Locally Advanced Pancreatic Cancer: Percutaneous Management Using Ablation, Brachytherapy, Intra-arterial Chemotherapy, and Intra-tumoral Immunotherapy

Abstract

Purpose of review: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasms, bearing a terrible prognosis. Stage III tumors, also known as locally advanced pancreatic cancer (LAPC), are unresectable, and current palliative chemotherapy regimens have only modestly improved survival in these patients. At this stage of disease, interventional techniques may be of value and further prolong life. The aim of this review was to explore current literature on locoregional percutaneous management for LAPC.

Recent findings: Locoregional percutaneous interventional techniques such as ablation, brachytherapy, and intra-arterial chemotherapy possess cytoreductive abilities and have the potential to increase survival. In addition, recent research demonstrates the immunomodulatory capacities of these treatments. This immune response may be leveraged by combining the interventional techniques with intra-tumoral immunotherapy, possibly creating a durable anti-tumor effect. This multimodality treatment approach is currently being examined in several ongoing clinical trials. The use of certain interventional techniques appears to improve survival in LAPC patients and may work synergistically when combined with immunotherapy. However, definitive conclusions can only be made when large prospective (randomized controlled) trials confirm these results.

Keywords: Ablation; Brachytherapy; Cryoablation; Intra-arterial chemotherapy; Intra-tumoral immunotherapy; Irreversible electroporation; Locally advanced pancreatic cancer; Microwave ablation; Radiofrequency ablation.

Fig. 1

Changing immune status upon treatment with local interventional treatment in combination with local immunotherapy. Pre-treatment: pancreatic ductal adenocarcinoma (PDAC) maintains a heavily immunosuppressive environment, established by (among others) regulatory T-cells (Tregs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and suppressive cytokines. Treatment: combination treatment with intra-tumoral immune modulation and ablation, brachytherapy, or intra-arterial chemotherapy potentially creates synergism resulting in a durable anti-tumor effect. Immune potentiation combined with local ablation leads to the release of tumor antigens and damage-associated molecular patterns (DAMPs). Subsequently activated dendritic cells (DCs) are now able to capture antigens and migrate towards the draining lymph nodes. Here, antigens are presented to lymphocytes, inducing antigen-specific expansion of effector T-cells, including T-helper-1 cells (Th1) and CD8⁺ (cytotoxic) T-cells, which will provide systemic anti-tumor immunity. Immune activation will lead to reduced TAMs, Tregs and MDSCs. Post-treatment: The tumor microenvironment demonstrates a more immunopermissive state, comprising of natural killer cells, M1 macrophages, anti-tumor T-cells (Th1 and CD8⁺), and permissive cytokines such as interferon (IFN). T-cells are also primed to roam the body in search of tumor cells, both at the primary tumor site as well as other locations, possibly resulting in the regression of untreated concomitant (micro)metastases. Figure created with BioRender.com

Fig. 2

CT-guided percutaneous irreversible electroporation (IRE) for locally advanced pancreatic cancer (LAPC). Sixty-two-year-old male with LAPC on the basis of involvement of the superior mesenteric artery (0–90°, although complete encasement (360°) of the first jejunal branch), involvement of the aorta (0–90°), and involvement of the superior mesenteric vein/portal vein (0–90°). A biliary stent (black asterisks in a, b, c, e, f) was placed prior to IRE using endoscopic retrograde cholangiopancreatography (ERCP). a Perprocedural contrast enhanced (ce)-CT of the LAPC in the head of the pancreas (white arrows) and biliary stent (black asterisk) prior to IRE treatment. The white asterisk shows significant dilation of the pancreatic duct. b Perprocedural axial view of 2 of the 4 needle electrodes in situ. c Perprocedural coronal view of all 4 needle electrodes in situ. The needles were successfully placed, bypassing all major blood vessels. d Sagittal view of 2 of the 4 needle electrodes in situ. e ce-CT immediately after IRE. The white arrows delineate the ablation zone, wherein formation of gas pockets is clearly visible (black arrow). The gas pockets maybe the result of water electrolysis and/or vaporization. f ce-CT 3 months post-IRE demonstrates a hypointense ablation zone (white arrows). The portal vein is open; dilation of the pancreatic duct (white asterisk) remains unchanged. No evidence of local recurrence or distant metastases