Elsevier

Pharmacology & Therapeutics

Volume 155, November 2015, Pages 80-104
Pharmacology & Therapeutics

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

https://doi.org/10.1016/j.pharmthera.2015.08.006Get rights and content

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second cause of cancer-related death in 2030. PDAC is the poorest prognostic tumor of the digestive tract, with 80% of patients having advanced disease at diagnosis and 5-year survival rate not exceeding 7%.

Until 2010, gemcitabine was the only validated therapy for advanced PDAC with a modest improvement in median overall survival as compared to best supportive care (5–6 vs 3 months). Multiple phase II–III studies have used various combinations of gemcitabine with other cytotoxics or targeted agents, most in vain, in attempt to improve this outcome.

Over the past few years, the landscape of PDAC management has undergone major and rapid changes with the approval of the FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens in patients with metastatic disease. These two active combination chemotherapy options yield an improved median overall survival (11.1 vs 8.5 months, respectively) thus making longer survival a reasonably achievable goal. This breakthrough raises some new clinical questions about the management of PDAC. Moreover, better knowledge of the environmental and genetic events that underpin multistep carcinogenesis and of the microenvironment surrounding cancer cells in PDAC has open new perspectives and therapeutic opportunities.

In this new dynamic context of deep transformation in basic research and clinical management aspects of the disease, we gathered updated preclinical and clinical data in a multifaceted review encompassing the lessons learned from the past, the yet unanswered questions, and the most promising research priorities to be addressed for the next 5 years.

Introduction

Pancreatic cancer is the 12th most frequent malignancy and the seventh leading cause of cancer-related death in men and the eighth in women worldwide (Torre et al., 2015). In developed countries, it is the fourth cause of cancer-related death (Siegel et al., 2015). Its incidence is dramatically increasing worldwide; it is expected to become the second cause of cancer death in the United States in 2030 (Rahib et al., 2014).

The vast majority of malignant pancreatic tumor cases (85%) are pancreatic ductal adenocarcinoma (PDAC). PDAC has the poorest prognostic among digestive tract malignancies with a 5-year survival rate of 5%–7%, with no significant change in death rate in 1997–2007 (National Cancer Institute. Cancer Statistics, 1975–2007 (SEER 9)). Complete surgical resection is the only treatment that can provide prolonged survival. However, due to lack of initial symptoms at early stage and high invasive potential, diagnosis is made at an advanced stage in 80% of cases, when patients already have metastases or locoregional extension (Rhim et al., 2012, Ryan et al., 2014a). Moreover, most patients with an apparently localized disease who may undergo a curative-intent resection will promptly develop metastatic and/or local relapses. The median survival after curative resection is about 20–24 months, 9–15 months in patients with locally advanced PDAC, and 6–9 months in those with metastatic disease (Ryan et al., 2014a).

Advanced PDAC remains a challenging, non-curable disease attracting attention of medical and surgical specialists, as well as pharmacologists. Over a decade (1997–2010), gemcitabine was the only validated chemotherapy regimen for advanced PDAC, yet the improvement obtained with this drug in terms of median overall survival (OS) was only of about 3 months as compared with best supportive care (BSC) (5–6 months vs 3 months). Several phase II and III studies have been designed as add-on benefit using various combinations of gemcitabine with other cytotoxics or targeted agents such as tyrosine kinase inhibitors and monoclonal antibodies. However, most of these doublets failed to demonstrate a superiority over gemcitabine monotherapy (Ryan et al., 2014a).

The landscape of PDAC management has undergone major changes during the 5 past years with the approval of two active combinations of cytotoxics: the FOLFIRINOX (5-fluorouracil [5FU], irinotecan, and oxaliplatin) and the gemcitabine plus nab-paclitaxel regimens. These combination regimens were shown to be superior to gemcitabine in patients with metastatic PDAC, yielding median OS of 11.1 and 8.5 months, respectively (Conroy et al., 2011, Von Hoff et al., 2013). After advent of these chemotherapy regimens, longer survival for patients with advanced PDAC has turned to a reasonably achievable goal, while before median life expectancy rarely got beyond one year. This breakthrough has raised some new specific clinical questions about the management of PDAC patients. Moreover, better knowledge of the environmental etiological factors (particularly, obesity/insulin resistance and nicotine exposure), the molecular and genetic events that underpin multistep carcinogenesis, and the microenvironment surrounding cancer cells (pancreatic stellate cells [PSC], immune cells, neural cells, abundance and composition of stroma) has opened new perspectives of therapeutic opportunities in PDAC. Accumulation of preclinical data, especially in recent years, provides a strong rational for the development of news drugs and strategies aiming to better control disease progression.

In this dynamic context of deep changes in both the basic research and clinical management aspects of a disease that is becoming a major health issue, it appears crucial to gather updated preclinical and clinical data on PDAC. In this review, we summarize the lessons learned from the past, the yet unanswered questions, and the most promising research pathways to draw up a state of the art and the future directions in PDAC management.

Section snippets

Cell of origin (acinar vs ductal cell)

Activating KRAS mutations are present in more than 90% of PDAC and represent one of the earliest oncogenic events driving pancreatic carcinogenesis (Hezel et al., 2006). It has long been a matter of controversy which pancreatic cell type(s) can give rise to PDAC when mutant KRAS is expressed. Although PDAC displays ductal characteristics, it may not necessarily emerge from the ductal compartment. Moreover, there is some preclinical evidence for its non-ductal origin, i.e. acinar, centroacinar,

Clinical presentation and value of carbohydrate antigen 19-9

The majority (75%) of PDAC occur in the pancreatic head, 15%–20% in the body, and 5%–10% in the tail of the pancreas (Seufferlein et al., 2012). PDAC primarily metastasize to lymph nodes, the liver, peritoneum, and lungs.

The type and timing of clinical manifestations depend on primary tumor location (Modolell et al., 1999). Tumors located in the pancreatic body and tail tend to remain asymptomatic longer than those located in the head and, consequently, these are often diagnosed at a more

Metastatic pancreatic ductal adenocarcinoma

About 50% of PDAC are diagnosed at a metastatic stage requiring systemic treatment. An important feature of PDAC is its high resistance to most of systemic therapies. Drug resistance in PDAC is driven by various mechanisms including aberrant gene expression (such as high ABC transporters expression [MDR phenotype], low human equilibrative nucleoside transporter [hENT]-1 expression or ribonucleotide reductase M1/2 [RRM1/2] and deoxycytidine kinase [dCK] leading to limited intracellular uptake

Unanswered clinical questions

Currently unanswered clinical questions in the management of PDAC are summarized in Table 4.

Challenges and advances in preclinical models

A key issue in the development of therapies for PDAC is the establishment of appropriate preclinical models that are able to reproduce the complexity of human PDAC microenvironment and to reliably predict treatment efficacy in the clinical setting. Indeed, many of the drugs designed based on preclinical studies have failed to demonstrate a clinically relevant benefit for patients with PDAC.

General conclusion: from benchside to bedside

These are exciting times in both preclinical and clinical PDAC research. Better knowledge of the fundamental aspects of PDAC development, progression, and biology has translated into slow but significant therapeutic advances. Progress has been made during the past decade in the management of PDAC in all its forms, from precancerous lesions to advanced cancer stages and from anti-tumor treatments to the management of symptoms. If the 5-year OS has not (yet) changed in PDAC patients, it is likely

Conflict of interest

The authors declare no conflict of interest.

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