Casciani et al. 2021), the benefits of
extended pancreatectomy mean a greater proportion of patients
undergo potentially curative treatment and may be best applied
following a neoadjuvant pathway as tumors are usually larger
and have adverse features, which affect survival (Hartwig et al.
2014; Wang et al. 2014a).
Venous Resection
Patients with up to 180-degrees contact venous abutment on
preoperative imaging may have, true portal vein invasion
observed in 41%, whereas over 180-degree venous involvement,
distortion or occlusion of the vessel results in rates of true PVI
are much higher (59%). Even tumors with no porto-mesenteric
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venous contact on CT scanning have very low rates of true
portal vein invasion, only 6% (Tran Cao et al. 2014; Yamada
et al. 2009).
This is evidenced by a positive margin rate (R1 = 0mm)
which is significantly lower in the no vein contact group, 24%
versus 34% when vein contact is observed, despite an additional 65% of patients requiring vein resection, when tumor
contact of the vein was present on imaging (Zhou et al. 2012,
Yamada et al. 2013). Patients undergoing PV and SMV resections generally have similar mortality and morbidity to patients
who have standard resections (Murakami et al. 2015; Ravikumar
et al. 2014).
This has great implications for the surgical management of
patients with resectable tumors, the need for portal vein resection mandates the ability for pancreatic surgeons to perform
venous resection and reconstruction, even when unexpected.
The argument against venous resection is that true portal vein
involvement is associated with poor survival (irrespective of
successful venous resection) and that patients without true
portal vein involvement do not require vein resection, effectively rendering the procedure to have limited benefit. However,
venous resection may also aid clearance of the critical posterior
margins and the SMV/SMA groove. Vein resection is also associated with less bleeding and less potential for catastrophic
bleeding when compared to stripping of a tumor from an
involved or densely adhered vessel and the outcomes of SMV/
PV resection are significantly better than R2 resection.
Arterial Resection
In contrast, due to the high mortality and high local failure
rates, resection of the SMA is only recommended in exceptional circumstances, as there is a paucity of data to support
arterial resection increasing survival over palliative chemotherapy. In exceptional circumstances, and following a period
of neoadjuvant therapy and multidisciplinary approval, arterial
resection may be appropriate (Bockhorn et al. 2014; Ouaïssi et
al. 2014).
Palliative Surgery in Obstructing
Periampullary Tumors
In up to 25% of cases of pancreatic cancer patients will present
with obstruction of the duodenum or bile duct. Of these 50%
will present with metastases at presentation. The gold standard
for palliation of the effects of gastric outflow obstruction and
bile duct obstruction was “double bypass surgery” consisting of
open hepaticojejunostomy and gastrojejunostomy. These procedures carry a 2% mortality and up to 35% morbidity.
However, they render the best functional outcomes for patients
and may be more durable.
Endoscopic stenting procedures have largely replaced palliative surgical options for obstructed pancreatic cancer.
Endoscopic biliary stenting is feasible in over 90% of cases and
is associated with low morbidity, low rates of mortality, reduced
length of stay, and a higher proportion of patients receiving
systemic chemotherapy. For patients diagnosed with metastatic
disease at presentation we recommend endoscopic stenting of
any biliary and duodenal obstruction.
For patients who have proceeded to laparotomy (without
prior endoscopic stenting) and the finding of unresectable disease or low volume metastatic disease the recommendation is
less clear. This group of patients may inherently have a better
prognosis, than those with grossly metastatic disease. In the
metastatic setting, biliary and gastric bypass procedures are
associated with increased time to systemic therapy compared
non-therapeutic surgical exploration (Azari et al. 2020). For
patients diagnosed with unresectable disease at surgical exploration via laparotomy surgical bypass is a reasonable option. If
metastatic disease is encountered conferring a worse prognosis
nontherapeutic surgery and subsequent endoscopic stenting is
preferred. However, this should be judged by the operating surgeon on a case-by-case basis.
Systemic Therapy
Omali Pitiyarachchi & David Goldstein
Neoadjuvant Therapy
Neoadjuvant therapy is utilized in borderline resectable and
locally advanced pancreatic cancer to downstage tumors allowing resection in 6–60% of cases (Gemenetzis et al. 2019; Hackert
et al. 2016; Lakatos et al. 2017; Rombouts et al. 2016). Ability to
undergo surgical resection translates to a significantly improved
OS (Gemenetzis et al. 2019; Kunzmann et al. 2019). Only
50–60% of patients complete adjuvant chemotherapy (Barbour
et al. 2020; Baugh et al. 2019; Mayo et al. 2012; Tran Cao et al.
2017), which adds to the appeal of neoadjuvant therapy. There
is no negative impact on surgical outcome identified for
patients with likely moderate to severe poor outcomes with
upfront surgery (Barbour et al. 2020; Da Costa et al. 2020;
Sohal et al. 2021), with the added benefit of downstaging cN1
patients to ypN0 (Tran Cao et al. 2017). Survival data will be
available with randomized trials soon.
Locally Advanced Disease
Quality randomized data is lacking, but conversion to surgical
resection after neoadjuvant therapy is possible in 20–30% of
patients (Gemenetzis et al. 2019; Kunzmann et al. 2019; Suker et
al. 2016) with apparent improved median OS in those resected
(Gemenetzis et al. 2019; Kunzmann et al. 2019). The NEOLAP
trial (Kunzmann et al. 2019) showed a 30.6% conversion rate to
surgery in the gemcitabine + nab-paclitaxel arm and 45% in the
FOLFIRINOX arm (OR 0.54; 95% CI, 0.26–1.13; p=0.135) with
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a statistically significant improved in OS of 27.4 months compared to 14.2 months for patients unable to have surgical resection (p=0.0035). Similarly, in another study (Gemenetzis et al.
2019), the median OS was 19 months greater (35.3 mo vs 16.3
mo; p< 0.001) in patients able to undergo surgical resection
after FOLFIRINOX-based neoadjuvant therapy.
For patients with poor performance status and locally
advanced disease, consider single agent chemotherapy with
gemcitabine (Glimelius et al. 1996), or palliative radiation for
local symptom control. Alternatively, consider best supportive
care if the patient is unsuitable for chemotherapy or radiotherapy. Also refer to the Radiation section for the use of radiation in locally advanced disease.
Borderline Resectable Disease
Multimodality neoadjuvant therapy should be considered in
patients with borderline resectable pancreatic cancer. The results
of ESPAC-5F (Ghaneh et al. 2020), which was designed to show
feasibility of neoadjuvant therapy showed promising results.
Ninety-nine patients were randomized to four groups, upfront
surgery, gemcitabine/capecitabine, FOLFIRINOX, and chemoradiation (capecitabine). Although not statistically significant,
the R0 resection rate for patients that received neoadjuvant
therapy was 23% compared to 15% for patients that had upfront
surgery (p=0.721). Survival at one year was higher for neoadjuvant therapy, 77% vs 40% for upfront surgery (p<0.001), although
not powered for this. Similarly, the proportion of patients converted to surgical resection was 67.8% in a meta-analysis which
included 313 patients who received neoadjuvant FOLFIRINOX.
In those patients, 83.9% of patients achieved a R0 resection, and
a median OS of 22.2 months (Janssen et al. 2019).
PREOPANC-1 trial (Versteijne et al. 2022) which evaluated
neoadjuvant chemoradiation (gemcitabine) showed a slightly
better mean OS of 1.4 months (15.7months v 14.3 months) [HR
0.73; 95% CI, 0.56–0.96; p=0.025], but the five-year OS rate was
substantially greater with neoadjuvant therapy (20.5% v 6%).
The trial randomized 246 patients with resectable or borderline
resectable pancreatic cancer to either upfront surgery followed
by six cycles of adjuvant gemcitabine, or neoadjuvant CRT with
gemcitabine, followed by resection and four cycles of adjuvant
gemcitabine. The benefit from neoadjuvant chemoradiation led
to the early termination of a Phase II/III study (Jang et al. 2018)
comparing neoadjuvant chemoradiation with gemcitabine to
upfront surgical resection. Nevertheless, it showed a two-year
survival rate with chemoradiation of 40.7% compared to 26.1%
with upfront surgery, and an improved mOS of 21 months compared to 12 months with upfront surgery [HR 1.495, 95% CI
0.66–3.36; p = 0.028]. A greater proportion of patients achieved
an R0 resection in the neoadjuvant arm (52.5%) compared to
26.1% in the patients that had upfront surgery.
This encouraging data is being further explored, in the
ongoing phase 3 PREOPANC-2 study which updated the
neoadjuvant chemotherapy regimen to FOLFIRINOX.
Patients are randomized to eight cycles of neoadjuvant
FOLFIRINOX followed by surgery, to neoadjuvant CRT with
gemcitabine, followed by surgery and four cycles of adjuvant
gemcitabine. In addition, MASTERPLAN, an AGITGsponsored random ized Phase II study, is exploring the safety
and efficacy of adding stereotactic body radiotherapy (SBRT)
to three months of neoadjuvant chemotherapy, in patients
with high risk, borderline resectable or locally advanced pancreas cancer (Oar etal. 2021). The results of both these trials
are awaited.
Consequently, neoadjuvant therapy is recommended for
patients with borderline resectable pancreatic cancer, due to
the high conversion rate for surgical resection which is related
to improved overall survival (Tempero et al. 2019). It is reasonable to use either mFOLFIRINOX or gemcitabine/nabpaclitaxel in patients with a good performance status.
Currently, the practice is to give all neoadjuvant treatment
prior to surgery, but this may change to a perioperative
approach in future.
Resectable Disease
The evidence for the use of neoadjuvant therapy in patients
with resectable disease is evolving. A meta-analysis which
included 38 studies (principally Phase II randomized) and 1738
patients who had neoadjuvant treatment for resectable and
borderline resectable pancreatic cancer (Versteijne et al. 2018)
showed an improved OS in the intention to treat population of
18.8 months compared to 14.8 months for those who had
upfront surgery. Interestingly, the resection rate was lower in
patients who had neoadjuvant therapy (66% v 81.3%), but a
higher R0 rate was achieved (86.8% v 66.9%). This data is
mainly from phase II randomized trials.
The Italian Phase II trial PACT-15 showed an improved OS of
38 months with 3 cycles of preoperative and postoperative
PEXG (cisplatin, epirubicin, gemcitabine, and capecitabine), as
compared to the two arms which received adjuvant chemotherapy, which was 20 months in the adjuvant gemcitabine arm,
and 26 months in the adjuvant PEXG arm (p-value not reported)
(Reni et al. 2019). The Japanese Prep-02/JSAP-05(Motoi et al.
2019) study showed a clear survival benefit with neoadjuvant
therapy, with a median OS of 36.7 months in the patients who
received neoadjuvant gemcitabine/S-1 chemotherapy, and 26.6
months for the patients who had upfront surgery [HR 0.72 (95%
CI, 0.55‐0.94; p=0.015)]. A Phase II randomized trial of mFOLFIRINOX compared with gemcitabine/nab-paclitaxel in resectable pancreatic cancer (Sohal et al. 2021) showed similar
two-year overall survival rates (47% v 48%) and mOS (23.2
months v 23.6 months), and resection rates (73% v 70%). mDFS
after resection was 10.9 months v 14.2 months favoring the
gemcitabine/nab-paclitaxel arm.
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