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Page 2 of 23 Koukourakis et al. J Cancer Metastasis Treat 2022;8:38 https://dx.doi.org/10.20517/2394-4722.2022.43

INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging malignancies due to the
high mortality rates and the lack of effective treatment. According to the Surveillance, Epidemiology, and
End Results (SEER) Program of the National Cancer Institute of the United States of America, there were an
[1]
estimated 60,430 new PDAC cases and 48,220 deaths in 2021 . Its increasing incidence has been attributed
to numerous causative factors, including cigarette smoking, diabetes mellitus, obesity, alcohol consumption,
[2]
pancreatitis, and a family history of pancreatic cancer . Germline mutations concerning BRCA2, BRCA1,
PALB2, ATM, CDKN2A, MSH2, MSH6, and TP53 have been shown to be present in up to 9.7% of PDAC
cases. Somatic alterations in KRAS, TP53, CDKN2A, and SMAD4, on the other hand, are detected in nearly
[3]
all of PDAC . The best-studied mutations concern KRAS and are thought to be responsible for the
progression of pancreatic intraepithelial neoplasia to PDAC by triggering metabolic, signaling, apoptotic,
and homeostatic pathways . Furthermore, BRCA1 and BRCA2 mutations, involved in the pathogenesis of
[4]
breast and ovarian cancer, also characterize familial PDAC . Therefore, meticulous monitoring of patients
[5]
with a familial history of the aforementioned malignancies could allow early detection of a significant
proportion of PDACs and, moreover, introduce early detection genetic tests.

PDACs are usually classified as resectable (R-PDAC), borderline resectable (BR-PDAC), and unresectable-
locally advanced (LA-PDAC) . This classification reflects the different prognoses and therapeutic
[6]
approaches applied. Although surgery is considered the backbone of therapy for R-PDAC and BR-PDAC,
there has recently been a shift of focus towards neoadjuvant therapies in these two categories. Due to its
extremely fast metastatic potential and subsequent unfavorable prognosis, it is believed that localized
PDAC, in most cases, represents a metastatic disease in its early stages. In this context, neoadjuvant
treatment could exhibit dual function. The first concerns the eradication of micrometastatic lesions and the
increased probability of completion of systemic therapy, as a large proportion of patients are not fit to
receive postoperative chemotherapy. The second one aims at recognizing diseases that will progress even
during systemic therapy, thus suggesting a highly aggressive biological behavior. The subset of patients with
PDAC bearing these adverse properties will avoid unnecessary surgical operations, which is often associated
with a sharp decrease in the quality of life. Moreover, neoadjuvant chemotherapy or chemoradiotherapy
(chemo-RT) could lead to tumor downstaging locally, facilitating surgery and a potential R0 resection .
[7-9]
The above rationale certainly applies to locally advanced disease, assumed inoperable at diagnosis, as
preoperative chemotherapy and radiotherapy could down-stage the disease and allow a reappraisal of
surgery.

This review focuses on the clinical experience gained from retrospective and phase II/III randomized trials,
reporting on the outcomes of neoadjuvant chemotherapy and chemo-RT for PDAC. Moreover, the
currently ongoing trials, including those that involve immunotherapy and targeting agents, are summarized.
The literature search was performed in the EMBASE and MEDLINE databases using the text words
“pancreatic adenocarcinoma”, “neoadjuvant”, “chemotherapy”, “radiotherapy”, “immunotherapy”,
“targeting agents”, and “surgery”. Phase II and III studies published between 1990 and April 2022 were
retrieved. Ongoing phase II and III trials were identified on ClinicalTrials.gov.

CHEMO- AND RADIORESISTANCE
Chemoresistance is one of the most prominent challenges physicians have to face when treating different
types of malignancies. As far as PDAC is concerned, genomic alterations, such as KRAS and SMAD4
mutations and TP53 inactivation, were originally believed to be the main drivers of the increased
chemoresistance of PDAC. In a study by Yang et al., chemosensitivity to gemcitabine and cisplatin was
increased in KRAS shRNA knockdown pancreatic cancer cells, suggesting that KRAS oncogene expression