The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

Keywords: chemotherapy; immunotherapy; pancreatic cancer; radiation; surgery; targeted therapy; treatment.

Figure 1

Generalized treatment guidelines for PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) typically presents with vague clinical symptoms, including poorly localized pain, jaundice, or unintended weight loss. When PDAC is suspected, patients are typically diagnosed through computed tomography (CT) scan of the chest, abdomen, and pelvis to assess the extent of disease or ultrasound with or without a fine-needle aspiration (FNA) biopsy. Following confirmatory diagnosis, the patient’s surgical candidacy is determined based on a combination of imaging studies, Eastern Cooperative Oncology Group performance status (ECOG PS), symptom burden, surgical risk, and comorbidity profile. For operable disease, the type of surgery is determined based on the anatomical location of the tumor, as well as several additional factors described in this review article, with most patients receiving either a Whipple procedure or distal pancreatectomy. Regardless of whether a patient is treated with surgery, the current guidelines recommend chemotherapy, and the precise regimen given is based mostly on ECOG PS and comorbidity profile.

Figure 2

Representative images of resectable, borderline-resectable, and non-resectable PDAC. (A) Representative image of a patient with resectable disease as defined by NCCN guidelines. There is no tumor contact with the superior mesenteric artery (SMA, white arrow) and <180° of tumor contact with the superior mesenteric vein (SMV, red arrow). (B) Patient with borderline resectable disease due to >180° of tumor contact with the SMV but no involvement of the SMA. (C) Patient with locally advanced disease due to >180° of tumor contact with the SMA.

Figure 3

Chemical structure of deoxycytidine and its halogenated chemical mimic Gemcitabine. Gemcitabine (2’, 2’-difluoro 2’deoxycytidine or dFdC) is a nucleoside analog identical in structure to deoxycytidine apart from two fluoride molecules at the 2’-position.

Figure 4

Gemcitabine mechanism of action. Gemcitabine enters cells via several nucleotide transporters, primarily Human Equilibrative Nucleoside Transporter 1 (hENT1). In the cytoplasm, Gemcitabine is modified extensively by a series of enzymatic reactions. Gemcitabine is phosphorylated by Deoxycytidine Kinase (dCK) to form dFdC monophosphate (dFdCMP), the rate-limiting step in Gemcitabine metabolism. Subsequently, dFdCMP can be deaminated by Deoxycytidylate Deaminase to form dFdUMP, a potent inhibitor of Thymidylate Synthase. Alternatively, dFdCMP can be phosphorylated by Nucleoside Monophosphate Kinase to become dFdC diphosphate (dFdCDP), inhibiting Ribonucleotide Reductase. dFdCDP can be further phosphorylated by Nucleoside Monophosphate Kinase A to form dFdCTP, which inhibits DNA polymerases. As an alternative to these activating modifications, Gemcitabine can be deaminated by Deoxycytidylate Deaminase to form dFdU, an inactive metabolite with no known anti-neoplastic effects.

Figure 5

Chemical structure of Paclitaxel and the albumin conjugated variant Nab-Paclitaxel. Nab-Paclitaxel, used in combination with Gemcitabine in PDAC, varies from Paclitaxel in that it is conjugated to albumin as a delivery vehicle.

Figure 6

Chemical structure of uracil and its chemical mimic 5-Fluorouracil. 5-Fluorouracil (5-FU) is a nucleoside analog identical in structure to uracil apart from a single fluoride molecule at the 5’-position.

Figure 7

5-Fluorouracil mechanism of action. 5-Fluorouracil (5-FU) enters target cells in a similar manner to uracil, mainly by facilitated transport. Like Gemcitabine, 5-Fluorouracil (5-FU) is modified extensively in the cytoplasm. This includes conversion to Fluorodeoxyuridine monophosphate (FdUMP) by Thymidine Phosphorylase, inhibiting Thymidylate Synthase and potentiated by the addition of Leucovorin. In a parallel mechanism, 5-FU can be further modified to Fluorodeoxyuridine triphosphate, which subsequently inhibits RNA Polymerase.

Figure 8

Chemical structure of Irinotecan and conversion to its active metabolite SN-38. In the intestinal mucosa, liver, and plasma, Irinotecan undergoes carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain, converting water-soluble Irinotecan to lipid-soluble SN-38, its active metabolite.

Figure 9

Chemical structure of Oxaliplatin and structural similarity to Cisplatin. Oxaliplatin is structurally similar to Cisplatin, though it differs in the replacement of amine groups with diaminocyclohexane and the chlorine ligands with oxalate, thereby increasing antitumor activity and water solubility.