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New Indications for Endoscopic Radiofrequency Ablation
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New Indications for Endoscopic Radiofrequency Ablation Q17
Thomas R. McCarty* and Tarun Rustagi‡ *Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; ‡Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico
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Radiofrequency ablation (RFA) is a well-established treatment for several benign, premalignant, and malignant disorders. Although the role of RFA has been clearly defined, new indications for luminal and extraluminal applications of endoscopic RFA-directed therapies have emerged. RFA has recently produced promising results in patients with a variety of gastrointestinal and hepatopancreatobiliary pathologies. For example, endoscopic RFA has been used to treat patients with gastric antral vascular ectasia, chronic radiation proctitis, malignant biliary strictures, and ampullary adenomas with intraductal extension. Furthermore, endoscopic ultrasound-guided RFA appears to be an effective, minimally invasive treatment for ablation of solid and cystic lesions—particularly in the pancreas. We review the newer indications for RFA and discuss potential limitations of endoscopic RFA. Keywords: GAVE; CRP; EUS; Cancer.
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ithin the field of gastroenterology, radiofrequency ablation (RFA) is a well-established modality for the treatment of a variety of benign, premalignant, and malignant conditions.1 Endoscopic RFA has been described to achieve mucosal ablation in several types of benign hemorrhagic gastrointestinal diseases. In addition, endoscopic RFA has been validated as an approved treatment for premalignant conditions as seen in patients with Barrett’s esophagus with dysplasia, in whom it has been shown to achieve highly effective and durable results.1–5 RFA for the treatment of esophageal metaplasia and dysplasia, although similar to electrocautery, initially was established for and patented in a porcine and human model by Ganz et al6 in 1999. The device involved a balloon-based, bipolar radiofrequency system that created a circumferential, thin-layer, epithelial ablation zone within the esophagus. Still today, the technique involves high-frequency alternating electrical current delivered locally to tissue or mucosa. This localized controlled heating results in targeted destruction and thermal coagulative necrosis. Although the role of RFA has been clearly defined in the management of Barrett’s esophagus, new indications for endoscopic RFA-directed treatment have emerged with the promise of improving the management of patients who do not have many options at the present time.5,7,8 Endoscopic RFA possesses the potential for
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expanded use in a multitude of gastrointestinal and hepatopancreatobiliary diseases. This review highlights these newer luminal and extraluminal indications and reviews the existing literature to support an emerging role of endoscopic RFA for these indications.
Gastric Antral Vascular Ectasia Classically detailed as having a watermelon or honeycomb appearance, gastric antral vascular ectasia (GAVE) is a collection of dilated tortuous vessels first described by Rider et al9,10 in 1953. Pharmaco- Q8 therapy with octreotide, tranexamic acid, and estrogen–progesterone hormonal therapy typically is ineffective.11–13 Endoscopic therapy is presently the preferred treatment modality with options that include nonthermal and thermal approaches. At this time, a thermal approach with argon plasma coagulation (APC) is considered the first-line endoscopic treatment of choice.14 This is in large part because APC is associated with a low complication rate and is cost effective. Despite this, studies have shown mixed success rates to date, with approximately two thirds of GAVE patients remaining transfusion-dependent.15 Recently, RFA has emerged as a viable alternative endoscopic modality for GAVE with many devices available to gastroenterologists (Table 1). The procedure involves mounting the RFA electrode array on an endoscope with the device advanced to the pylorus.16,17 After insertion, the endoscope is deflected to place the articulated electrode against the mucosal area of desired treatment. Typically, 2 to 4 consecutive pulses of energy are delivered (at a preset and automated energy density dose of 12 J/cm2) in the same area without scraping off to promote optimal hemostasis. The goal of each session is to perform circumferential ablation of the desired lesions and eradicate at least 90% of abnormal gastric mucosa.17
Abbreviations used in this paper: APC, argon plasma coagulation; CRP, chronic radiation proctitis; EUS, endoscopic ultrasound; GAVE, gastric antral vascular ectasia; PDT, photodynamic therapy; RFA, radiofrequency ablation; SEMS, self-expanding metal stent. © 2018 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2017.10.023
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Table 1. List of Available Radiofrequency Ablation Devices for the Treatment of Gastric Antral Vascular Ectasia
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Devices
Electrode length
Electrode width
Channel Catheter HALO60 (Covidien, GI Solutions) HALO90 (Covidien, GI Solutions) HALOULTRA (Covidien, GI Solutions)
15.7 mm 15 mm 20 mm 40 mm
7.5 mm 10 mm 13 mm 13 mm
In 2008, Gross et al18 designed a pilot study to explore RFA in 6 patients, 5 of whom (83.33%) were observed to no longer be transfusion-dependent. Several years later, McGorisk et al17 revived this procedure and reported on the efficacy and safety of RFA for patients with GAVE. This was an open-label, prospective cohort of 21 patients who underwent at least 1 RFA session with ablation of GAVE lesions. RFA was performed using the HALO-90 ULTRA ablation catheter (Covidien, GI Solutions, Sunnyvale, CA) delivered at high-power density (40 W/cm2) at a preset and automated energy density dose of 12 J/cm2. On follow-up evaluation 6 months after ablation, 18 of 21 patients (86%) became transfusionindependent with a mean hemoglobin level increasing from 7.8 to 10.2 g/dL in responders. Pre- and post-RFA treatment for GAVE is shown in Figure 1.17 A subsequent retrospective study by Dray et al16 found similar results. In this study of 24 patients, 23 of whom were transfusion-dependent, the mean number of red cell units transfused decreased in all transfusiondependent patients (mean, 10.6 12.1 before RFA compared with 2.5 5.9 at 6 mo after RFA; P < .001). A more recent case series of 7 patients by Jana et al19 found endoscopic RFA to be an effective alternative to APC for the treatment of GAVE in patients refractory to previous endoscopic therapy. Although a limited number of patients were enrolled and a median number of 2 RFA sessions produced a modest improvement in hemoglobin level after the procedure, 71% of patients (5 of 7) were no longer transfusion-dependent, with no immediate complications reported. Drawing on these data, RFA appears to be an attractive endoscopic option for gastroenterologists because the modality allows for
Catheter length 135 160 160 160
Maximum treatments per session
cm cm cm cm
120 80 80 80
larger mucosal surfaces to be treated when compared with APC.17,18,20 Although few studies have sought to compare RFA directly with APC, our recent meta-analysis reported clinical and endoscopic success for RFA to be significantly higher compared with APC.21 In addition, endoscopic RFA required fewer treatment sessions for clinical or endoscopic resolution as compared with APC (a difference of 1.27 endoscopies per successfully treated patient) (Table 2).16–19,21–23 Furthermore, both APC and RFA achieved similar increases in mean hemoglobin level; the number of complications also was similar across the 2 modalities. Although only a limited number of studies have been performed to evaluate RFA for the treatment of GAVE (6 RFA studies were included in this meta-analysis), likely in part owing to the novelty of the procedure for this pathology, available evidence suggests that RFA may possess a better efficacy and tolerability compared with APC.21 Although future controlled trials and comparator studies are needed to compare treatment efficacy, long-term durability, cost effectiveness, and safety between these interventions, the use of endoscopic RFA for the treatment of GAVE may become standard of care.
Chronic Radiation Proctitis Chronic radiation proctitis (CRP) may occur in as many as 20% of patients who have received pelvic radiation.24 Again, just as was the case for GAVE, APC presently provides a cost-effective endoscopic modality for CRP traditionally used by gastroenterologists. In fact,
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Figure 1. (A) A representative photograph of the classic watermelon appearance of gastric antral vascular ectasia. (B) Gastric mucosa after 1 application of the HALO-90 ULTRA ablation catheter. (C) Gastric mucosa after complete ablation with the HALO-90 ULTRA ablation catheter. Figure included with permission from Elsevier Publishing.
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Table 2. Characteristics of Included Radiofrequency Ablation Studies for the Treatment of Gastric Antral Vascular Ectasia Q15
Study
Year
Patients, n
Follow-up period, mo
Preprocedure hemoglobin level, g/dL
Postprocedure hemoglobin level, g/dL
Transfusion free, %
Gross et al Dray et al McGorisk et al Soota et al Raza et al Jana et al
2008 2013 2013 2013 2015 2015
6 24 21 5 9 7
2 6 6 19.6 11 5
8.6 6.8 7.8 9.13 7.3 9.3
10.2 9.8 10.2 11.05 10.53 10.16
100% (18/18) 71% (5/7)
the American Society for Gastrointestinal Endoscopy currently considers APC for hemostasis best suited for superficial vascular lesions, such as those seen in GAVE and CRP.25 Despite this recommendation, there remains insufficient comparative data to truly assess the performance of APC in relation to other modalities for CRP. Perhaps more importantly, current ablative therapies, APC included, have a high complication rate of up to 47%, with the potential for deep tissue injury leading to ulcerations, perforations, and fistulae in patients with CRP.24 Given this unacceptably high adverse event rate coupled with a lack of comparative data, Zhou et al26 explored the feasibility of RFA as a potential alternative modality in a small case series of 3 patients with refractory CRP. Hemostasis was achieved in all patients with 1 to 2 RFA sessions, and no ulcerations or stricturing was observed on follow-up evaluation 19 months after the procedure. Additional data from a retrospective series of 4 patients by Pigo et al27 showed endoscopic RFA to be an efficacious procedure achieving complete control of patient symptoms. All patients were no longer transfusion-dependent after the procedure, and no major complications were noted, although 2 patients (50%) developed limited, post-treatment superficial ulcers that healed within 2 to 3 weeks. Recently, a retrospective multicenter analysis of prospectively collected data was performed involving RFA for the treatment of CRP.28 A total of 39 CRP patients were enrolled, with the study’s primary end point being complete resolution of rectal bleeding. To achieve ablation of CRP, the HALO-90 ablation catheter was mounted on the endoscope in the 6 o’clock position with an energy setting of 12 J/cm2. Generally, 2 applications of the RFA were performed per site, in the retroflexed position, to best visualize the dentate line. Ablations were placed approximately 1 mm proximal to the dentate line to avoid the sensory tissues of the anal mucosa, and treatments were limited to less than 270 of circumference during any single session to minimize the potential risk of stricture formation. Re-treatment was performed 12 to 16 weeks after the first treatment only if rectal bleeding persisted. Importantly, this study enrolled patients regardless of previous therapy, with 59% of patients having
undergone previous medical treatment and 36% with a prior endoscopic therapy (n ¼ 13 patients with failed APC, n ¼ 1 patient with prior cryoablation). Impressively, endoscopic RFA achieved complete cessation of rectal bleeding in all patients during a mean follow-up period of 28 months (range, 7–53 mo). The mean hemoglobin levels before and after the procedure increased from 11.8 to 13.5 g/dL, respectively, with a mean number of 1.49 RFA sessions required and a mean interval of 18 weeks between sessions. In addition, 92% of patients no longer required transfusions and 82% of patients discontinued iron therapy. Most importantly, no major adverse events occurred. Figure 2 contains followup endoscopic images that show gradual healing and complete re-epithelialization in patients with CRP after treatment with RFA.28 Similar results were reported by Dray et al29 in another multicenter retrospective study of 17 patients. Six of the 17 patients received previous treatment with APC. With a median of 2 RFA sessions (range, 1–4 sessions), the hemoglobin concentration increased in all 17 patients (preprocedure mean, 8.3 2.8 g/dL; postprocedure mean, 11.3 2.2 g/dL; P < .01). Two patients developed rectal ulcerations with no local symptoms and no serious adverse events occurred. During the 6 months after RFA, 53% of patients who were transfusiondependent (9 of 13 patients total) no longer required transfusion therapy. Table 3 includes important baseline characteristics of studies evaluating RFA for the treatment of CRP.26–30 Based on these studies, endoscopic RFA appears to a promising modality capable of providing a first- or second-line treatment option for patients with CRP.
Malignant Biliary Strictures Biliary strictures continue to present a diagnostic and therapeutic dilemma for biliary endoscopists. Malignant biliary obstruction is caused most commonly by cholangiocarcinoma or pancreatic adenocarcinoma. Traditionally used as a palliative measure in patients with nonresectable or borderline resectable biliary disease, self-expanding metal stents (SEMS) have been shown to be superior to plastic stents in regard to patency and decreased risk of stent migration with improved tissue
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Figure 2. (A) Hemorrhagic CRP with active bleeding before RFA. (B) Two weeks after RFA. (C) Four weeks after RFA. (D) Eight weeks after RFA. (E) Twelve weeks after RFA. (F) Sixteen weeks after RFA. Figure included with permission from Elsevier Publishing.
engraftment. Despite SEMS providing a superior alternative to plastic stents, the high occlusion rate limits the effectiveness of SEMS. With occlusion rates of up to 40% within 6 months of insertion, adjunctive endoscopic modalities have been proposed.31,32 Although endoscopically delivered photodynamic therapy (PDT) has shown improved stent patency, biliary drainage, mortality, and quality of life, the associated
phototoxicity requiring patients to avoid direct sunlight limits PDT’s application.33–38 The other modality added to reduce SEMS dysfunction involves intraductal RFA—a procedure that entails using a biliary catheter device, via an endoscopic or percutaneous approach. The RFA catheter (Habib EndoHPB; EMcision Ltd, London, UK) is a single-use, disposable, bipolar device that is suitable for endoluminal delivery of RFA into the biliary tree over a
Table 3. Characteristics of Included Radiofrequency Ablation Studies for the Treatment of Chronic Radiation Proctitis
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Study
Year
Patients, n
Follow-up period, mo
Preprocedure hemoglobin level, g/dL
Postprocedure hemoglobin level, g/dL
Transfusion free, %
Zhou et al Pigo et al Dray et al Rustagi et al Markos et al
2009 2014 2014 2015 2017
3 4 17 39 5
14 19.5 19.6 28 12
8.3 11.8 98.6
11.3 13.5 10.3
100% (4/4) 69% (9/13) 92% (11/12) -
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Figure 3. Habib EndoHPB catheter (EMcision Ltd).
0.035-inch guidewire (Figure 3). It consists of an 8F (2.6-mm) catheter with a 180-cm working length that can be deployed through endoscope working channels of at least 3.2 mm in diameter.39 This modality allows for ablation of the tumors within the bile duct lumen for the maintenance of biliary drainage. Endobiliary RFA additionally acts directly on the local tumor and can be an adjunct to endoscopic palliation in that it has been suggested to increase SEMS patency and potentially improve survival.39 A recent retrospective German study by Schimdt et al40 sought to compare the efficacy and safety of intraductal RFA with PDT for the treatment of hilar cholangiocarcinoma. Fourteen patients treated with biliary RFA (n ¼ 31 sessions total) were compared with a historical control of 20 patients treated with PDT (n ¼ 66 sessions total). A total of 14 patients enrolled in the biliary RFA cohort showed a significant decrease in their 2-week postprocedure bilirubin level, with no significant change in the PDT cohort of 20 patients (P ¼ .046 and P ¼ .67, respectively) (Figure 4).40 In addition, stent patency also was improved in the intraductal RFA group with a rate of premature stent replacement (defined as
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replacement < 3 mo, PDT 65% vs RFA 29%; P < .001) that was significantly higher in the PDT cohort, with a trend toward more adverse events in the PDT than in the RFA group (40% vs 21%, respectively; P ¼ .277). These results, combined with a potential lower procedureassociated complication rate, may suggest an increased role for intraductal RFA as a therapeutic alternative to PDT for palliative treatment of malignant biliary obstruction. Further attempts to compare RFA and PDT have been performed, although a truly comparative trial is lacking. A retrospective cohort study by Strand et al33 found a comparable survival rate of endoscopic retrograde cholangiopancreatography–directed RFA vs PDT for the treatment of unresectable cholangiocarcinoma. Patients who underwent RFA (n ¼ 16) showed a comparable survival rate with patients who underwent PDT (n ¼ 32) (9.6 vs 7.5 mo; respectively; P ¼ .799). The RFA group differed significantly from the PDT cohort (ie, lower mean number of plastic stents placed per month [0.45 vs 1.10; P ¼ .001], yet reported more episodes of stent occlusion [0.06 vs 0.02; P ¼ .008], respectively) (Figure 5).33 Although intraductal RFA may be an emerging modality, future prospective controlled trials are needed to determine which palliative option increases the odds of short- and long-term survival.41 To date, numerous additional case series have evaluated the use of endoscopic biliary RFA for the treatment of malignant biliary strictures.33,42–52 Of these included studies, Figueroa-Barojas et al47 showed encouraging clinical data reporting pre- and post-RFA luminal diameter of the stricture to have significant improvement (1.7 mm; range, 0.5–3.4 vs 5.2 mm; range, 2.6–9, respectively). Additional studies have described similarly impressive results, with 1 study reporting a pooled mean increase in stricture diameter of 3.7 mm after RFA therapy.39,42,43 However, despite the dramatic improvement in post-RFA luminal diameter, this modality is not without complications (Table 4).46,49,53,54 Adverse events
Figure 4. Mean bilirubin value in patients undergoing RFA vs photodynamic therapy for hilar cholangiocarcinoma. Figure adapted from included data with permission from SAGE Publishing.
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Figure 5. Rate of stent occlusions per month in patients undergoing RFA vs photodynamic therapy for unresectable cholangiocarcinoma. Figure adapted from included data with permission from Elsevier Publishing.
may occur in 10% to 62% of patients ranging from selflimited abdominal pain (reported in up to 50% patients), cholangitis, acute cholecystitis, and major hemobilia from hepatic artery pseudoaneurysm.39,54 Therefore, it is important for the biliary endoscopist to be aware of these adverse events. Multiple factors may account for such a wide variability in adverse events including differences in etiology, location, thickness of stricture and duct wall, proximity of hepatic artery branches to the bile duct, variability in energy settings, and type of biliary stents placed after RFA, and perhaps surgeon technique and experience. In addition, the notion that RFA may improve stent patency has been debated.54 Although many studies have suggested that RFA may decrease the rate of SEMS occlusion, 2 studies that aimed to evaluate this theory showed statistically insignificant results compared with controls.55,56 However, a recent retrospective study by Kadayifci et al57 showed that mean stent patency time was significantly longer in the RFA group. Patients treated with endoscopic RFA using a Habib Endoprobe for the treatment of occluded SEMS (n ¼ 25) were compared with a control group treated with plastic stent insertion (n ¼ 25). The stent patency rate at 90 days and the mean stent patency time during the 5-year study Table 4. Adverse Events Associated With Biliary Radiofrequency Ablation Abdominal pain Cholangitis and cholangiosepsis Hemobilia Gallbladder empyema Pancreatitis Cholecystitis Liver infarction Hepatic artery pseudoaneurysm
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639 period were significant higher for patients who under640 went RFA (rate, 56% vs 24%; P ¼ .04; time, 119.5 vs 641 65.3 d; P ¼ .03). Another study by Yang et al58 examined 642 survival time and stent patency in patients with unre643 sectable extrahepatic cholangiocarcinoma. Twenty-nine 644 patients underwent RFA and stenting whereas 30 645 patients underwent stent placement alone. The mean 646 overall survival and stent patency was significantly 647 longer in the RFA and stent group compared with the 648 stent alone group (13.8 vs 3.5 mo; P < .002; and 6.9 vs 649 3.5 mo; P ¼ .02; respectively). Importantly, no significant 650 difference was noted in the incidence of postprocedural 651 complications between the RFA group and stent cohort 652 (6.9% vs 10%, respectively; P ¼ .67). 653 Recently, a systematic review and meta-analysis was 654 performed to evaluate the efficacy and safety of biliary 655 stenting with RFA compared with stenting alone in patients 656 with malignant biliary strictures.59 This meta-analysis 657 included 8 studies (n ¼ 416) with a similar method of 658 biliary RFA across all studies. Patient demographics, num659 ber with pancreatitis cancer, and mean length of biliary 660 stricture was similar between the 2 groups. Overall, stent 661 patency was improved significantly in biliary stenting with 662 RFA patients compared with stenting alone (pooled 663 weighted mean difference, 45.07 d), with no significant 664 difference seen between the 2 cohorts in regard to risk of 665 cholangitis, acute cholecystitis, pancreatitis, and hemobilia. 666 Furthermore, a pooled survival analysis showed improved 667 survival in patients treated with RFA (hazard ratio, 1.49; 668 P < .001) (Figure 6).59 An additional meta-analysis by 669 Zheng et al60 found similar results including a significant 670 increase in stricture diameter and survival time, suggesting 671 that endoscopic RFA may be preferable in the management 672 of malignant biliary obstruction.60 Although prospective 673 randomized trials are needed to further validate these 674 findings, it appears that endoscopic RFA may improve stent patency and suggest it may be used as an alternative Q9 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 Figure 6. Reconstructed Kaplan–Meier curve showing sig694 nificant difference in survival between RFA group and control 695 group. Figure included with permission from Elsevier 696 Publishing.
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treatment for occluded SEMS from tissue ingrowth in malignant biliary obstruction. Ultimately, intraductal endoscopic RFA, although still a novice procedure, holds promise in the ability to manage malignant biliary strictures.
Intraductal Extension of Ampullary Adenoma Ampullary adenomas often are treated by endoscopic papillectomy. However, endoscopic management of ampullary adenomas extending into the common bile duct or pancreatic duct remains challenging. Intraductal extension typically has been considered a contraindication to endoscopic management and, as such, patients have been referred for surgical management. However, a pancreaticoduodenectomy or a Whipple procedure has high associated morbidity and mortality, thus making endoscopic management an attractive alternative. Recently, a retrospective multicenter study evaluated the feasibility, safety, and efficacy of endoscopic RFA for ampullary neoplasms with intraductal extension.61 In this study, a total of 14 patients with adenoma extension into the common bile duct (13 7 mm; n ¼ 14) and pancreatic duct (7 2 mm; n ¼ 3) were treated with a RFA catheter. With treatment failure documented and persistent tumor invasion shown
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histologically, these patients underwent a median of 1 RFA session (range, 1–5 sessions). At a median follow-up period of 16 months after RFA, complete intraductal ablation was achieved in 91.6% of patients. Adverse events occurred in 43% and included ductal strictures (n ¼ 5) and a retroduodenal abscess (n ¼ 1), all of which were successfully treated endoscopically.62 Another small case series of 4 patients by Suarez et al63 found similar results, with 3 patients achieving complete eradication of the intraductal adenoma extension with no immediate adverse events noted during the short follow-up period. In summation, these studies, although small in number, show RFA to be a relatively safe and effective modality for the treatment of ampullary neoplasms with intraductal extension. Although more studies are needed before this can be implemented routinely, early data suggest an expanded role for endoscopic RFA in future clinical practice.
Early Data on Endoscopic UltrasoundGuided Radiofrequency Ablation Another potential avenue for endoscopic RFA is in regard to the modality’s use with endoscopic ultrasound (EUS). Although the clinical application of EUS-guided RFA is not as well established as the previously discussed indications, with very few studies on the topic, the combined
Figure 7. Imaging findings of patients with cancer of the pancreatic head. (A) CT shows low-density mass at the pancreas head, which did not respond to second-line chemotherapy. (B) EUSguided RFA was performed by using forward-viewing EUS with 50 W of ablation power for 10 seconds and was repeated 8 times. (C) One month after RFA, follow-up CT showed necrosis and air bubbles in the mass (arrow). (D) Two months after RFA, CT showed a decrease of the low-density mass. Figure included with permission from Elsevier Publishing.
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Figure 8. (A) Abdominal contrast-enhanced CT in the arterial phase shows a large enhancing lesion in the head and genu of the pancreas (arrow). (B) After EUS-guided RFA ablation at 3 months. Abdominal contrastenhanced CT shows a pancreatic head lesion with rim enhancement and a central nonenhancing hypodense area (arrow). Figure included with permission from Elsevier Publishing.
use of EUS with ablation holds promise. EUS-guided RFA offers the best combination of real-time visualization and precise localization coupled with a minimally invasive strategy to achieve selective ablation of a variety of lesions previously inaccessible or difficult to access via percutaneous routes.64 At present, EUS-guided RFA has been shown to be effective for targeting lesions within the liver, pancreas, lymph node, and for ablation of celiac ganglia for pain control in pancreatic carcinoma. Although these indications remain experimental and currently performed only at centers with expertise under predetermined protocols, there are emerging data supporting a potential role for EUS-guided RFA in select patients. EUS-guided liver RFA first was shown experimentally by Varadarajulu et al65 in 2009, using a 19-gauge echogenic, umbrella-shaped, monopolar electrode in 5 porcine models. In this study, RFA achieved discrete, well-demarcated, 2.6-cm spherical focus of coagulation necrosis with tissue ablation within 7 minutes. On histopathology, all pigs showed complete coagulative necrosis without damage to the surrounding liver parenchyma or vasculature. Despite these findings, translation of these impressive results to human studies has been limited.66 Ex vivo data regarding the ideal power setting or the duration of ablation needed to effectively treat hepatic masses has been another limiting factor in the expanded use of EUS-guided RFA. Use of the Habib RFA catheter (Habib, EndoHPB, EUS; EMcision Ltd) in a recent study, again in an animal model, showed that maximal zones of injury were achieved using an ablation power of 10 W for a duration of 90 seconds.67 Higher power settings (ie, 15 W, 20 W, and 50 W) were noted to paradoxically achieve a smaller radial length or small ablation zones. This has been attributed to rapid charring of the hepatic tissue around the small-caliber RFA wire at high power with subsequently increased impedance, thus interfering with the conduction of the current with no further spread of ablation. Given these data, future studies may highlight an expanded role for EUS-guided RFA for treatment of primary and secondary hepatic masses; however, translation to human models is lacking at this time.
With regards to pancreatic lesions, Goldberg et al68 first conducted EUS-guided RFA on 16 porcine models and showed discrete histologic progression of coagulation necrosis followed by fibrotic capsule contraction. Although pancreatic RFA has a high risk of complication owing to increased sensitivity of pancreatic tissue and proximity to vascular and biliary structures, early animal studies have shown impressive results.68,69 An early human study by Pai et al70 relieved many concerns by showing no immediate or early major postprocedural complications. In this prospective multicenter trial using an innovative monopolar RFA probe (1.2-mm Habib EUSRFA catheter; EMcision Ltd), 8 patients (n ¼ 6 with pancreatic cystic neoplasms; n ¼ 2 with neuroendocrine tumors) were treated successfully with EUS RFA. The mean size of these lesions was 36.5 17.9 mm and 27.5 17.7 mm for cystic lesions and neuroendocrine tumors, respectively. At a follow-up period of 3 to 6 months, RFA achieved complete resolution in 2 cystic lesions, with a 48.4% reduction noted in 3 remaining patients. A change in vascularity and central necrosis was observed in both neuroendocrine tumor cases after EUS RFA. Importantly, no serious adverse events were reported among patients with cystic lesions and neuroendocrine tumors.
Figure 9. Habib EUS-RFA probe (EMcision Ltd).
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Table 5. Emerging Indications for Endoscopic Radiofrequency Ablation Upper GI endoscopy Gastric antral vascular ectasia Lower GI endoscopy Chronic radiation proctitis ERCP Malignant biliary strictures Biliary metal stent dysfunction from tumor ingrowth Intraductal extension of ampullary adenoma EUS Hepatic lesionsa Pancreatic cystic and solid lesions Celiac–ganglia neurolysis Lymph node ablationa
ERCP, endoscopic retrograde cholangiopancreatography; GI, gastrointestinal. a Animal studies only.
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A more recent study by Song et al71 used an 18-gauge RFA electrode inserted into the pancreatic mass with increased blood flow after RFA. This study used a RFA generator activated to deliver 20 to 50 W ablation power for 10 seconds and was performed successfully in all 6 patients included in the study. The mean diameter of pancreatic masses was 3.8 cm (range, 3–9 cm), with the head (n ¼ 4) and body (n ¼ 2) of the pancreas tumors included. Figure 7 highlights significant improvement in the size of the pancreatic head cancer after treatment with RFA.71 Again, no adverse events such as pancreatitis or bleeding occurred. Additional studies by Lakhtakia et al72 and Arcidiacono et al73 have shown the feasibility and safety of EUS-guided pancreatic RFA for pancreatic insulinoma and locally advanced pancreatic cancer, respectively. Lakhtakia et al72 used a prototype 19-gauge needle electrode, generator, and internal cooling system in 3 patients with nonsurgical pancreatic insulinomas and achieved rapid symptom relief with patients remaining symptom free at the 12-month follow-up evaluation (Figure 8).72 In patients with local progression of advanced pancreatic adenocarcinoma status-post neoadjuvant therapy, Arcidiacono et al73 achieved EUS-guided cryotherm probe ablation in 72.8% (16 of 22 patients). The median post-RFA ablation survival time was 6 months, with tumor size appearing smaller on followup computed tomography imaging. These innovative RFA catheters have allowed endoscopists to deliver RFAdirected treatment to patients with lesions previously inaccessible through surgical approaches. Lymph node ablation with novel EUS-guided RFA also has been performed in animal models, again with positive results. Sethi et al74 analyzed the modality on 18 porcine mediastinal lymph nodes with a mean node length of 2.08 cm. By using a prototype RFA probe (EMcision Ltd) with a 0.01-mm diameter and a 3-cm ablation tip, the mean length and diameter of necrosis achieved was 9.8 mm and 5.5 mm, respectively (mean, 17.6% of lymph node area ablated). Importantly, no complications occurred with the procedure. With these
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data and prototype EUS-compatible RFA probe, EUS-RFA lymph node ablation may have the potential for future translation into human studies for management of patients with malignant/metastatic lymph nodes.74 Specifically with regard to pancreatic cancer, EUS-guided celiac ganglion RFA for pain control has been shown in a single-patient case report.75 Significant improvement in pain with a reduction in narcotic intake was reported after EUSguided celiac ganglion RFA using the Habib RFA probe through a 19G EUS needle (Figure 9). Identification of the celiac ganglia with EUS has enhanced the efficacy and safety of the celiac plexus nerve block by enabling direct visualization and precise ablation.76 Whether using RFA over the current standard chemical ablation with EUS-guided celiac neurolysis using alcohol has any clinical advantages needs to be evaluated. More data are needed to establish the safety, long-term durability, and cost effectiveness of EUS-guided celiac RFA neurolysis.
Conclusions At present, endoscopic RFA is well validated for the treatment of dysplastic Barrett’s; however, the use of this endoscopic modality has been expanded to include several other difficult-to-treat diseases (Table 5). These newer indications may provide definitive treatment, palliation, or alternative therapies for a wide variety of gastrointestinal and hepatopancreatobiliary pathologies. Despite being a feasible and safe modality, high RFAassociated costs may limit these expanded applications. Still, with more widespread use and improved implementation, the cost of this innovative modality likely will decrease, making this a more affordable and practical option. Similar to any innovative technique, future direct comparative trials and cost-effective analyses are needed, along with long-term follow-up data to establish the long-term safety and efficacy of endoscopic RFA for these newer indications. Until such time, based on the limited data as presented earlier, endoscopic RFA appears to be a viable, innovative, and emerging modality with expanding indications.
References 1. Almond LM, Hodson J, Barr H. Meta-analysis of endoscopic therapy for low-grade dysplasia in Barrett’s oesophagus. Br J Surg 2014;101:1187–1195. 2. Coron E, Robaszkiewicz M, Chatelain D, et al. Advanced precancerous lesions in the lower oesophageal mucosa: highgrade dysplasia and intramucosal carcinoma in Barrett’s oesophagus. Best Pract Res Clin Gastroenterol 2013; 27:187–204. 3. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology 2011;141:460–468. 4. Lyday WD, Corbett FS, Kuperman DA, et al. Radiofrequency ablation of Barrett’s esophagus: outcomes of 429 patients from a multicenter community practice registry. Endoscopy 2010; 42:272–278.
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5. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360:2277–2288. 6. Ganz RA, Utley DS, Stern RA, et al. Complete ablation of esophageal epithelium with a balloon-based bipolar electrode: a phased evaluation in the porcine and in the human esophagus. Gastrointest Endosc 2004;60:1002–1010. 7. Lang L. Radiofrequency ablation is effective treatment for dysplasia in Barrett’s esophagus. Gastroenterology 2008;135:6. 8. Nayna L, Emma W, Vani K. Radiofrequency ablation for low-grade dysplasia in Barrett’s esophagus. Curr Opin Gastroenterol 2016;32:294–301.
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24. Rustagi T, Mashimo H. Endoscopic management of chronic radiation proctitis. World J Gastroenterol 2011;17:4554–4562. 25. Ginsberg GG, Barkun AN, Bosco JJ, et al. The argon plasma coagulator: February 2002. Gastrointest Endosc 2002;55:807–810. 26. Zhou C, Adler DC, Becker L, et al. Effective treatment of chronic radiation proctitis using radiofrequency ablation. Ther Adv Gastroenterol 2009;2:149–156. 27. Pigo F, Bertani H, Manno M, et al. Radiofrequency ablation for chronic radiation proctitis: our initial experience with four cases. Tech Coloproctol 2014;18:1089–1092. 28. Rustagi T, Corbett FS, Mashimo H. Treatment of chronic radiation proctopathy with radiofrequency ablation (with video). Gastrointest Endosc 2015;81:428–436.
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29. Dray X, Battaglia G, Wengrower D, et al. Radiofrequency ablation for the treatment of radiation proctitis. Endoscopy 2014;46:970–976.
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30. Markos P, Bilic B, Ivekovic H, et al. Radiofrequency ablation for gastric antral vascular ectasia and radiation proctitis. Indian J Gastroenterol 2017;36:145–148.
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31. Ridtitid W, Rerknimitr R. Management of an occluded biliary metallic stent. World J Gastrointest Endosc 2012;4:157–161.
12. Barbara G, De Giorgio R, Salvioli B, et al. Unsuccessful octreotide treatment of the watermelon stomach. J Clin Gastroenterol 1998;26:345–346. 13. Park RH, Danesh BJ, Upadhyay R, et al. Gastric antral vascular ectasia (watermelon stomach)–therapeutic options. Postgrad Med J 1990;66:720–723. 14. Yusoff I, Brennan F, Ormonde D, et al. Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 2002; 34:407–410.
32. Rogart JN, Boghos A, Rossi F, et al. Analysis of endoscopic management of occluded metal biliary stents at a single tertiary care center. Gastrointest Endosc 2008;68:676–682. 33. Strand DS, Cosgrove ND, Patrie JT, et al. ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma. Gastrointest Endosc 2014;80:794–804. 34. Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology 2000;31:291–298.
15. Sebastian S, O’Morain CA, Buckley MJ. Review article: current therapeutic options for gastric antral vascular ectasia. Aliment Pharmacol Ther 2003;18:157–165.
35. Cheon YK, Lee TY, Lee SM, et al. Longterm outcome of photodynamic therapy compared with biliary stenting alone in patients with advanced hilar cholangiocarcinoma. HPB (Oxford) 2012;14:185–193.
16. Dray X, Repici A, Gonzalez P, et al. Radiofrequency ablation for the treatment of gastric antral vascular ectasia. Endoscopy 2014;46:963–969.
36. Gao F, Bai Y, Ma SR, et al. Systematic review: photodynamic therapy for unresectable cholangiocarcinoma. J Hepatobiliary Pancreat Sci 2010;17:125–131.
17. McGorisk T, Krishnan K, Keefer L, et al. Radiofrequency ablation for refractory gastric antral vascular ectasia (with video). Gastrointest Endosc 2013;78:584–588.
37. Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol 2008;6:290–297.
18. Gross SA, Al-Haddad M, Gill KR, et al. Endoscopic mucosal ablation for the treatment of gastric antral vascular ectasia with the HALO90 system: a pilot study. Gastrointest Endosc 2008; 67:324–327. 19. Jana T, Thosani N, Fallon MB, et al. Radiofrequency ablation for treatment of refractory gastric antral vascular ectasia (with video). Endosc Int Open 2015;3:E125–E127. 20. Peter S, Wilcox CM. Radiofrequency ablation therapy - the grave for GAVE (gastric antral vascular ectasia)? Endosc Int Open 2015;3:E128E129. 21. Rustagi T, McCarty T. Comparative effectiveness of radiofrequency ablation and argon plasma coagulation for treatment of gastric antral vascular ectasia: a systematic review and metaanalysis. Gastroint Endosc 2015;81:5, AB125. 22. Raza N, Diehl DL. Radiofrequency ablation of treatmentrefractory gastric antral vascular ectasia (GAVE). Surg Laparosc Endosc Percutan Tech 2015;25:79–82. 23. Soota K, Lingutla D, Kothari T. Radiofrequency ablation using halo ablation catheter for gastric antral vascular ectasia: a case series from a community hospital. Am J Gastroenterol 2013;108:S50.
38. Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection. Ann Surg 2006;244:230–239. 39. Rustagi T, Jamidar PA. Intraductal radiofrequency ablation for management of malignant biliary obstruction. Dig Dis Sci 2014; 59:2635–2641. 40. Schmidt A, Bloechinger M, Weber A, et al. Short-term effects and adverse events of endoscopically applied radiofrequency ablation appear to be comparable with photodynamic therapy in hilar cholangiocarcinoma. United European Gastroenterol J 2016;4:570–579. 41. Tyberg A, Gaidhane M, Kahaleh M. Endoscopic palliation of advanced cholangiocarcinoma: a need for a real trial! Gastrointest Endosc 2015;81:1052–1053. 42. Steel AW, Postgate AJ, Khorsandi S, et al. Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction. Gastrointest Endosc 2011;73:149–153.
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43. Alis H, Sengoz C, Gonenc M, et al. Endobiliary radiofrequency ablation for malignant biliary obstruction. Hepatobiliary Pancreat Dis Int 2013;12:423–427. 44. Sharaiha RZ, Sethi A, Weaver KR, et al. Impact of radiofrequency ablation on malignant biliary strictures: results of a collaborative registry. Dig Dis Sci 2015;60:2164–2169.
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60. Zheng X, Bo ZY, Wan W, et al. Endoscopic radiofrequency ablation may be preferable in the management of malignant biliary obstruction: a systematic review and meta-analysis. J Dig Dis 2016;17:716–724. 61. Rustagi T, Irani S, Reddy DN, et al. Radiofrequency ablation for intraductal extension of ampullary neoplasms. Gastrointest Endosc 2017;86:170–176.
45. Wu TT, Li HC, Li WM, et al. Percutaneous intraluminal radiofrequency ablation for malignant extrahepatic biliary obstruction: a safe and feasible method. Dig Dis Sci 2015; 60:2158–2163.
62. Rustagi T, Irani S, Reddy ND, et al. Endoscopic radiofrequency ablation for intraductal extension of ampullary neoplasms. Gastroint Endosc 2016;83:5, Sa2015.
46. Dolak W, Schreiber F, Schwaighofer H, et al. Endoscopic radiofrequency ablation for malignant biliary obstruction: a nationwide retrospective study of 84 consecutive applications. Surg Endosc 2014;28:854–860.
63. Suarez AL, Cote GA, Elmunzer BJ. Adjunctive radiofrequency ablation for the endoscopic treatment of ampullary lesions with intraductal extension (with video). Endosc Int Open 2016; 4:E748–E751.
47. Figueroa-Barojas P, Bakhru MR, Habib NA, et al. Safety and efficacy of radiofrequency ablation in the management of unresectable bile duct and pancreatic cancer: a novel palliation technique. J Oncol 2013;2013:910897.
64. Rustagi T, Chhoda A. Endoscopic radiofrequency ablation of the pancreas. Dig Dis Sci 2017;62:843–850.
48. Laquiere A, Boustiere C, Leblanc S, et al. Safety and feasibility of endoscopic biliary radiofrequency ablation treatment of extrahepatic cholangiocarcinoma. Surg Endosc 2016; 30:1242–1248. 49. Tal AO, Vermehren J, Friedrich-Rust M, et al. Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction. World J Gastrointest Endosc 2014;6:13–19. 50. Monga A, Gupta R, Ramchandani M, et al. Endoscopic radiofrequency ablation of cholangiocarcinoma: new palliative treatment modality (with videos). Gastrointest Endosc 2011; 74:935–937. 51. Mao EJ, Watson JB, Soares G, et al. Successful percutaneous endobiliary radiofrequency ablation for unresectable malignant biliary obstruction: a case report and review of the literature. J Gastrointest Cancer 2014;45(Suppl 1):55–57. 52. Pai M, Valek V, Tomas A, et al. Percutaneous intraductal radiofrequency ablation for clearance of occluded metal stent in malignant biliary obstruction: feasibility and early results. Cardiovasc Interv Radiol 2014;37:235–240. 53. Topazian M, Levy MJ, Patel S, et al. Hepatic artery pseudoaneurysm formation following intraductal biliary radiofrequency ablation. Endoscopy 2013;45(Suppl 2):E161–E162. 54. Mensah ET, Martin J, Topazian M. Radiofrequency ablation for biliary malignancies. Curr Opin Gastroenterol 2016;32:238–243. 55. Sharaiha RZ, Natov N, Glockenberg KS, et al. Comparison of metal stenting with radiofrequency ablation versus stenting alone for treating malignant biliary strictures: is there an added benefit? Dig Dis Sci 2014;59:3099–3102. 56. Kallis Y, Phillips N, Steel A, et al. Analysis of endoscopic radiofrequency ablation of biliary malignant strictures in pancreatic cancer suggests potential survival benefit. Dig Dis Sci 2015; 60:3449–3455. 57. Kadayifci A, Atar M, Forcione DG, et al. Radiofrequency ablation for the management of occluded biliary metal stents. Endoscopy 2016;48:1096–1101. 58. Yang J, Zhou Y, Jin H, et al. Endoscopic biliary radiofrequency ablation prolong the survival of patients with unrespectable extrahepatic cholangiocarcinoma. Gastrointest Endosc 2017; 85:5, AB605. 59. Sofi AA, Nawras A, Khuder S, et al. Radiofrequency ablation combined with biliary stenting versus stenting alone for malignant biliary strictures-a systematic review and meta-analysis. Gastroint Endosc 2017;85:5, AB59.
65. Varadarajulu S, Jhala NC, Drelichman ER. EUS-guided radiofrequency ablation with a prototype electrode array system in an animal model (with video). Gastrointest Endosc 2009;70:372–376. 66. Yoon WJ, Daglilar ES, Kamionek M, et al. Evaluation of radiofrequency ablation using the 1-Fr wire electrode in the porcine pancreas, liver, gallbladder, spleen, kidney, stomach, and lymph Q12 nodes: a pilot study. Dig Endosc 2015. Epub ahead of print. 67. Rustagi T, Abu Dayyeh BK, Gleeson F, et al. Evaluation of effects of endoscopic ultrasound guided radiofrequency ablation of ex-vivo liver. Gastroint Endosc 2016;83:5, Mo2034. 68. Goldberg SN, Mallery S, Gazelle GS, et al. EUS-guided radiofrequency ablation in the pancreas: results in a porcine model. Gastrointest Endosc 1999;50:392–401. 69. Kim HJ, Seo DW, Hassanuddin A, et al. EUS-guided radiofrequency ablation of the porcine pancreas. Gastrointest Endosc 2012;76:1039–1043. 70. Pai M, Habib N, Senturk H, et al. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. World J Gastrointest Surg 2015;7:52–59. 71. Song TJ, Seo DW, Lakhtakia S, et al. Initial experience of EUSguided radiofrequency ablation of unresectable pancreatic cancer. Gastrointest Endosc 2016;83:440–443. 72. Lakhtakia S, Ramchandani M, Galasso D, et al. EUS-guided radiofrequency ablation for management of pancreatic insulinoma by using a novel needle electrode (with videos). Gastrointest Endosc 2016;83:234–239. 73. Arcidiacono PG, Carrara S, Reni M, et al. Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer. Gastrointest Endosc 2012;76:1142–1151. 74. Sethi A, Ellrichmann M, Dhar S, et al. Endoscopic ultrasoundguided lymph node ablation with a novel radiofrequency ablation probe: feasibility study in an acute porcine model. Endoscopy 2014;46:411–415. 75. Jin ZD, Wang L, Li Z. Endoscopic ultrasound-guided celiac ganglion radiofrequency ablation for pain control in pancreatic carcinoma. Dig Endosc 2015;27:163–164. 76. Zhu J, Jin Z. Interventional therapy for pancreatic cancer. Gastrointest Tumors 2016;3:81–89. Reprint requests Address requests for reprints to: Tarun Rustagi, MD, Division of Gastroenterology and Hepatology, University of New Mexico, MSC10 5550, 1 University of New Mexico, Albuquerque, New Mexico 87131. e-mail: [email protected]; fax: (505) 272-9751.
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Conflicts of interest The authors disclose no conflicts.
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New Indications for Endoscopic Radiofrequency Ablation Q17
Thomas R. McCarty* and Tarun Rustagi‡ *Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; ‡Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico
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Radiofrequency ablation (RFA) is a well-established treatment for several benign, premalignant, and malignant disorders. Although the role of RFA has been clearly defined, new indications for luminal and extraluminal applications of endoscopic RFA-directed therapies have emerged. RFA has recently produced promising results in patients with a variety of gastrointestinal and hepatopancreatobiliary pathologies. For example, endoscopic RFA has been used to treat patients with gastric antral vascular ectasia, chronic radiation proctitis, malignant biliary strictures, and ampullary adenomas with intraductal extension. Furthermore, endoscopic ultrasound-guided RFA appears to be an effective, minimally invasive treatment for ablation of solid and cystic lesions—particularly in the pancreas. We review the newer indications for RFA and discuss potential limitations of endoscopic RFA. Keywords: GAVE; CRP; EUS; Cancer.
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ithin the field of gastroenterology, radiofrequency ablation (RFA) is a well-established modality for the treatment of a variety of benign, premalignant, and malignant conditions.1 Endoscopic RFA has been described to achieve mucosal ablation in several types of benign hemorrhagic gastrointestinal diseases. In addition, endoscopic RFA has been validated as an approved treatment for premalignant conditions as seen in patients with Barrett’s esophagus with dysplasia, in whom it has been shown to achieve highly effective and durable results.1–5 RFA for the treatment of esophageal metaplasia and dysplasia, although similar to electrocautery, initially was established for and patented in a porcine and human model by Ganz et al6 in 1999. The device involved a balloon-based, bipolar radiofrequency system that created a circumferential, thin-layer, epithelial ablation zone within the esophagus. Still today, the technique involves high-frequency alternating electrical current delivered locally to tissue or mucosa. This localized controlled heating results in targeted destruction and thermal coagulative necrosis. Although the role of RFA has been clearly defined in the management of Barrett’s esophagus, new indications for endoscopic RFA-directed treatment have emerged with the promise of improving the management of patients who do not have many options at the present time.5,7,8 Endoscopic RFA possesses the potential for
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expanded use in a multitude of gastrointestinal and hepatopancreatobiliary diseases. This review highlights these newer luminal and extraluminal indications and reviews the existing literature to support an emerging role of endoscopic RFA for these indications.
Gastric Antral Vascular Ectasia Classically detailed as having a watermelon or honeycomb appearance, gastric antral vascular ectasia (GAVE) is a collection of dilated tortuous vessels first described by Rider et al9,10 in 1953. Pharmaco- Q8 therapy with octreotide, tranexamic acid, and estrogen–progesterone hormonal therapy typically is ineffective.11–13 Endoscopic therapy is presently the preferred treatment modality with options that include nonthermal and thermal approaches. At this time, a thermal approach with argon plasma coagulation (APC) is considered the first-line endoscopic treatment of choice.14 This is in large part because APC is associated with a low complication rate and is cost effective. Despite this, studies have shown mixed success rates to date, with approximately two thirds of GAVE patients remaining transfusion-dependent.15 Recently, RFA has emerged as a viable alternative endoscopic modality for GAVE with many devices available to gastroenterologists (Table 1). The procedure involves mounting the RFA electrode array on an endoscope with the device advanced to the pylorus.16,17 After insertion, the endoscope is deflected to place the articulated electrode against the mucosal area of desired treatment. Typically, 2 to 4 consecutive pulses of energy are delivered (at a preset and automated energy density dose of 12 J/cm2) in the same area without scraping off to promote optimal hemostasis. The goal of each session is to perform circumferential ablation of the desired lesions and eradicate at least 90% of abnormal gastric mucosa.17
Abbreviations used in this paper: APC, argon plasma coagulation; CRP, chronic radiation proctitis; EUS, endoscopic ultrasound; GAVE, gastric antral vascular ectasia; PDT, photodynamic therapy; RFA, radiofrequency ablation; SEMS, self-expanding metal stent. © 2018 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2017.10.023
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Table 1. List of Available Radiofrequency Ablation Devices for the Treatment of Gastric Antral Vascular Ectasia
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Devices
Electrode length
Electrode width
Channel Catheter HALO60 (Covidien, GI Solutions) HALO90 (Covidien, GI Solutions) HALOULTRA (Covidien, GI Solutions)
15.7 mm 15 mm 20 mm 40 mm
7.5 mm 10 mm 13 mm 13 mm
In 2008, Gross et al18 designed a pilot study to explore RFA in 6 patients, 5 of whom (83.33%) were observed to no longer be transfusion-dependent. Several years later, McGorisk et al17 revived this procedure and reported on the efficacy and safety of RFA for patients with GAVE. This was an open-label, prospective cohort of 21 patients who underwent at least 1 RFA session with ablation of GAVE lesions. RFA was performed using the HALO-90 ULTRA ablation catheter (Covidien, GI Solutions, Sunnyvale, CA) delivered at high-power density (40 W/cm2) at a preset and automated energy density dose of 12 J/cm2. On follow-up evaluation 6 months after ablation, 18 of 21 patients (86%) became transfusionindependent with a mean hemoglobin level increasing from 7.8 to 10.2 g/dL in responders. Pre- and post-RFA treatment for GAVE is shown in Figure 1.17 A subsequent retrospective study by Dray et al16 found similar results. In this study of 24 patients, 23 of whom were transfusion-dependent, the mean number of red cell units transfused decreased in all transfusiondependent patients (mean, 10.6 12.1 before RFA compared with 2.5 5.9 at 6 mo after RFA; P < .001). A more recent case series of 7 patients by Jana et al19 found endoscopic RFA to be an effective alternative to APC for the treatment of GAVE in patients refractory to previous endoscopic therapy. Although a limited number of patients were enrolled and a median number of 2 RFA sessions produced a modest improvement in hemoglobin level after the procedure, 71% of patients (5 of 7) were no longer transfusion-dependent, with no immediate complications reported. Drawing on these data, RFA appears to be an attractive endoscopic option for gastroenterologists because the modality allows for
Catheter length 135 160 160 160
Maximum treatments per session
cm cm cm cm
120 80 80 80
larger mucosal surfaces to be treated when compared with APC.17,18,20 Although few studies have sought to compare RFA directly with APC, our recent meta-analysis reported clinical and endoscopic success for RFA to be significantly higher compared with APC.21 In addition, endoscopic RFA required fewer treatment sessions for clinical or endoscopic resolution as compared with APC (a difference of 1.27 endoscopies per successfully treated patient) (Table 2).16–19,21–23 Furthermore, both APC and RFA achieved similar increases in mean hemoglobin level; the number of complications also was similar across the 2 modalities. Although only a limited number of studies have been performed to evaluate RFA for the treatment of GAVE (6 RFA studies were included in this meta-analysis), likely in part owing to the novelty of the procedure for this pathology, available evidence suggests that RFA may possess a better efficacy and tolerability compared with APC.21 Although future controlled trials and comparator studies are needed to compare treatment efficacy, long-term durability, cost effectiveness, and safety between these interventions, the use of endoscopic RFA for the treatment of GAVE may become standard of care.
Chronic Radiation Proctitis Chronic radiation proctitis (CRP) may occur in as many as 20% of patients who have received pelvic radiation.24 Again, just as was the case for GAVE, APC presently provides a cost-effective endoscopic modality for CRP traditionally used by gastroenterologists. In fact,
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Figure 1. (A) A representative photograph of the classic watermelon appearance of gastric antral vascular ectasia. (B) Gastric mucosa after 1 application of the HALO-90 ULTRA ablation catheter. (C) Gastric mucosa after complete ablation with the HALO-90 ULTRA ablation catheter. Figure included with permission from Elsevier Publishing.
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Table 2. Characteristics of Included Radiofrequency Ablation Studies for the Treatment of Gastric Antral Vascular Ectasia Q15
Study
Year
Patients, n
Follow-up period, mo
Preprocedure hemoglobin level, g/dL
Postprocedure hemoglobin level, g/dL
Transfusion free, %
Gross et al Dray et al McGorisk et al Soota et al Raza et al Jana et al
2008 2013 2013 2013 2015 2015
6 24 21 5 9 7
2 6 6 19.6 11 5
8.6 6.8 7.8 9.13 7.3 9.3
10.2 9.8 10.2 11.05 10.53 10.16
100% (18/18) 71% (5/7)
the American Society for Gastrointestinal Endoscopy currently considers APC for hemostasis best suited for superficial vascular lesions, such as those seen in GAVE and CRP.25 Despite this recommendation, there remains insufficient comparative data to truly assess the performance of APC in relation to other modalities for CRP. Perhaps more importantly, current ablative therapies, APC included, have a high complication rate of up to 47%, with the potential for deep tissue injury leading to ulcerations, perforations, and fistulae in patients with CRP.24 Given this unacceptably high adverse event rate coupled with a lack of comparative data, Zhou et al26 explored the feasibility of RFA as a potential alternative modality in a small case series of 3 patients with refractory CRP. Hemostasis was achieved in all patients with 1 to 2 RFA sessions, and no ulcerations or stricturing was observed on follow-up evaluation 19 months after the procedure. Additional data from a retrospective series of 4 patients by Pigo et al27 showed endoscopic RFA to be an efficacious procedure achieving complete control of patient symptoms. All patients were no longer transfusion-dependent after the procedure, and no major complications were noted, although 2 patients (50%) developed limited, post-treatment superficial ulcers that healed within 2 to 3 weeks. Recently, a retrospective multicenter analysis of prospectively collected data was performed involving RFA for the treatment of CRP.28 A total of 39 CRP patients were enrolled, with the study’s primary end point being complete resolution of rectal bleeding. To achieve ablation of CRP, the HALO-90 ablation catheter was mounted on the endoscope in the 6 o’clock position with an energy setting of 12 J/cm2. Generally, 2 applications of the RFA were performed per site, in the retroflexed position, to best visualize the dentate line. Ablations were placed approximately 1 mm proximal to the dentate line to avoid the sensory tissues of the anal mucosa, and treatments were limited to less than 270 of circumference during any single session to minimize the potential risk of stricture formation. Re-treatment was performed 12 to 16 weeks after the first treatment only if rectal bleeding persisted. Importantly, this study enrolled patients regardless of previous therapy, with 59% of patients having
undergone previous medical treatment and 36% with a prior endoscopic therapy (n ¼ 13 patients with failed APC, n ¼ 1 patient with prior cryoablation). Impressively, endoscopic RFA achieved complete cessation of rectal bleeding in all patients during a mean follow-up period of 28 months (range, 7–53 mo). The mean hemoglobin levels before and after the procedure increased from 11.8 to 13.5 g/dL, respectively, with a mean number of 1.49 RFA sessions required and a mean interval of 18 weeks between sessions. In addition, 92% of patients no longer required transfusions and 82% of patients discontinued iron therapy. Most importantly, no major adverse events occurred. Figure 2 contains followup endoscopic images that show gradual healing and complete re-epithelialization in patients with CRP after treatment with RFA.28 Similar results were reported by Dray et al29 in another multicenter retrospective study of 17 patients. Six of the 17 patients received previous treatment with APC. With a median of 2 RFA sessions (range, 1–4 sessions), the hemoglobin concentration increased in all 17 patients (preprocedure mean, 8.3 2.8 g/dL; postprocedure mean, 11.3 2.2 g/dL; P < .01). Two patients developed rectal ulcerations with no local symptoms and no serious adverse events occurred. During the 6 months after RFA, 53% of patients who were transfusiondependent (9 of 13 patients total) no longer required transfusion therapy. Table 3 includes important baseline characteristics of studies evaluating RFA for the treatment of CRP.26–30 Based on these studies, endoscopic RFA appears to a promising modality capable of providing a first- or second-line treatment option for patients with CRP.
Malignant Biliary Strictures Biliary strictures continue to present a diagnostic and therapeutic dilemma for biliary endoscopists. Malignant biliary obstruction is caused most commonly by cholangiocarcinoma or pancreatic adenocarcinoma. Traditionally used as a palliative measure in patients with nonresectable or borderline resectable biliary disease, self-expanding metal stents (SEMS) have been shown to be superior to plastic stents in regard to patency and decreased risk of stent migration with improved tissue
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Figure 2. (A) Hemorrhagic CRP with active bleeding before RFA. (B) Two weeks after RFA. (C) Four weeks after RFA. (D) Eight weeks after RFA. (E) Twelve weeks after RFA. (F) Sixteen weeks after RFA. Figure included with permission from Elsevier Publishing.
engraftment. Despite SEMS providing a superior alternative to plastic stents, the high occlusion rate limits the effectiveness of SEMS. With occlusion rates of up to 40% within 6 months of insertion, adjunctive endoscopic modalities have been proposed.31,32 Although endoscopically delivered photodynamic therapy (PDT) has shown improved stent patency, biliary drainage, mortality, and quality of life, the associated
phototoxicity requiring patients to avoid direct sunlight limits PDT’s application.33–38 The other modality added to reduce SEMS dysfunction involves intraductal RFA—a procedure that entails using a biliary catheter device, via an endoscopic or percutaneous approach. The RFA catheter (Habib EndoHPB; EMcision Ltd, London, UK) is a single-use, disposable, bipolar device that is suitable for endoluminal delivery of RFA into the biliary tree over a
Table 3. Characteristics of Included Radiofrequency Ablation Studies for the Treatment of Chronic Radiation Proctitis
Q16
Study
Year
Patients, n
Follow-up period, mo
Preprocedure hemoglobin level, g/dL
Postprocedure hemoglobin level, g/dL
Transfusion free, %
Zhou et al Pigo et al Dray et al Rustagi et al Markos et al
2009 2014 2014 2015 2017
3 4 17 39 5
14 19.5 19.6 28 12
8.3 11.8 98.6
11.3 13.5 10.3
100% (4/4) 69% (9/13) 92% (11/12) -
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Figure 3. Habib EndoHPB catheter (EMcision Ltd).
0.035-inch guidewire (Figure 3). It consists of an 8F (2.6-mm) catheter with a 180-cm working length that can be deployed through endoscope working channels of at least 3.2 mm in diameter.39 This modality allows for ablation of the tumors within the bile duct lumen for the maintenance of biliary drainage. Endobiliary RFA additionally acts directly on the local tumor and can be an adjunct to endoscopic palliation in that it has been suggested to increase SEMS patency and potentially improve survival.39 A recent retrospective German study by Schimdt et al40 sought to compare the efficacy and safety of intraductal RFA with PDT for the treatment of hilar cholangiocarcinoma. Fourteen patients treated with biliary RFA (n ¼ 31 sessions total) were compared with a historical control of 20 patients treated with PDT (n ¼ 66 sessions total). A total of 14 patients enrolled in the biliary RFA cohort showed a significant decrease in their 2-week postprocedure bilirubin level, with no significant change in the PDT cohort of 20 patients (P ¼ .046 and P ¼ .67, respectively) (Figure 4).40 In addition, stent patency also was improved in the intraductal RFA group with a rate of premature stent replacement (defined as
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replacement < 3 mo, PDT 65% vs RFA 29%; P < .001) that was significantly higher in the PDT cohort, with a trend toward more adverse events in the PDT than in the RFA group (40% vs 21%, respectively; P ¼ .277). These results, combined with a potential lower procedureassociated complication rate, may suggest an increased role for intraductal RFA as a therapeutic alternative to PDT for palliative treatment of malignant biliary obstruction. Further attempts to compare RFA and PDT have been performed, although a truly comparative trial is lacking. A retrospective cohort study by Strand et al33 found a comparable survival rate of endoscopic retrograde cholangiopancreatography–directed RFA vs PDT for the treatment of unresectable cholangiocarcinoma. Patients who underwent RFA (n ¼ 16) showed a comparable survival rate with patients who underwent PDT (n ¼ 32) (9.6 vs 7.5 mo; respectively; P ¼ .799). The RFA group differed significantly from the PDT cohort (ie, lower mean number of plastic stents placed per month [0.45 vs 1.10; P ¼ .001], yet reported more episodes of stent occlusion [0.06 vs 0.02; P ¼ .008], respectively) (Figure 5).33 Although intraductal RFA may be an emerging modality, future prospective controlled trials are needed to determine which palliative option increases the odds of short- and long-term survival.41 To date, numerous additional case series have evaluated the use of endoscopic biliary RFA for the treatment of malignant biliary strictures.33,42–52 Of these included studies, Figueroa-Barojas et al47 showed encouraging clinical data reporting pre- and post-RFA luminal diameter of the stricture to have significant improvement (1.7 mm; range, 0.5–3.4 vs 5.2 mm; range, 2.6–9, respectively). Additional studies have described similarly impressive results, with 1 study reporting a pooled mean increase in stricture diameter of 3.7 mm after RFA therapy.39,42,43 However, despite the dramatic improvement in post-RFA luminal diameter, this modality is not without complications (Table 4).46,49,53,54 Adverse events
Figure 4. Mean bilirubin value in patients undergoing RFA vs photodynamic therapy for hilar cholangiocarcinoma. Figure adapted from included data with permission from SAGE Publishing.
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Figure 5. Rate of stent occlusions per month in patients undergoing RFA vs photodynamic therapy for unresectable cholangiocarcinoma. Figure adapted from included data with permission from Elsevier Publishing.
may occur in 10% to 62% of patients ranging from selflimited abdominal pain (reported in up to 50% patients), cholangitis, acute cholecystitis, and major hemobilia from hepatic artery pseudoaneurysm.39,54 Therefore, it is important for the biliary endoscopist to be aware of these adverse events. Multiple factors may account for such a wide variability in adverse events including differences in etiology, location, thickness of stricture and duct wall, proximity of hepatic artery branches to the bile duct, variability in energy settings, and type of biliary stents placed after RFA, and perhaps surgeon technique and experience. In addition, the notion that RFA may improve stent patency has been debated.54 Although many studies have suggested that RFA may decrease the rate of SEMS occlusion, 2 studies that aimed to evaluate this theory showed statistically insignificant results compared with controls.55,56 However, a recent retrospective study by Kadayifci et al57 showed that mean stent patency time was significantly longer in the RFA group. Patients treated with endoscopic RFA using a Habib Endoprobe for the treatment of occluded SEMS (n ¼ 25) were compared with a control group treated with plastic stent insertion (n ¼ 25). The stent patency rate at 90 days and the mean stent patency time during the 5-year study Table 4. Adverse Events Associated With Biliary Radiofrequency Ablation Abdominal pain Cholangitis and cholangiosepsis Hemobilia Gallbladder empyema Pancreatitis Cholecystitis Liver infarction Hepatic artery pseudoaneurysm
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639 period were significant higher for patients who under640 went RFA (rate, 56% vs 24%; P ¼ .04; time, 119.5 vs 641 65.3 d; P ¼ .03). Another study by Yang et al58 examined 642 survival time and stent patency in patients with unre643 sectable extrahepatic cholangiocarcinoma. Twenty-nine 644 patients underwent RFA and stenting whereas 30 645 patients underwent stent placement alone. The mean 646 overall survival and stent patency was significantly 647 longer in the RFA and stent group compared with the 648 stent alone group (13.8 vs 3.5 mo; P < .002; and 6.9 vs 649 3.5 mo; P ¼ .02; respectively). Importantly, no significant 650 difference was noted in the incidence of postprocedural 651 complications between the RFA group and stent cohort 652 (6.9% vs 10%, respectively; P ¼ .67). 653 Recently, a systematic review and meta-analysis was 654 performed to evaluate the efficacy and safety of biliary 655 stenting with RFA compared with stenting alone in patients 656 with malignant biliary strictures.59 This meta-analysis 657 included 8 studies (n ¼ 416) with a similar method of 658 biliary RFA across all studies. Patient demographics, num659 ber with pancreatitis cancer, and mean length of biliary 660 stricture was similar between the 2 groups. Overall, stent 661 patency was improved significantly in biliary stenting with 662 RFA patients compared with stenting alone (pooled 663 weighted mean difference, 45.07 d), with no significant 664 difference seen between the 2 cohorts in regard to risk of 665 cholangitis, acute cholecystitis, pancreatitis, and hemobilia. 666 Furthermore, a pooled survival analysis showed improved 667 survival in patients treated with RFA (hazard ratio, 1.49; 668 P < .001) (Figure 6).59 An additional meta-analysis by 669 Zheng et al60 found similar results including a significant 670 increase in stricture diameter and survival time, suggesting 671 that endoscopic RFA may be preferable in the management 672 of malignant biliary obstruction.60 Although prospective 673 randomized trials are needed to further validate these 674 findings, it appears that endoscopic RFA may improve stent patency and suggest it may be used as an alternative Q9 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 Figure 6. Reconstructed Kaplan–Meier curve showing sig694 nificant difference in survival between RFA group and control 695 group. Figure included with permission from Elsevier 696 Publishing.
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treatment for occluded SEMS from tissue ingrowth in malignant biliary obstruction. Ultimately, intraductal endoscopic RFA, although still a novice procedure, holds promise in the ability to manage malignant biliary strictures.
Intraductal Extension of Ampullary Adenoma Ampullary adenomas often are treated by endoscopic papillectomy. However, endoscopic management of ampullary adenomas extending into the common bile duct or pancreatic duct remains challenging. Intraductal extension typically has been considered a contraindication to endoscopic management and, as such, patients have been referred for surgical management. However, a pancreaticoduodenectomy or a Whipple procedure has high associated morbidity and mortality, thus making endoscopic management an attractive alternative. Recently, a retrospective multicenter study evaluated the feasibility, safety, and efficacy of endoscopic RFA for ampullary neoplasms with intraductal extension.61 In this study, a total of 14 patients with adenoma extension into the common bile duct (13 7 mm; n ¼ 14) and pancreatic duct (7 2 mm; n ¼ 3) were treated with a RFA catheter. With treatment failure documented and persistent tumor invasion shown
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histologically, these patients underwent a median of 1 RFA session (range, 1–5 sessions). At a median follow-up period of 16 months after RFA, complete intraductal ablation was achieved in 91.6% of patients. Adverse events occurred in 43% and included ductal strictures (n ¼ 5) and a retroduodenal abscess (n ¼ 1), all of which were successfully treated endoscopically.62 Another small case series of 4 patients by Suarez et al63 found similar results, with 3 patients achieving complete eradication of the intraductal adenoma extension with no immediate adverse events noted during the short follow-up period. In summation, these studies, although small in number, show RFA to be a relatively safe and effective modality for the treatment of ampullary neoplasms with intraductal extension. Although more studies are needed before this can be implemented routinely, early data suggest an expanded role for endoscopic RFA in future clinical practice.
Early Data on Endoscopic UltrasoundGuided Radiofrequency Ablation Another potential avenue for endoscopic RFA is in regard to the modality’s use with endoscopic ultrasound (EUS). Although the clinical application of EUS-guided RFA is not as well established as the previously discussed indications, with very few studies on the topic, the combined
Figure 7. Imaging findings of patients with cancer of the pancreatic head. (A) CT shows low-density mass at the pancreas head, which did not respond to second-line chemotherapy. (B) EUSguided RFA was performed by using forward-viewing EUS with 50 W of ablation power for 10 seconds and was repeated 8 times. (C) One month after RFA, follow-up CT showed necrosis and air bubbles in the mass (arrow). (D) Two months after RFA, CT showed a decrease of the low-density mass. Figure included with permission from Elsevier Publishing.
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Figure 8. (A) Abdominal contrast-enhanced CT in the arterial phase shows a large enhancing lesion in the head and genu of the pancreas (arrow). (B) After EUS-guided RFA ablation at 3 months. Abdominal contrastenhanced CT shows a pancreatic head lesion with rim enhancement and a central nonenhancing hypodense area (arrow). Figure included with permission from Elsevier Publishing.
use of EUS with ablation holds promise. EUS-guided RFA offers the best combination of real-time visualization and precise localization coupled with a minimally invasive strategy to achieve selective ablation of a variety of lesions previously inaccessible or difficult to access via percutaneous routes.64 At present, EUS-guided RFA has been shown to be effective for targeting lesions within the liver, pancreas, lymph node, and for ablation of celiac ganglia for pain control in pancreatic carcinoma. Although these indications remain experimental and currently performed only at centers with expertise under predetermined protocols, there are emerging data supporting a potential role for EUS-guided RFA in select patients. EUS-guided liver RFA first was shown experimentally by Varadarajulu et al65 in 2009, using a 19-gauge echogenic, umbrella-shaped, monopolar electrode in 5 porcine models. In this study, RFA achieved discrete, well-demarcated, 2.6-cm spherical focus of coagulation necrosis with tissue ablation within 7 minutes. On histopathology, all pigs showed complete coagulative necrosis without damage to the surrounding liver parenchyma or vasculature. Despite these findings, translation of these impressive results to human studies has been limited.66 Ex vivo data regarding the ideal power setting or the duration of ablation needed to effectively treat hepatic masses has been another limiting factor in the expanded use of EUS-guided RFA. Use of the Habib RFA catheter (Habib, EndoHPB, EUS; EMcision Ltd) in a recent study, again in an animal model, showed that maximal zones of injury were achieved using an ablation power of 10 W for a duration of 90 seconds.67 Higher power settings (ie, 15 W, 20 W, and 50 W) were noted to paradoxically achieve a smaller radial length or small ablation zones. This has been attributed to rapid charring of the hepatic tissue around the small-caliber RFA wire at high power with subsequently increased impedance, thus interfering with the conduction of the current with no further spread of ablation. Given these data, future studies may highlight an expanded role for EUS-guided RFA for treatment of primary and secondary hepatic masses; however, translation to human models is lacking at this time.
With regards to pancreatic lesions, Goldberg et al68 first conducted EUS-guided RFA on 16 porcine models and showed discrete histologic progression of coagulation necrosis followed by fibrotic capsule contraction. Although pancreatic RFA has a high risk of complication owing to increased sensitivity of pancreatic tissue and proximity to vascular and biliary structures, early animal studies have shown impressive results.68,69 An early human study by Pai et al70 relieved many concerns by showing no immediate or early major postprocedural complications. In this prospective multicenter trial using an innovative monopolar RFA probe (1.2-mm Habib EUSRFA catheter; EMcision Ltd), 8 patients (n ¼ 6 with pancreatic cystic neoplasms; n ¼ 2 with neuroendocrine tumors) were treated successfully with EUS RFA. The mean size of these lesions was 36.5 17.9 mm and 27.5 17.7 mm for cystic lesions and neuroendocrine tumors, respectively. At a follow-up period of 3 to 6 months, RFA achieved complete resolution in 2 cystic lesions, with a 48.4% reduction noted in 3 remaining patients. A change in vascularity and central necrosis was observed in both neuroendocrine tumor cases after EUS RFA. Importantly, no serious adverse events were reported among patients with cystic lesions and neuroendocrine tumors.
Figure 9. Habib EUS-RFA probe (EMcision Ltd).
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929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986
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Table 5. Emerging Indications for Endoscopic Radiofrequency Ablation Upper GI endoscopy Gastric antral vascular ectasia Lower GI endoscopy Chronic radiation proctitis ERCP Malignant biliary strictures Biliary metal stent dysfunction from tumor ingrowth Intraductal extension of ampullary adenoma EUS Hepatic lesionsa Pancreatic cystic and solid lesions Celiac–ganglia neurolysis Lymph node ablationa
ERCP, endoscopic retrograde cholangiopancreatography; GI, gastrointestinal. a Animal studies only.
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A more recent study by Song et al71 used an 18-gauge RFA electrode inserted into the pancreatic mass with increased blood flow after RFA. This study used a RFA generator activated to deliver 20 to 50 W ablation power for 10 seconds and was performed successfully in all 6 patients included in the study. The mean diameter of pancreatic masses was 3.8 cm (range, 3–9 cm), with the head (n ¼ 4) and body (n ¼ 2) of the pancreas tumors included. Figure 7 highlights significant improvement in the size of the pancreatic head cancer after treatment with RFA.71 Again, no adverse events such as pancreatitis or bleeding occurred. Additional studies by Lakhtakia et al72 and Arcidiacono et al73 have shown the feasibility and safety of EUS-guided pancreatic RFA for pancreatic insulinoma and locally advanced pancreatic cancer, respectively. Lakhtakia et al72 used a prototype 19-gauge needle electrode, generator, and internal cooling system in 3 patients with nonsurgical pancreatic insulinomas and achieved rapid symptom relief with patients remaining symptom free at the 12-month follow-up evaluation (Figure 8).72 In patients with local progression of advanced pancreatic adenocarcinoma status-post neoadjuvant therapy, Arcidiacono et al73 achieved EUS-guided cryotherm probe ablation in 72.8% (16 of 22 patients). The median post-RFA ablation survival time was 6 months, with tumor size appearing smaller on followup computed tomography imaging. These innovative RFA catheters have allowed endoscopists to deliver RFAdirected treatment to patients with lesions previously inaccessible through surgical approaches. Lymph node ablation with novel EUS-guided RFA also has been performed in animal models, again with positive results. Sethi et al74 analyzed the modality on 18 porcine mediastinal lymph nodes with a mean node length of 2.08 cm. By using a prototype RFA probe (EMcision Ltd) with a 0.01-mm diameter and a 3-cm ablation tip, the mean length and diameter of necrosis achieved was 9.8 mm and 5.5 mm, respectively (mean, 17.6% of lymph node area ablated). Importantly, no complications occurred with the procedure. With these
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data and prototype EUS-compatible RFA probe, EUS-RFA lymph node ablation may have the potential for future translation into human studies for management of patients with malignant/metastatic lymph nodes.74 Specifically with regard to pancreatic cancer, EUS-guided celiac ganglion RFA for pain control has been shown in a single-patient case report.75 Significant improvement in pain with a reduction in narcotic intake was reported after EUSguided celiac ganglion RFA using the Habib RFA probe through a 19G EUS needle (Figure 9). Identification of the celiac ganglia with EUS has enhanced the efficacy and safety of the celiac plexus nerve block by enabling direct visualization and precise ablation.76 Whether using RFA over the current standard chemical ablation with EUS-guided celiac neurolysis using alcohol has any clinical advantages needs to be evaluated. More data are needed to establish the safety, long-term durability, and cost effectiveness of EUS-guided celiac RFA neurolysis.
Conclusions At present, endoscopic RFA is well validated for the treatment of dysplastic Barrett’s; however, the use of this endoscopic modality has been expanded to include several other difficult-to-treat diseases (Table 5). These newer indications may provide definitive treatment, palliation, or alternative therapies for a wide variety of gastrointestinal and hepatopancreatobiliary pathologies. Despite being a feasible and safe modality, high RFAassociated costs may limit these expanded applications. Still, with more widespread use and improved implementation, the cost of this innovative modality likely will decrease, making this a more affordable and practical option. Similar to any innovative technique, future direct comparative trials and cost-effective analyses are needed, along with long-term follow-up data to establish the long-term safety and efficacy of endoscopic RFA for these newer indications. Until such time, based on the limited data as presented earlier, endoscopic RFA appears to be a viable, innovative, and emerging modality with expanding indications.
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Conflicts of interest The authors disclose no conflicts.
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