Advances in locally advanced pancreatic cancer treatment

Abstract

Pancreatic cancer is the fourth leading cause of cancer related death in the Western world. The survival of patients with pancreatic cancer has not improved substantially over nearly 40 years with a current overall 5-years survival of only 7%. Surgical resection provides the best chance of survival. However, its aggressive tumor biology leading to early tumor infiltration in combination with late diagnosis, prevent successful surgical therapy as the majority of patients presents with an advanced stage. At presentation, 40-50% have distant metastases and 30-40% locally advanced pancreatic cancer (LAPC). LAPC is defined as pancreatic cancer that has extended beyond the borders of the pancreas with extensive vascular involvement precluding upfront resection, in absence of distant metastases. The last decade gemcitabine monotherapy has been regarded as the most effective chemotherapy for patients with LAPC. However, it prolongs survival with only a few months and has a low response rate (<10%).This thesis outlines current research on improving survival of patients with LAPC. Part 1 and 2 emphasize the most important advances in treatment, by focusing on the potential benefit of FOLFIRINOX and local ablative therapies, respectively, with regard to feasibility, safety and efficacy. Part 3 highlights the importance of accurate CT-assessment in pancreatic cancer staging and treatment response as well as outlines the advances in treatment of relevance to the pathologist. Part 1. A systematic review of the literature on FOLFIRINOX treatment in LAPC, demonstrates that FOLFIRINOX provides a relatively high response rate of 29% and a promising survival benefit ranging between 8.9 and 25.0 months, with grade 3 and 4 toxicity (severe or life threatening complications) in 23% of patients with LAPC. Moreover, it can downstage LAPC to resectable disease in around one third of patients.In our own institution we reportedsimilar outcomes regarding response rate (25%) and median overall survival (14.8 months for LAPC). Moreover, we demonstrated that over 75% of complications related to FOLFIRINOX were resolved after dose reduction.Part 2. Regarding local ablative therapies, both radiofrequency ablation (RFA) and irreversible electroporation (IRE) were feasible and safe in LAPC, providing a median overall survival up to 25.6 months and 20.2 months, respectively, according to retrospective cohort studies. BothRFA and IRE used today, require the implementation of probes directly into and/ or around the tumor, by performing a laparotomy or direct percutaneous probe placement. Needle placement has some disadvantages, of which the occurrence of postoperative pancreatic fistula via the needle tracks is most important. We therefore investigated the use of plate electrodes placed in parallel fashion alongside the tumor, and proven the feasibility and safety of paddle-assisted IRE as new IRE-technique in healthy porcine pancreas. Feasibility, safety and efficacy have yet to be evaluated in pancreatic cancer tissue.Part 3 demonstrates the importance of the correct measurement of tumor extent and vascular involvement exposed on CT-imaging, as clinical decision-making is based on this CT-assessment. It appears however that delineability of LAPC is problematic and there is no consensus on the method to be applied.