Metastatic pancreatic cancer: Is there a light at the end of the tunnel?

Abstract

Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.

Glucose Metabolism Reprogrammed by Overexpression of IKKϵ Promotes Pancreatic Tumor Growth

“…PDACs are highly aggressive, exhibiting rapid growth and metastasis, which is one important reason for their high lethality in patients (2, 30, 31). As a result, efforts have focused on understanding the molecular causes of PDAC aggressiveness as well as on formulating strategies that could target this very feature of pancreatic malignancy.…”

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

“…In this study, gemcitabine was associated with higher clinical benefit (the primary endpoint; 23.8% vs 4.8%, p = 0.0022) and also improved OS (5.6 months vs 4.4 months, p = 0.0025). Then, over more than a decade (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010), multiple phase II and III studies attempted to improve gemcitabine results either by pharmacokinetic modulation or by combining it with other agents (Ryan et al, 2014a;Vaccaro et al, 2015). The first approach was based on the observation that dCK, the enzyme that catalyzes the conversion of gemcitabine to its active triphosphate metabolite, is rapidly saturated at plasma concentrations achieved with the standard 30-minute infusion.…”

Early surgical bypass versus endoscopic stent placement in pancreatic cancer.

“…14 Furthermore, advances in palliative treatments may help patients with terminal pancreatic cancer live longer. 15 Moreover, with recent advances in chemotherapy for advanced pancreatic cancer, improved survival times might provide more time for potential complications, reinterventions, and rehospitalizations to occur. More recent data is single-center and highly variable.…”