Perspectives in the treatment of pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.

Keywords: Pancreatic adenocarcinoma, Tumor surveillance, Biomarkers, Immune surveillance, Chemotherapy, Immunotherapy, Antibody therapy, Adoptive T cell therapy, Vaccines, Stroma, Inhibitors

Core tip: Pancreatic adenocarcinoma is a life threatening, fast evolving disease for which there is no cure. Recently, new chemotherapy regimens have shown significant improvement in survival in patients with advanced disease, opening a way for further progress. New therapeutic strategies based on targeted inhibitors or immunotherapy approaches, in particular antibody and adoptive T cell therapies, are getting growing attention as they are proving beneficial in pre-clinical and early phase clinical studies in combination with chemotherapy. Progress in understanding pancreatic tumor genetics, epigenetics and metabolism is providing new biomarkers that may be of value in early detection and progression assessments.