Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients’ quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

Risk factors for unresectable pancreatic cancer following high‐intensity focused ultrasound treatment

“…At the same time, the hyperthermia produced by the action of HIFU increases blood flow and vascular permeability, disrupt the stromal architecture, thus improving anti-tumor effects. 8 HIFU also uses the cavitation and mechanical effect of ultrasound to increase vascular permeability, promote drugs penetration, 9 induce subcellular fragmentation, and trigger activation of cytotoxic T cells in other types of tumors. [10][11][12] However, it is very difficult to obtain the tumorinfiltrating lymphocytes in pancreatic cancer in clinical work.…”

“…In anticancer immunity, the complex interaction between immune cells such as NK, CD4 + T, and CD8 + T cells can significantly affect the survival rate, which has been reported in tumor‐infiltrating lymphocytes in pancreatic cancer 7 . Encouragingly, locoregional therapies have been shown to induce changes in the structure, composition and properties of the pancreatic cancer tumor microenvironment, which may help in the treatment of the disease 8 . HIFU uses a focused ultrasound beam to create a thermal effect at the lesion, which can cause rapid coagulative necrosis with limited inflammatory response and minimal damage to outside the focal area.…”

“…HIFU uses a focused ultrasound beam to create a thermal effect at the lesion, which can cause rapid coagulative necrosis with limited inflammatory response and minimal damage to outside the focal area. At the same time, the hyperthermia produced by the action of HIFU increases blood flow and vascular permeability, disrupt the stromal architecture, thus improving anti‐tumor effects 8 . HIFU also uses the cavitation and mechanical effect of ultrasound to increase vascular permeability, promote drugs penetration, 9 induce subcellular fragmentation, and trigger activation of cytotoxic T cells in other types of tumors 10–12 …”

Irreversible electroporation of the pancreas – A decade on

“… 1 , 2 To date, the 5-year overall survival for patients with pancreatic adenocarcinoma is approximately 8%. 3 Surgical resection with adjuvant chemotherapy is considered the best treatment option for long-term survival. However, fewer than 20% of patients present with resectable disease.…”

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts

“…These doses are limited to prevent toxicities in the small bowel and stomach. Further, conventional chemoradiation can induce TP alterations in the TME where CAF u responses to therapy play a central role 6 . Hence, developing safer methods to escalate radiation dosages, without triggering TP-CAF u responses that further expand desmoplasia, could address the clinically unmet need for more effective TNT strategies.…”