Locally Advanced Pancreatic Cancer: Exploring treatment strategies

Abstract

With a worldwide incidence of approximately 496,000 new cases and 466,000 deaths in 2020, pancreatic cancer is among the most deadliest of cancers. The majority of patients present with an advanced stage of cancer at diagnosis. This includes 30-40% of patients with locally advanced pancreatic cancer (LAPC), due to extensive perivascular tumor infiltration without distant metastases.

This thesis evaluates treatment strategies and clinical outcomes in patients with locally advanced pancreatic cancer (LAPC) in current clinical practice, investigates tools for selecting patients who will benefit chemotherapy, and prepares for the PELICAN trial: a randomized controlled trial investigating the efficacy of radiofrequency ablation in combination with chemotherapy in patients with LAPC.

Part 1 Current treatment strategies This part provides a literature overview and evaluates the results of FOLFIRINOX-based treatment for patients with LAPC. From literature, the resection rate after FOLFIRINOX is 28% and median overall survival ranges between 8.9 and 25.0 months. Selection bias occurres in the included studies. Therefore a Dutch multicenter registry including unselected patients with LAPC was initiated. In total 77% of all patients start chemotherapy treatment after the diagnosis of LAPC. Most patients (77%) are able to receive FOLFIRINOX and have a median overall survival of 14 months. A proportion of 13% undergoes a resection after FOLFIRINOX with a median overall survival of 23 months.

Part 2 Outcome prediction and patient selection In this part prediction models are developed to predict at baseline, those patients with favorable outcomes after FOLFIRINOX chemotherapy. Overall survival is difficult to predict at baseline, but positively influenced by older age, female sex, less comorbidity and a CA19.9<274. A surgical resection is predicted by performance score and vascular involvement at baseline (c-index 0.79), with the best patients having a chance for resection after chemotherapy of 35%.

Part 3 Local ablative therapies In the last part of this thesis a basis is formed for an international multicenter randomized controlled trial, designed together with the Dutch Pancreatic Cancer Group. After applicability and safety of a new treatment strategy, radiofrequency ablation (RFA), was ensured, the PELICAN trial was initiated. RFA is performed with direct intra-operative ultrasound guidance and a predefined distance is kept to vital structures. Patients with LAPC, who have stable disease or an objective response without the possibility for a resection, after 2 months of chemotherapy are eligible for inclusion. Eligible patients are randomized to intra-operative RFA followed by continuation of chemotherapy versus chemotherapy without RFA. The PELICAN trial primary investigates survival. Since this is the only trial worldwide on this specific topic, executed by a large collaboration of 20 (inter)national centers, the results of the trial will be of great relevance. The trial is currently ongoing and results are estimated to become available in 2022.

In summary the LAPC registry cohort, as described within this thesis, enables the Dutch clinical practitioners to inform patients with LAPC with real world data on survival and resection after FOLFIRINOX treatment. Moreover, this thesis provides the basis for the PELICAN trial.