Evaluation of Safety and Feasibility of EUS-guided RFA for Solid Pancreatic Neoplasms

Study Overview
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Brief Summary
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This study aims to evaluate the safety and efficacy of new ablation catheter developed by MEDICAL TAEWOONG for the treatment of pancreatic neoplasm (pancreatic adenocarcinoma or neuroendocrine tumour). The ablation is performed using EUSRA needle and radio frequency waves under ultrasound imaging. The subject who will be recruited into this study are patients who are deemed as non-surgical candidates.

Detailed Description
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RFA causes tissue destruction through the application of a high frequency alternating current, generating local temperatures above 60°C and leading to coagulative necrosis. The technique has been widely used in many solid organ tumours and has been shown to result in 5-year survival rates comparable to surgery. The technique is currently the standard therapy in hepatocellular carcinoma and colorectal pulmonary metastasis particular in patients that are not suitable for surgery. The application of RFA in the pancreas was first described in 1999. Thereafter, several studies performed in the porcine model demonstrated the feasibility of RFA under EUS guidance. In the first porcine study by Goldberg et al, RFA was applied through a modified 19 gauge Vilmann-type needle (GIP/MediGlobe, Grassau, Germany). The needles were electrically insulated with shrink tubing for all but the distal 1 to 1.5cm. 16 ablations were performed and the procedure resulted in hypodense foci of non-enhancing pancreas 1 to 2 days after ablation. Pathologic examination showed well demarcated spherical foci of coagulation necrosis measuring 8 to 12mm in size. One swine developed hyperlipasemia, a focal zone of pancreatitis and another with pancreatic fluid collection. 4 swine also suffered from thermal injury to the gastrointestinal wall caused by improper electrode placement. Thereafter, 4 subsequent porcine studies also demonstrated the feasibility of RFA under EUS guidance with proprietary radiofrequency electrodes. In the most recent study, EUS-guided RFA was delivered by a novel 18-gauge RFA electrode and a VIVA RF generator (STARmed, Korea). RFA was applied to both the ex-vivo and in-vivo models to determine the optimum power settings and efficacy of the device. A power setting of 50 W for 6 minutes was shown to result in the most effective depth and size of ablation zone, whilst a higher power setting resulted in tissue charring and reduced the conductive coagulative necrosis effect. 10 swine then received EUS-guided RFA to the pancreas and the mean size of the ablated lesions were 23 +/- 6.9mm. None of the swine suffered from any adverse events and there were no significant changes in the serum levels of amylase and lipase, both before and after the procedures. On the other hand, the experience of RFA in human pancreas is accumulating. Earlier studies using first generation percutaneous RFA probes applied intra-operatively to pancreatic carcinomas were associated with unacceptably high rates of mortality (0% - 25%) and morbidity (0% - 40%). Subsequently, human data on new generation EUS-guided RFA probes with improved design and outcomes have become available. 22 patients with locally advanced pancreatic ductal adenocarcinoma were treated the cryotherm probe (CTP) (ERBE Elektromedizin GmbH, Tübingen, Germany). The CTP was successfully applied in 16 patients (72.8%), amylase rose in 3 of 16 patients but none had clinical signs of pancreatitis. The median post ablation survival time was 6 months. In another 2 studies, the Habib RFA catheter was used (EMcision, United Kingdom). 7 patients with unresectable pancreatic ductal carcinoma and 8 patients with pancreatic neuroendocrine tumour and cystic tumours were treated with EUS-guided RFA. In patients suffering from pancreatic ductal carcinoma, post procedural imaging showed a decrease in size of the lesions in 2 patients and 1 patient suffered from mild pancreatitis. Whilst in patients with cystic neoplasms and neuroendocrine tumours, all showed complete resolution or reduction in size of the lesions. Only 2 patients suffered from abdominal pain that resolved spontaneously. On the other hand, RFA with the VIVA generator was applied in 6 patients with unresectable pancreatic adenocarcinoma. Two patients suffered from mild abdominal pain but no serious adverse events reported. Thus, based on these preliminary results, we conclude that the new generation EUS-guided RFA probe is safe and feasible. The next stage in development with conduction of this study would involve recruitment of larger patient cohorts to further establish the efficacy and risk profile of the procedure. HYPOTHESIS AND OBJECTIVES The aim of the current study is to perform a single center prospective study on EUS-guided radiofrequency ablation (RFA) of solid pancreatic neoplasms. We hypothesize that EUS-guided RFA is safe, feasible and effective for treating solid pancreatic neoplasms. EXPECTED RIKS AND BENEFITS The expected risks for the patients include mild abdominal pain. The benefit may include RFA destroy the tumour cells via coagulative necrosis process hence providing some form of disease control. Besides, the current study could establish the safety and feasibility of EUS-guided RFA of solid pancreatic neoplasms. These results could provide insights as to whether the procedure is comparable to surgery for treatment of these lesions in the future. STUDY POPULATION We aim to recruit 10 subjects over the period of 18 months. The subjects must have pancreatic neuroendocrine tumour or pancreatic ductal carcinoma that was unsuitable for surgery or not keen for surgery. STUDY DESIGN AND PROCEDURES/METHODOLOGY The RFA system It consists of two components, a19-gauge RFA electrode and a VIVA combo RF generator. The total length of the electrode including the delivery system is 150 cm. The distal end of the electrode is needle-shaped and echogenic that allows EUS guided puncture of the target lesion. The active electrode tip is 1 cm in length. During ablation, the RF electrode is cooled and perfused internally with circulating chilled saline solution (0°C) delivered via a pump to maintain a constant temperature. A setting of 50W energy would be used for RFA and the duration of application is 10 seconds. EUS-guided radiofrequency ablation This procedure is very similar to the standard technique of EUS-guided fine needle aspiration. The location and size of the lesion would be assessed for suitability of treatment. After locating the lesion, the RFA needle would be inserted to the centre of the lesion. RFA would then be initiated and hyperechoic interferences would be observed around the electrode signifying heating of the tissue. Post procedural, the site of needle entry would be inspected endoscopically to assess for presence of thermal injury to the gastrointestinal wall. Follow-up protocol There will be clinic visit scheduled by both gastroenterologist and oncologist at two weeks after discharging from hospital to review participant's condition and to plan for further treatment. Follow-up phone call will be made at 1st week and 1st month after discharging from the ward to determine for any adverse event and whether they are attributable. When reporting complication rates, only definite and probably attributable events occurring within 30 days will be include.

Official Title
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Evaluation of Safety and Feasibility of Endoscopic Ultrasound (EUS)-Guided Radiofrequency Ablation (RFA) for Solid Pancreatic Neoplasms

Conditions
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Pancreatic Cancer, Pancreatic Neoplasms, Pancreatic Adenocarcinoma, Pancreatic Neuroendocrine Tumor, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Device: EUSRA RFA needle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21 years-old or above Suffering from pancreatic neuroendocrine tumour or pancreatic ductal carcinoma that was confirmed by fine needle aspiration cytology Unsuitable for surgery, due to one (or more) of the following items: ASA score >/= III An alternative advanced malignancy Unsuitable for surgery upon expert's opinion for any other reason Individuals who are not keen for surgical resection Eligible for endoscopic intervention Written informed consent Exclusion Criteria: Coagulopathy (international normalized ratio >1.5, partial thromboplastin time greater than twice that of control), platelet count <50,000x103/uL Pregnancy Patients with a poor mental condition or mental retardation, unable to understand the nature and possible consequences of the study Patients unwilling to undergo follow-up assessments Patients with liver cirrhosis, portal hypertension and/or gastric varices.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: prospective, open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EUSRA RFA needle<br>This procedure is very similar to the standard technique of EUS-guided fine needle aspiration. All patients would undergo EUS with a linear array or therapeutic echoendoscope. The location and size of the lesion would be assessed for suitability of treatment. After locating the lesion, the EUSRA RFA needle would be inserted to the centre of the lesion. RFA would then be initiated and hyperechoic interferences would be observed around the electrode signifying heating of the tissue. | Device: EUSRA RFA needle<br>* A 19-gauge RFA electrode and a RF generator with a electrode that is needle-shaped and echogenic that allows EUS guided puncture of the target lesion. The active electrode tip is 1 cm in length. During ablation, the RF electrode is cooled and perfused internally with circulating chilled saline solution (0°C) delivered via a pump to maintain a constant temperature. A setting of 50W energy would be used for RFA and the duration of application is 10 seconds. Sequential applications of up to 7 times per session are allowed for complete ablation of the lesions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the technical success of EUS-guided RFA | It is defined as successful puncture of the pancreatic lesion with the RFA needle and completion of the ablation cycle. | 18 months | 
| To measure side effects and adverse event of EUS-guided RFA | Adverse events specific to RFA would be graded according to the lexicon of endoscopic adverse events (PB Cotton GIE 2010). Potential adverse events specific to RFA include: Post-RFA syndrome: Combination of flu like symptoms including fever, malaise, pain at the site of ablation, nausea, and/or vomiting and that no other septic source is identified. Pancreatitis: Clinical presence of abdominal pain with an increase in amylase level >3 times above the normal serum amylase levels. Pancreatic leak: The presence of an abdominal collection with an amylase level that is >3 times normal serum amylase levels. Thermal injury: Coagulative necrosis occurring at the site of needle entry within the gastrointestinal tract with or without clinical sequelae. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EUS-guided RFA, Endoscopic ultrasound, radio frequency ablation