The first initial report of the use of RFA in an animal model was by Goldberg et al. [16] who reported that RFA could be used safely and effectively. This conclusion was extrapolated to the clinical scenario of small neuroendocrine tumors and possibly in the palliation of LAPC. An additional report from Date et al. [17] reported the safety of RFA in a normal pancreas of a porcine model. The first clinical report on 20 patients was published by Matsui et al. [18] in 2000 (Table 18.5). Since then, several case reports have been published from various groups of investigators [19–22] (Table 18.3). The use of RFA in the pancreas has been recently summarized in a systematic review in the treatment of LAPC [19]. Five cohort studies (four prospective and one retrospective) were reported through 2012. This report did not include reports of < five cases and included only studies that reported RFA of pancreatic adenocarcinoma. A total 158 patients were treated with four different ablation devices: 100 patients using a 1500× generator (RITA Medical Systems, Mountain View, CA), 28 patients using a Radionics generator (Radionics Inc., Burlington, MA), 10 patients using a generator manufactured by Berchtold GmbH & Co., KG (Tuttlingen Germany), and 20 patients using a generator manufactured by Omron Co., Ltd (Kyoto, Japan). In the initial study by Matsui et al. [18], the technique they utilized was a controlled ablation of 50 °C for 15 min using 4 needles and reported a median overall survival of 3 months. Matsui’s poor survival outcomes may have been related to the fact that they included patients with metastatic disease. Overall survival was reported to be better in two additional studies at 20 months [20] and 33 months, respectively [21]. A systematic review by Singh et al. [23] reported an overall survival range of 9–36 months. The largest series published to date was from Girelli et al. [20]. In this series of 100 patients, a morbidity of 15 % and mortality of 3 % was reported. The authors utilized extreme heat (105 °C) in the first 25 patients leading to significant vascular and intestinal injury. They then modified their technique slightly with target temperatures of 90 °C. Others have also reported significant morbidity and mortality rates. Wu et al. reported a morbidity of 38 % and mortality of 25 % [22]. These results were related to three patients developing a pancreatic fistulas, three having massive gastrointestinal bleeding after portal vein thrombosis, with four procedure-related deaths. These results demonstrate that the use of a coagulative temperature will not only result in necrosis of the tumor, but also of the surrounding soft tissue(s). In an attempt to minimize these complications, several authors have described using cooling devices inserted endoscopically into the duodenum [24]. Similar intraoperative cooling devices have also been utilized as reported by Cavallini et al. [25] with encouraging results.