EUS-RFA is a local treatment that uses heat generated by the agitation of ions in cells to induce cell death and coagulation necrosis. Ion agitation is achieved by applying a high-frequency alternating current of approximately 500 kHz [16]. In addition to the thermal ablation effect, RFA appears to play a role in the secondary anticancer immune response by inducing activation of tumor-specific T lymphocytes and expression of heat shock protein 70 [17]. RFA has been widely used for the treatment of solid cancers in organs such as the liver, lungs, and kidneys. However, it is not often used in the treatment of pancreatic tumors due to the risk of pancreatitis caused by heat damage, damage to the pancreatic ducts and structures around the pancreas, and technical difficulties. EUS-RFA for the pancreas using an animal model was first reported by Goldberg et al. [16] in 1999. They observed coagulation necrosis of approximately 10 mm in diameter as a result of maintaining the electrode temperature at 90±2℃ for 6 min after inserting a 19 G needle electrode into the tail of a pig’s pancreas under EUS guidance. In early animal experimental models, there were technical difficulties, such as the location of the pancreas in the retroperitoneum, proximity to the bile duct, and distribution of main blood vessels around it. It was also difficult to set the ideal temperature for optimal thermal ablation with minimal complications. Kim et al. [18] demonstrated the stability, feasibility, and efficacy of EUS-RFA on the body and tail of the pancreas in a study of 10 adult mini pigs. In this study, EUS-RFA was performed on the normal pancreas of a pig for 5 min at a power of 50 W using an 18 G needle electrode, equipped with a cooling system using cold saline inside the electrode. After RFA, coagulation necrosis with an average diameter of 23 mm was noted. The autopsy did not reveal any complications such as pancreatic tissue necrosis or pancreatic duct or blood vessel damage outside the RFA site. Therefore, EUS-RFA for the pancreas was considered a safe, feasible, and effective treatment method. Subsequent studies investigated the technical applicability and stability of EUS-RFA for unresectable pancreatic cancer and its treatment outcomes (Table 2). In 2012, Arcidiacono et al. [19] performed cryothermal ablation on 22 patients with unresectable pancreatic cancer using a bipolar RFA electrode (cryotherm probe [CTP]; ERBE, Tübingen, Germany), where the inside of the electrode was cooled with carbon dioxide. An electric power of 18 W was used for heating, a fixed pressure of 650 psi was used for cooling, and the average energy transfer time was 107 sec (10–360 sec). There was a significant reduction in tumor volume in 16 patients. Early complications included temporary abdominal pain (three patients) and mild duodenal bleeding (one patient); late complications included jaundice (two patients), duodenal stenosis (one patient), and fluid retention around the pancreas (one patient). In 2016, Song et al. [6] published a study on EUS-RFA using an 18 G needle electrode in six patients with unresectable pancreatic cancer. Of these, four patients had pancreatic head cancer and two had pancreatic body cancer with the median tumor size 3.8 cm (range, 3–9 cm). Depending on the size of the tumor, RFA was performed for 10 s at one site with 20–50 W of power, and then moved to another location until the entire tumor was cauterized. An average of 1.3 RFA sessions were conducted. When contrast-enhanced EUS was performed after the procedure, there was no contrast enhancement in the RFA-treated area, but increased blood flow was observed in the surrounding tissue. Complications included mild abdominal pain in two patients. In 2018, Scopelliti et al. [20] conducted EUS-RFA on 10 patients with unresectable pancreatic cancer undergoing systemic chemotherapy using an 18 G, 10 mm needle electrode. They used 20–30 W of power, and the average energy transfer time was 285 sec (100–560 sec). Abdominal computed tomography (CT) performed 30 days after the procedure to evaluate treatment response showed low-density necrotic areas inside the tumor in all 10 patients. Procedural complications included mild asymptomatic ascites (two patients) and fluid retention around the pancreas (two patients), but there were no serious complications associated with the procedure. The results of the above animal and human experiments indicate that EUS-RFA is technically safe for patients with unresectable pancreatic cancer. It may be used as an aid to existing systemic chemotherapy or considered as an alternative treatment for patients at high risk of systemic adverse events of chemotherapy.

IRE is a non-thermal resection technique that locally resects a tumor using high-voltage electric pulses generated by needle electrodes inserted into and around the tumor. Electric pulses induce irreversible damage by producing nanopores in the tumor cell membrane to induce apoptosis [21]. Martin et al. [22] published a study conducted on patients with unresectable pancreatic cancer, where the prognosis of a group treated with a combination of standard therapy (chemotherapy ± radiotherapy) and IRE (54 patients) was compared to that of a group treated with standard therapy alone (85 patients). There was a significant improvement in the patient group treated with IRE in terms of local progression-free survival (14 months vs. 6 months, p=0.01), distant progression-free survival (15 months vs. 9 months, p=0.02), and overall survival (20 months vs. 13 months, p=0.03). IRE has been reported to minimize thermal damage, unlike RFA, which can cause thermal damage to major blood vessels, bile ducts, and nerves around the pancreas. However, in some conditions using high-intensity electric currents, IRE has also been reported to cause coagulation necrosis, similar to RFA. This effect is likely due to the partial thermal damage caused by high-intensity currents [23]. Therefore, further study on the stability of IRE and development of tools to safely apply this technique is required. Conventional IRE is performed using a CT-guided percutaneous method by inserting electrodes into the tumor during open or laparoscopic surgery. However, the development of EUS technology and equipment allows IRE to be performed more safely and accurately under EUS guidance. Recently, Lee et al. [24] published a study on the effectiveness and reproducibility of EUS-guided IRE using animal experiments, with new electrodes developed for use in EUS. Further studies on the development of a standardized needle electrode that can be used for EUS, identification of safe and effective voltage settings, and demonstration of clinical applications are required.

Stereotactic body radiation therapy (SBRT) is a method of delivering intensively high doses of radiation to a tumor site using a cyberknife or a similar tool. The treatment period is short when compared to that of conventional radiotherapy, and several studies have proven it to be effective even against unresectable pancreatic cancer. Jung et al. [25] conducted a retrospective analysis of the treatment outcomes of 95 patients with unresectable pancreatic cancer treated in a single institution between 2011 and 2016. They reported that freedom from local disease progression and overall survival were better, with lower treatment toxicity, in patients who simultaneously received systemic chemotherapy and SBRT. A significant challenge in applying SBRT to pancreatic cancer is the necessity to navigate movement caused by breathing. Unlike intracranial tumors, the pancreas does not exist in a fixed space such as the skull, and is estimated to move 2–3 cm during the breathing cycle. The fiducial marker inserted into the border area of pancreatic cancer acts as a fixed reference point in the tumor, helping in accounting the movement of the target during stereotactic radiotherapy. Traditionally, fiducial markers were inserted percutaneously under CT or ultrasound guidance. However, the location of the pancreas in the retroperitoneal space makes percutaneous fiducial marker insertion risky, causing potential vascular damage due to poor accuracy. Park et al. [26] predicted that EUS-guided insertion of fiducial markers using real-time Doppler imaging could decrease the risk of bleeding. They performed EUS-guided fiducial marker insertion in 57 patients with unresectable pancreatic cancer, and minor bleeding was reported in only one patient.

Although rare, another risk of the percutaneous approach is peritoneal dissemination of the tumor. During CT or ultrasound-guided fine needle aspiration, peritoneal dissemination of the tumor occurs in 0.005%–0.009% of all cases. However, the EUS-guided approach is thought to have a lower risk of peritoneal dissemination because the perforation pathway is very short compared to percutaneous methods [27].

Thus, EUS-guided fiducial marker insertion is rapidly becoming an essential procedure when preparing for SBRT in patients with unresectable pancreatic cancer. It is a technically safe and accurate approach compared to other mesthods.

Brachytherapy is a method of treating tumors by inserting a radioactive source into or around the tumor tissue. Radioactive sources used for brachytherapy include iodine-125, iridium-192, palladium-103, and iodine-125, the last of which has the longest half-life and is thought to be useful for pancreatic cancer with rapid tumor growth. Bhutani et al. [28] reported a 58% reduction in tumor volume in patients with unresectable pancreatic cancer treated with brachytherapy using a new radioactive source, phosphorus-32 microparticles (P-32; OncoSil Medical Ltd., Sydney, Australia), in combination with standard chemotherapy. The development of new radioactive sources and more data on treatment outcomes are required in the future.