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Page 2 of 12 Lo et al. J Cancer Metastasis Treat 2022;8:30 https://dx.doi.org/10.20517/2394-4722.2022.48

Keywords: Borderline resectable, locally advanced, pancreatic ductal adenocarcinoma, neoadjuvant chemotherapy

INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) incidence is increasing worldwide and is associated with a
[1-4]
high mortality rate owing to its aggressive biology and oftentimes late presentation. It is now the third
leading cause of cancer-related death in the United States , expected to become the third leading cause in
[3]
[5]
[2]
Canada , and the fourth leading cause in Europe . Surgical resection currently remains the only option for
cure, although rates remain dismal at < 4% at 10 years . The spectrum of non-metastatic disease is currently
[6]
classified as resectable, borderline resectable, and locally advanced disease, the latter is considered
unresectable. In reality, these classifications represent a continuum and have evolved over time based on a
combination of surgical expertise and high-quality imaging of disease involvement with nearby vasculature.
Unfortunately, early pancreatic cancer is often asymptomatic, with only 15%-20% of patients presenting
with resectable disease and approximately 30%-35% presenting with locoregional/vessel involvement that
[7]
precludes upfront resection .

For patients with resectable or borderline resectable disease, the traditional treatment paradigm includes
[8]
upfront resection followed by adjuvant systemic therapy, with regimens such as FOLFIRINOX (FFX) ,
gemcitabine with capecitabine , or gemcitabine alone . However, 10%-20% of such patients are actually
[10]
[9]
found to have unresectable disease at the time of surgery , and another 20% of patients are too unwell after
[11]
[12]
resection to receive adjuvant systemic therapy , or develop metastatic recurrence soon after resection, thus
causing iatrogenic morbidity without substantial benefit. As a result, there has been recent interest in using
systemic therapy in the neoadjuvant setting for patients with localized disease, with the potential benefit of
treating micrometastatic and measurable disease early, improving the R0 resection rate (R0: microscopically
margin-negative resection), delivering systemic therapy to a higher number of patients, and avoiding non-
therapeutic laparotomy in patients with aggressive disease biology. For patients with locally advanced
unresectable disease, neoadjuvant systemic therapy has the potential to convert their disease to a resectable
state. Conversely, there is the potential risk that the disease is not responsive to neoadjuvant systemic
therapy, resulting in a delay to curative resection. Further, it will be important to identify how and when to
optimally assess treatment response in the neoadjuvant setting for surgical planning. Ultimately, whether
the aforementioned benefits outweigh this risk and result in longer survival and higher rates of cure has
been under active investigation, particularly over the last decade.

In this article, we review the evidence behind the use of systemic therapy in the neoadjuvant setting for
borderline resectable PDAC (BR-PDAC) and locally advanced PDAC (LA-PDAC) [Table 1].

BORDERLINE RESECTABLE DISEASE (BR-PDAC)
The National Comprehensive Cancer Network (NCCN) was the first to adopt the terminology “borderline
resectable pancreatic ductal adenocarcinoma” in 2006 for patients identified to be at high risk of a margin-
positive resection and for whom neoadjuvant treatment should be considered. In the most recent NCCN
guidelines for pancreatic cancer (Version 1.2022) published in February 2022 , BR-PDAC is defined by the
[22]
following criteria, assessing the tumor’s relation to both arterial and venous structures [Table 2]. In clinical
practice, determination about resectability should be made by consensus at a multidisciplinary discussion,
primarily by the surgeon involved in the case. The consensus and classification of the patient’s disease have
significant implications on the approach to treatment, such as the use of neoadjuvant treatment vs. upfront
resection.