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

Table 1 Locoregional therapies and their main effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

	Vasculature	Stroma	Immune response
Hyperthermia	Increased blood flow and vascular permeability. Recruitment of bradykinin and histamin. Increased iNOS.	Destructuration of collagen fibers. Reduction of CAF. Reduction of tumor stiffness.	Promotes APC activation. Increased infiltrating CD8+. Increased pro-inflammatory cytokines. Abscopal effect (RFA).
Radiation therapy	Reduced blood perfusion. Destructuration of microvessels with thickening vessel walls. Platelet aggregation. Microthrombus formation. Increased HIF-1 and VEGF. Increased vascular permeability.	Accumulation of extracellular matrix proteins. Increased stromal cells (fibroblasts). Thickened and stiffened tissue. Loss of hyaluronic acid. Collagen remodeling. Modification of CAF population.	Release of tumor antigens (DAMPs) ≥ APC presentation and CD8+ activation. Increased peptide availability and T cell repertoire. Release of inflammatory cytokines, CD8+, and CD4+ cells. Increased adhesion molecules (VCAM-1, ICAM-1). T cells homing. Increased PDL-1.
HIFU (mechanical effect)	Reduced blood perfusion and microvascular density.	Disruption of the collagen matrix.	Released DAMPs ≥ T cell activation. Induction of Th1 inflammation. Increased CD8+/Treg ratio.

iNOS: Inducible nitric oxide synthase; CAF: Carcinoma-associated fibroblasts; APC: Antigen presenting cell; RFA: Radiofrequency ablation; DAMPs: Damage-associated molecular patterns; HIFU: High-intensity focused ultrasound.

Table 2 Ongoing studies in locoregional therapies used alone or in combination with chemotherapy or immunotherapy for pancreatic ductal adenocarcinoma

	Clinical trial number	Study name	Number of patients	Status	Country
Hyperthermia	NCT04858009	Hyperthermic intraperitoneal chemotherapy for the treatment of pancreatic cancer and peritoneal metastasis.	40	Not yet recruiting	United States
	NCT04889742	HT enhanced reirradiation of loco-regional recurrent tumors (HETERERO).	100	Recruiting	Germany
	NCT04310111	EUS-RFA for unresectable pancreatic cancer.	18	Recruiting	China
	NCT03218345	EUS-guided RFA for pancreatic neoplasms.	30	Recruiting	China
	NCT02439593	Concurrent HT and chemoradiotherapy in LAPC: phase II study (HEATPAC).	78	Recruiting	Switzerland
	NCT04164992	EUS-RFA of not-resectable pancreatic cancer.	15	Not yet recruiting	Italy
	NCT03690323	Pancreatic locally advanced irresectable cancer ablation (PELICAN).	228	Recruiting	Netherlands
	NCT04156087	Progression-free survival after microwave ablation plus durvalumab and tremelimumab for unresectable LAPC (MIMIPAC).	20	Recruiting	Belgium
Radiation therapy	NCT04361162	Nivolumab + ipilimumab + radiation in microsatellite stable pancreatic cancer.	30	Recruiting	United States
	NCT01972919	Magnetic resonance guided, dose-escalated RT + chemotherapy in pancreatic cancer.	23	Recruiting	United States
	NCT03374293	Combination of radiation therapy and anti-PD-1 antibody in treating patients with pancreatic cancer.	21	Recruiting	China
	NCT03492671	Testing the combination of two approved chemotherapy drugs and radiation prior to surgery in localized pancreatic cancer.	30	Recruiting	United States
	NCT04975516	Standard of care chemotherapy with or without SBRT for the treatment of oligometastatic pancreatic cancer.	50	Not yet recruiting	United States
	NCT04327986	Immune checkpoint inhibitor m7824 and the immunocytokine m9241 in combination with SBRT in adults with advanced pancreas cancer.	52	Recruiting	United States
	NCT03991962	Phase II study to evaluate modified folfirinox and SBRT in nonmetastatic unresectable pancreatic adenocarcinoma.	28	Recruiting	United States
	NCT02128100	Effects of folfirinox and SBRT for advanced pancreatic cancer.	28	Recruiting	United States
	NCT04089150	Mfolfirinox and SBRT for pancreatic cancer with high risk and locally advanced disease.	120	Not yet recruiting	Australia
	NCT04172532	Testing the addition of a new anticancer drug, m3814 (peposertib), to radiation therapy for localized pancreatic cancer.	24	Recruiting	United States
HIFU	NCT04146441	Ultrasound-enhanced uptake of chemotherapy in patients with inoperable PDAC.	30	Recruiting	Norway
	NCT04852367	PanDox: targeted doxorubicin in pancreatic tumors.	18	Not yet recruiting	England
Irreversible elecroporation	NCT03257150	A study of the use of IRE in pancreatic ductal cancer.	47	Recruiting	Canada
	NCT03105921	IRE (nanoknife) for the treatment of pancreatic adenocarcinoma.	20	Recruiting	France
	NCT03899636	A pivotal study of safety and effectiveness of nanoknife IRE for stage 3 pancreatic cancer (direct).	528	Recruiting	United States
	NCT02822716	IRE for inoperable hepatic and pancreatic malignancy.	35	Recruiting	China
	NCT02343835	Antitumor immunity induced by IRE of unresectable pancreatic cancer.	20	Recruiting	China
	NCT03484299	Chemotherapy and IRE in the treatment of advanced pancreatic adenocarcinoma.	20	Recruiting	United States
	NCT04835402	Electroporation potentiated immunotherapy in cancer (EPIC-1).	16	Recruiting	Denmark
	NCT04276857	Systemic therapy with a loco-regional treatment in patients with LAPC (smart).	27	Not yet recruiting	Canada
	NCT04212026	IRE followed by nivolumab in patients with metastatic pancreatic cancer.	15	Recruiting	Switzerland
	NCT04612530	Panfire-3 trial: assessing safety and efficacy of IRE + nivolumab + CpG for metastatic pancreatic cancer.	18	Recruiting	Netherlands
	NCT02041936	Outcomes of ablation of unresectable pancreatic cancer using the nanoknife IRE system.	12	Recruiting	United States
	NCT04310553	An open-label, multicenter, prospective study of IRE (nanoknife) combined with RT and chemotherapy in patients with LAPC.	240	Recruiting	China
	NCT04093141	Chemotherapy followed by IRE in patients with unresectable LAPC (chemofire-2).	30	Recruiting	Denmark
	NCT03614910	Ablation of unresectable LAPC with IRE system.	30	Recruiting	United States

HT: Hyperthermia; EUS: Endoscopic ultrasound; RFA: Radiofrequency ablation; LAPC: Locally advanced pancreatic cancer; RT: Radiation therapy; SBRT: Stereotactic body radiation therapy; PDAC: Pancreatic ductal adenocarcinoma; IRE: Irreversible electrotherapy.