Surg Endosc (2014) 28:854–860 DOI 10.1007/s00464-013-3232-9
and Other Interventional Techniques
Endoscopic radiofrequency ablation for malignant biliary obstruction: a nationwide retrospective study of 84 consecutive applications Werner Dolak • Florian Schreiber • Hubert Schwaighofer • Michael Gschwantler Wolfgang Plieschnegger • Alexander Ziachehabi • Andreas Mayer • Ludwig Kramer • Andreas Kopecky • Christiane Schrutka-Ko¨lbl • Gernot Wolkersdo¨rfer • Christian Madl • Frieder Berr • Michael Trauner • Andreas Pu¨spo¨k • for the Austrian Biliary RFA Study Group
•
Received: 21 May 2013 / Accepted: 17 September 2013 / Published online: 3 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Biliary radiofrequency ablation (RFA) using the HabibTM EndoHBP catheter is a new endoscopic palliation therapy for malignant biliary obstruction. The aim of this study was to assess the feasibility and safety of this technique. Methods In this nationwide retrospective study of prospectively collected clinical data, all patients treated by biliary RFA in Austria between November 2010 and December 2012 were included. Procedure-related complications, adverse events within 30 days post-intervention, stent patency, and mortality rates were investigated. Results A total of 58 patients (31 male, 27 female, median age 75 years) underwent 84 RFA procedures at 11 Austrian
This study is conducted for the Austrian Biliary RFA Study Group.
Electronic supplementary material The online version of this article (doi:10.1007/s00464-013-3232-9) contains supplementary material, which is available to authorized users. W. Dolak (&) M. Trauner A. Pu¨spo¨k Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria e-mail:
[email protected] F. Schreiber Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria H. Schwaighofer Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria M. Gschwantler Department of Internal Medicine IV, Wilhelminenspital, Vienna, Austria
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referral centers for biliary endoscopy. The predominant underlying condition was Klatskin tumor (45 of 58 cases). All 84 RFA procedures were feasible without technical problems. A partial liver infarction was induced by RFA in a 49-year-old Klatskin tumor patient. During 30 days after each RFA procedure, five cases of cholangitis, three cases of hemobilia, two cases of cholangiosepsis, and one case each of gallbladder empyema, hepatic coma, and newly diagnosed left bundle branch block occurred. Median stent patency after last electively performed RFA was 170 days (95 % CI 63–277) and was almost significantly different between metal and plastic stenting (218 vs. 115 days; p = 0.051). Median survival was 10.6 months (95 % CI 6.9–14.4) from the time of the first RFA in each patient and 17.9 months (95 % CI 10.3–25.6) from the time of initial diagnosis. Conclusions Except for one severe interventional complication (hepatic infarct), RFA presented as a technically feasible and safe therapeutic option for the palliative treatment of malignant biliary obstruction. The good results of stent patency and survival in this study should be proven W. Plieschnegger Department of Internal Medicine, Barmherzige Bru¨der, St Veit an der Glan, Austria A. Ziachehabi Department of Internal Medicine IV, Krankenhaus der Elisabethinen Linz, Linz, Austria A. Mayer Department of Internal Medicine II, Landesklinikum, St Po¨lten, Austria L. Kramer Department of Internal Medicine I, Krankenhaus Hietzing, Vienna, Austria
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in prospective (controlled) trials to further quantify the efficacy of this promising new technique. Keywords Malignant biliary obstruction Endoscopic radiofrequency ablation Endoscopic retrograde cholangiopancreatography Therapeutic endoscopy Hilar cholangiocarcinoma
Biliary obstruction is the most relevant factor for survival and quality of life in patients suffering from primary or secondary bile duct malignancies. Underlying tumors, such as pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma (CCa) of Klatskin type, or metastases of colorectal cancer are often diagnosed at an advanced stage when presenting with biliary obstruction. Thus, therapy is restricted to palliative management in most cases. Within this setting, the prevention of biliary complications such as jaundice, cholangitis, or cholangiosepsis is one of the key therapeutic factors to extend survival and maintain quality of life [1, 2]. Endoscopic stenting of the biliary tract has been shown to be an easy and safe approach to maintain or restore biliary drainage [3]. Self-expanding metal stents (SEMS) are superior to plastic stents because of the lower risk of stent occlusion [4–6]. In addition to stenting, endoscopic therapies with direct affect to local tumor mass have been developed within the past years. First of all, photodynamic therapy (PDT) has shown promising results for the reduction of tumor size and maintenance of biliary drainage [7, 8]. However, the patient management for this treatment, involving peri-interventional photosensitivity, remains cumbersome for both patients and treating physicians. Recently, an endoscopically applicable radiofrequency ablation (RFA) catheter for the biliary tract, the so-called HabibTM EndoHBP probe (EMcision, London, UK) was introduced. RFA is well known from percutaneous applications, where it already proved to be effective as a treatment option for primary and secondary liver tumors [9]. Percutaneous RFA for extrahepatic CCa was first reported in 2008 [10]. One year later, the HabibTM EndoHBP catheter obtained US FDA clearance for destruction of biliary tumors and decompression of SEMS after obstruction by tumor ingrowth. Since that time, it has been A. Kopecky Department of Internal Medicine, Landesklinikum Thermenregion Baden, Baden, Austria C. Schrutka-Ko¨lbl C. Madl Department of Internal Medicine IV, Krankenanstalt Rudolfstiftung, Vienna, Austria G. Wolkersdo¨rfer F. Berr Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria
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evaluated ex vivo in resected fresh pig livers [11] and in an open-label pilot study involving 22 patients with malignant biliary obstruction. In this investigation, biliary RFA showed promising results concerning safety and prevention of stent occlusion [12]. The aim of the present study was to evaluate the feasibility and safety of endoscopic RFA with the HabibTM EndoHBP catheter for the treatment of malignant biliary obstruction based on a nationwide analysis.
Materials and methods This retrospective study was conducted at 11 Austrian hospitals, all of which were tertiary referral centers for bilio-pancreatic endoscopy. The study protocol was approved by the internal review board of the Medical University of Vienna (EK 1837/2012) and registered at clinicaltrials.gov (NCT017583410). Patients who underwent biliary RFA with the HabibTM EndoHBP catheter as treatment for malignant biliary obstruction were identified using examination report databases. Examination reports and patient charts were analyzed to assess procedure-related complications, hospital stay, adverse events within 30 days post-intervention, stent patency after the last electively performed RFA procedure in each patient, biliary reinterventions, and 30-day, 90-day, and overall mortality. All patient data had been de-identified using pseudonymization prior to any further processing. Stent patency and survival were assessed using Kaplan–Meier statistics; all other parameters were reported descriptively. SPSS version 19.0 was used for data analysis. RFA procedure The HabibTM EndoHBP probe is an 8 Fr. bipolar device with two radiologically marked electrodes at its tip (Fig. 1). It can be applied during a standard endoscopic retrograde cholangiopancreatography (ERCP) procedure or percutaneous transhepatic cholangiography (PTC) without any special patient preparation. After insertion into the bile duct over a 0.035 in. guidewire, the tip of the probe is placed across the malignant stricture under fluoroscopic guidance. Attached to a standard high-frequency generator, 7–10 W are typically applied for up to 120 s. This creates a heat zone around the electrodes, leading to tissue coagulation. It is also recommended that the probe be kept stable for 1 min after the delivery of RFA energy, in order to avoid the adhesion of tissue to the electrodes. Depending on the stricture size, the RFA energy can be delivered repetitively at different tumor sites within one procedure. After the RFA application is completed, plastic or metal stenting can be performed immediately.
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Fig. 1 HabibTM EndoHBP catheter. A Distal end of the catheter with radiofrequency ablation (RFA) electrodes (red arrows). B Cholangiogram showing catheter use in a Klatskin tumor patient of Bismuth IV type. C Endoscopic picture of the papilla in a patient with distal cholangiocarcinoma showing the RFA probe still in place directly after RFA application (Color figure online)
Results Between November 2010 and December 2012, a total of 58 patients (31 male, 27 female, median age 75 years at first RFA procedure, age range 28–88 years) underwent 84 biliary RFA procedures as a treatment for malignant biliary obstruction. Underlying diseases included 45 cases of Klatskin tumor (five tumors of Bismuth I stage, one of Bismuth II stage, six of Bismuth III stage, and 33 of Bismuth IV stage), five cases of distal CCa, four cases of pancreatic adenocarcinoma, and one case each of central hepatocellular carcinoma (HCC), mixed HCC/CCa, gallbladder carcinoma, and metastatic colorectal cancer (mCRC). In 27 patients, biliary RFA was the single treatment option (except for biliary drainage), 24 patients underwent previous or concomitant chemotherapy, four patients had undergone curatively intended liver surgery, two patients had been previously treated with PDT, two other patients had undergone prior radiotherapy, and the patient with mixed HCC/CCa had been
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previously treated by three sessions of transarterial chemoembolization (Table 1). All 84 RFA procedures were conducted without any technical problems (78 were performed via ERCP and six were performed via a percutaneous approach). A total of 15 RFA procedures were performed within previously implanted SEMS. The median energy and time level used during the single procedures was 10 W for 2 9 90 s (range 7–30 W for 1–6 9 60–90 s). Most patients (45 of 58) underwent only one RFA session, repetitive RFA sessions (up to five) were performed electively in 12 patients during prophylactic stent exchange, and re-RFA was performed non-electively in two patients because of stent occlusion. After the last electively performed RFA procedure, SEMS were placed in the majority of patients (35 of 58), 19 patients received plastic stents; no stenting was performed in four patients (supplementary table). One major complication occurred in a 49-year-old patient with Bismuth IV stage Klatskin tumor who
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Table 1 Patient characteristics (summary) Biliary tract cancer (Klatskin tumor, distal CCa, gallbladder carcinoma)
Pancreatic cancer
Central HCC, mixed HCC/CCa, mCRC
Total
51
4
3
58
Gender (m:f)
27:24
0:4
3:0
31:27
Age, years (range)
76 (28–88)
62 (55–82)
70 (63–71)
75 (28–88)
Co-therapies
CHT 20, S 3, RT 2, PDT 2
CHT 3
CHT 1, S 1, TACE 1
CHT 24, S 4, RT 2, PDT 2, TACE 1
RFA sessions
19 = 37, 29 = 6, 39 = 2, 49 = 4, 59 = 1
19 = 4
19 = 3
19 = 44, 29 = 6, 39 = 2, 49 = 4, 59 = 1
Interventional complications Adverse events within 30 days post RFA
Partial liver infarction
None
None
(as listed)
Cholangitis 5, hemobilia 2, cholangiosepsis 2, hepatic coma 1, left bundle branch block 1
Gallbladder empyema 1
Hemobilia 1
(as listed)
Survival after first RFA/ initial diagnosis (95% CI)
10.9/19.1 m
5.0/8.8 m
10.5/98.4 m
10.6 m (6.9–14.4)/ 17.9 m (10.3–25.6)
No. of patients
CCa cholangiocarcinoma, CHT chemotherapy, CI confidence interval, HCC hepatocellular carcinoma, mCRC metastatic colorectal cancer, PDT photodynamic therapy, RFA radiofrequency ablation, RT radiotherapy, S surgery, TACE transarterial chemoembolization
developed a partial liver infarction after the RFA procedure, probably caused by thermal injury of a segmental liver artery. Fortunately, this complication could be managed conservatively and the patient was discharged after 8 days. A computer tomography scan performed 3 months after the RFA procedure showed normal perfusion of the affected liver areas (Fig. 2). The median hospital stay of all included patients was 2 days (range 1–24). Within a 30-day control period, the following adverse events have been noted: five cases of cholangitis, three cases of hemobilia, two cases of cholangiosepsis, and one case each of gallbladder empyema hepatic coma and newly diagnosed left bundle branch block. Re-ERCP was performed for one case of hemobilia, gallbladder empyema led to cholecystectomy, hepatic coma had a fatal outcome; all other adverse events were treated conservatively. Stent patency was counted from the time point of the last electively performed RFA procedure in each patient; the median was 170 days (95 % CI 63–277). Between metal and plastic stents, an almost significantly different stent patency was observed at a log-Rank analysis (218 vs. 115 days; p = 0.051) (Fig. 3). During follow-up after RFA, eight patients required additional percutaneous biliary drainage and 13 needed to undergo non-elective reERCP because of stent occlusion or for treatment of adverse events. In two cases, these ERCP procedures were combined with re-RFA of occluded SEMS. Defining the first RFA procedure of each patient as starting point, the 30- and 90-day mortality were 1.7 and 19.0 %, respectively (six patients died due to cachexia after 36, 50, 50, 62, 75, and 85 days; two patients died due to cholangiosepsis after 55 and 71 days; and one patient each died from hepatic coma after 12 days, acute myocardial
infarction after 65 days, and esophageal variceal bleeding after 77 days). The extrapolated median survival after first RFA was 10.6 months (95 % CI 6.9–14.4 months) (Fig. 4). Overall median survival (from initial diagnosis until death) was 17.9 months (95 % CI 10.3–25.6).
Discussion This study reports on the largest clinical experience with biliary RFA published so far. All consecutive applications in Austria over 2 years were collected to represent a nationwide dataset, including long-term follow-up data on stent patency and survival. In general, biliary RFA using the HabibTM EndoHBP catheter was feasible and safe, with the important exception of one severe peri-interventional complication (liver infarction). This event was clearly associated with the use of the RFA probe. Although the affected patient presented with a favorable course, attention should be paid to this complication and its potential mechanisms, such as vascular injury, to optimize RFA usage for future applications. RFA has been previously used to treat a range of different diseases, such as atrial fibrillation, Barrett’s esophagus, or chronic back pain disorders. The most comparable experience to biliary RFA is represented by percutaneous RFA of primary or secondary intrahepatic malignancies. Many studies in this context have reported on the potential risk of thermal injury to structures in the proximity of the tumor [13]. Therefore, preinterventional imaging with accurate assessment of the surrounding tissue, particularly vascular and biliary structures, has been established prior to every percutaneous RFA procedure. Consequently, RFA energy can be adapted to the local
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Fig. 2 Peri-interventional complication in a patient with Klatskin tumor of Bismuth IV type. A Coronar plane and B axial plane, showing an infarction of the liver segments VII and VIII 3 days after
the radiofrequency ablation (RFA) procedure (red arrow). C Coronar plane and D axial plane showing normal liver perfusion again 3 months after the RFA procedure (Color figure online)
patho-anatomic situation or a different therapeutic technique can be chosen if the risk of collateral damage by RFA is classified as too high. For biliary RFA with the HabibTM EndoHBP catheter, the tissue effect of different power and time settings has been previously studied ex vivo in resected fresh pig livers. It revealed that the dimension of the heat zone at a typical setting of 10 W applied for 90 s measured 21.3 ± 1.6 9 8.3 ± 1.2 mm [10]. In our current study, the peri-interventional complication occurred in a Klatskin tumor patient of Bismuth IV stage; 10 W had been applied for 90 s at six different stricture locations in the common bile duct and both main biliary branches. Thereby, the proximity between a proximal tumor stricture of the right bile duct and a segmental right liver lobe artery might have been crucial, resulting in local arterial thrombosis leading to the partial liver infarction (Fig. 2). In this patient, pre-interventional computed tomography (CT) and positron emission tomography (PET)–CT
scans were carefully re-evaluated by a board certified radiologist 9 months after the RFA procedure. No specific local risk factors in the tumor surroundings could be identified, with the limitation that the tumor itself was only visible by indirect signs. In retrospect, it can be speculated whether other imaging techniques, such as recent magnetic resonance imaging, endosonography or intraductal endoscopic ultrasound could have revealed an anatomic risk, leading to an adaption of the RFA energy level. The retrospective design may be considered one of the shortcomings of our study. Therefore, this investigation naturally incurs a selection bias of the patients included. This is reflected by the different entities of underlying tumors and, of course, by the heterogeneity of palliatively intended co-therapies (31 of 58 patients underwent other treatment modalities prior to RFA), implying that RFA was not always initiated immediately after onset of
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Fig. 3 Kaplan–Meier curve on stent patency. Calculation starts on the day of the last electively performed radiofrequency ablation (RFA) procedure in each patient and ends on the day of proven stent occlusion, stent migration, or patient’s death
Fig. 4 Kaplan–Meier survival curve of the study patients. Calculation starts on the day of the first radiofrequency ablation (RFA) procedure. Extrapolated median survival is 10.6 months (95 % CI 6.9–14.4). Cum cumulative
malignant biliary obstruction. Therefore, reliable conclusions in regard to the efficacy of RFA cannot be drawn from the present study. Nevertheless, we assessed stent patency after RFA as surrogate parameter of RFA efficacy. Previous studies have shown the superiority of metal stents over plastic stents for maintaining biliary drainage by extending the median patency time from less than 3 months (plastic stents) to more than 6 months (metal stents) [1]. In our study, this difference was also seen, although it just missed significance. Overall, the stent patency of 115 days (plastic stents) and 218 days
(metal stents) observed in this study was superior to most publications on solitary plastic or metal stenting [4, 5, 14]. Focusing on the adverse events collected within 30 days after RFA, the high frequency of cholangitis (after 5 of 84 applications, 6.0 %) is especially salient. However, in comparison with safety data on other treatment modalities, such as PDT or even stenting alone, this finding is not uncommon and seems more to be caused by the poor general condition of the study population than by a certain medical intervention [7, 15].
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The 30- and 90-day mortality rate of this investigation is comparable to the other systematical dataset on RFA published so far [12]. Moreover, taking into account that, in our study, RFA was often applied as second-line treatment at late tumor stages or when other treatment attempts had failed, the extrapolated median survival of 10.6 months in the current study (calculated from the first RFA procedure until death of the patient) (Fig. 4) may be even more impressive. The overall median survival of 17.9 months (from initial diagnosis until death) is much better than the survival rates documented for best supportive care, which barely exceed 12 months [1]. It is even longer than most survival times reported for other palliative treatment modalities, such as PDT or stenting alone [16, 17], again with the limitation of the heterogeneous patient population due to the retrospective study design. In summary, despite one major interventional complication, endoscopic RFA with the HabibTM EndoHBP catheter was feasible and mostly safe for the treatment of malignant biliary obstruction in the context of this nationwide retrospective analysis. Accurate pre-interventional imaging assessment of the tumor surroundings must be recommended for future applications, especially for the treatment of proximal strictures. Stent patency and median survival were impressive in this study. Prospective (controlled) trials are warranted to further quantify the efficacy of the technique in regard to hard endpoints such as patient survival and quality of life. Acknowledgments The authors would like to acknowledge the following people who substantially contributed to the data collection in the context of this study: Barbara Tribl, Patricia Kump, Wolfgang Vogel, Brigitte Hellmich, Antje Holza¨pfel, Michael Wasilewski, Isolde Hinterberger, Franz Siebert, Andreas Maieron, Rainer Scho¨fl, Johann Pidlich, and Karl Dam. Disclosures Werner Dolak, Florian Schreiber, Hubert Schwaighofer, Michael Gschwantler, Wolfgang Plieschnegger, Alexander Ziachehabi, Andreas Mayer, Ludwig Kramer, Andreas Kopecky, Christiane Schrutka-Ko¨lbl, Gernot Wolkersdo¨rfer, Christian Madl, Frieder Berr, Michael Trauner and Andreas Pu¨spo¨k have no conflicts of interest or financial ties to disclose. This study did not receive any public funding or industrial sponsoring.
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