The morbidity associated with pancreatectomies limits surgical options for high-risk patients with pancreatic neoplasms that warrant resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) offers a minimally invasive and potentially definitive means to treat pancreatic neuroendocrine tumors and precancerous pancreatic cystic lesions. In addition, EUS-RFA may play a role in the treatment and palliation of non-surgical cases of pancreatic adenocarcinoma. The efficacy of RFA appears to be further enhanced by systemic immunomodulatory effects. Here, we review current studies on the developing role of EUS-RFA in these pancreatic pathologies.

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A Review on Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) of Pancreatic Lesions

Recently, endoscopic ultrasound (EUS)‐guided ablation therapy has been reported as a less invasive therapy for patients with pancreatic neoplasms. Some ablation techniques, including injective ablation (using ethanol or other ablative agents), radiofrequency ablation (RFA), photodynamic therapy, and laser ablation, have been described in the literature. Among these, injective ablation and RFA are more frequently used for treating pancreatic neoplasms. Few studies have evaluated the effectiveness of EUS‐guided ethanol ablation (EUS‐EA) for potentially malignant solid neoplasms (neuroendocrine neoplasms or solid pseudopapillary neoplasms) and have reported a complete response (CR) rate of 60–80%. In addition, the CR rate after EUS‐RFA for these lesions has been reported to be 55–100%, with no additional procedure‐related adverse events (AEs). Regarding the amelioration of the symptoms of an insulinoma, the success rates of both the therapies were found to be excellent. Regarding complete tumor ablation, EUS‐RFA appeared to be superior to EUS‐EA. Although EUS‐RFA has been reported as a safe treatment for pancreatic cancers, its effectiveness remains inadequate. Some studies have examined the effectiveness of EUS‐guided injection ablation therapy for pancreatic cystic neoplasms (PCNs) and have reported CR rates that range from 35% to 79%. Alcohol‐free chemotherapeutic agent ablation appears to be effective, with a low risk of AEs. However, studies on the effectiveness of EUS‐RFA for PCNs are limited. In the future, EUS‐guided ablation therapy could become a more widely used approach for potentially malignant and malignant pancreatic lesions.

Endoscopic ablation therapy for the pancreatic neoplasms

Abstract Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival. 

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Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Pancreatic malignancy is still the most lethal gastrointestinal malignancy. It has a very poor prognosis with low survival rate. Surgery is still the main treatment option for pancreatic malignancy. Most patients already have locally advanced and even late stage disease due to non-specific abdominal symptoms. Even though some cases are still suitable for surgical treatment, due to its aggressiveness adjuvant chemotherapy is becoming the standard treatment for controlling the disease. Radiofrequency ablation (RFA) is a thermal therapy that has been used as one of the standard treatments for liver malignancy. It can also be performed intraoperatively. There are several reports on percutaneous RFA treatment for pancreatic malignancy using transabdominal ultrasound and guided by computed tomography scan. However, due to its anatomical location and the risk of high radiation exposure, these methods seem to be very limited. Endoscopic ultrasound (EUS) has been widely used for pancreatic abnormality evaluation due to its ability to detect more accurately, especially small pancreatic lesions, compared to other imaging modalities. By the EUS approach, it is easier to achieve good visualization of tumor ablation and necrosis as the echoendoscope position is closer to the tumor area. Based on studies and a recent meta-analysis, EUS-guided RFA is a promising treatment approach for most pancreatic malignancy cases, but most studies only collected data from a small sample size. Larger studies are needed before clinical recommendations can be made.

Impact of endoscopic ultrasound-guided radiofrequency ablation in managing pancreatic malignancy

Current Approaches to the Management of Locally Advanced Pancreatic Cancer

Long term prognosis and 5-year survival for pancreatic adenocarcinoma (PDAC) remains suboptimal. Endoscopic ultrasound (EUS) guided RFA (EUS-RFA) is an emerging technology and limited data exist regarding safety and long-term outcomes. The aim of this study is to report safety-profile, feasibility and outcomes of EUS-RFA for advanced PDAC. Prospective review of patients with diagnosis of locally-advanced or metastatic PDAC undergoing EUS-RFA between October 2016 to March 2018 with long-term follow up (> 30 months). Study patients underwent a total of 1-4 RFA sessions. All patients were enrolled in longitudinal cohort study and received standard of care chemotherapy. 10 patients underwent EUS-RFA. Location of the lesions was in the head(4), neck(2), body(2), and tail(2). 22 RFA sessions were performed with a range of 1-4 sessions per patient. There were no major adverse events (bleeding, perforation, infection, pancreatitis) in immediate (up to 72 h) and short-term follow up (4 weeks). Mild worsening of existing abdominal pain was noted during post-procedure observation in 12/22 (55%) of RFA treatments. Follow-up imaging demonstrated tumor progression in 2 patients, whereas tumor regression was noted in 6 patients (> 50% reduction in size in 3 patients). Median survival for the cohort was 20.5 months (95% CI, 9.93-42.2 months). Currently, 2 patients remain alive at 61 and 81 months follow-up since initial diagnosis. One patient had 3 cm PDAC with encasement of the portal confluence, abutment of the celiac axis, common hepatic and superior mesenteric artery. This patient had significant reduction in tumor size and underwent standard pancreaticoduodenectomy. In our experience, EUS-RFA was safe, well-tolerated and could be concurrently performed with standard chemotherapy. In this select cohort, median survival was improved when compared to published survival based upon SEER database and clinical trials. Future prospective trials are needed to understand the role of EUS-RFA in overall management of PDAC. 

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Seshadri, Ram

Papers

Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for advanced pancreatic and periampullary adenocarcinoma