- Email: [email protected]
A novel antireflux metal stent for the palliation of biliary malignancies: a pilot feasibility study (with video)
A novel antireflux metal stent for the palliation of biliary malignancies: a pilot feasibility study (with video) Bing Hu, MD, PhD, Tian-Tian Wang, MD, Zhi-Mei Shi, RN, Shu-Zhi Wang, RN, Rui Lu, RN, Ya-Min Pan, MD, Hui Huang, RN, Shu-Ping Wang, RN Shanghai, China
Background: Antireflux stents that prevent duodenal biliary reflux may improve biliary drainage and prolong stent patency. However, the use of antireflux metal stents (ARMSs) in the human biliary system has not been reported. Objective: To evaluate the safety and efficacy of ARMSs for the palliation of unresectable distal biliary malignancies. Design and Setting: A retrospective case series in a tertiary referral center. Patients: From August 2007 to April 2009, a total of 23 patients with unresectable nonhilar malignant biliary obstruction. Intervention: Endoscopic placement of an ARMS. Main Outcome Measurements: Technical success and early complications with follow-up of stent patency and patient survival. Results: Placement of an ARMS was successful on the first attempt in all patients. There were no procedurerelated complications. Follow-up was obtained in 22 cases. Serum bilirubin level returned to normal within 1 month of stenting in 20 patients. Six stent malfunctions occurred as a result of tumor ingrowth (1 patient), tumor overgrowth (2 patients), and stent migration (3 patients). The remaining patients were free of biliary symptoms until death or final follow-up. The median duration of stent patency of ARMSs was 14 months, with cumulative patency rates at 3, 6, and 12 months of 95%, 74%, and 56%, respectively. The median survival of the patients was 7.9 months (range, 1-14 months). Limitations: Small number of patients in single endoscopy center. Conclusions: Endoscopic insertion of an ARMS is technically feasible, safe, and effective in patients with distal malignant biliary obstruction. The impact of ARMSs in prolonging stent patency and life expectancy deserves further randomized evaluation.
Endoscopic placement of a self-expandable metal stent (SEMS) is an established palliative treatment for unresectable pancreaticobiliary tumors. The fully expanded SEMS with a large diameter of 30F provides longer stent patency duration compared with the smaller-caliber plas-
tic stents.1-3 However, an SEMS placed across the major papilla predisposes to duodenal biliary reflux and ascending infection. In a recent study using barium examination, free reflux was demonstrated through the SEMSs in all patients.4 It is not uncommon for fever or colic to develop
Abbreviations: ARMS, antireflux metal stent; CBD, common bile duct; SEMS, self-expandable metal stent.
doi:10.1016/j.gie.2010.08.048
DISCLOSURE: The following author disclosed the following financial relationship relevant to this publication: Dr Hu is the inventor of the ARMS and has worked in collaboration with Micro-Tech (Nanjing) Co, Nanjing, China, in developing the stent. The stents used in this study were provided free of charge by the company. The other authors disclosed no financial relationships relevant to this publication. Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00
www.giejournal.org
Received April 27, 2010. Accepted August 28, 2010. Current affiliations: Department of Endoscopy, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China. Presented at Gastro 2009/United European Gastroenterology Federation, London, United Kingdom, November 21-25, 2009 (Endoscopy 2009;41(Suppl 1):A395). Reprint requests: Bing Hu, MD, PhD, 225 Changhai Road, Shanghai 200438, China.
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Take-home Message ●
Figure 1. The metal biliary stent with antireflux valve.
in patients with an SEMS in situ, and cholangitis is a major complication after SEMS placement that affects the patient’s quality of life. The frequency of cholangitis after SEMS placement ranges from 6.5% to 22% in reported series.5-9 We hypothesize that SEMSs with an antireflux valve will prevent duodenal biliary reflux and improve bile drainage. To the best of our knowledge, there has been no report on antireflux metal biliary stents in the literature, and the feasibility of such a stent remains unknown. This study was designed as a pilot feasibility study. The aim was to develop a new antireflux SEMS and assess its safety and efficacy in the palliation of nonhilar biliary malignancies.
PATIENTS AND METHODS Design of an antireflux metal stent A new antireflux metal stent (ARMS) was braided with nitinol wire with or without a membrane cover. A hemispheric silicon valve with a cross-shaped outlet was attached to its distal (duodenal) end. In an uncovered ARMS, a silicon membrane (2 cm in length) was added on the duodenal side. A recent modification included the addition of 4 slim wires attached to the valve to maintain its shape and a proximal enlarged bare wire part for anchorage to reduce the risk of stent migration (Fig. 1). The diameter of the ARMS was 10 mm, and its length was 6 or 8 cm for biliary obstructions at different locations. The modified ARMS was a covered stent with the exception of its proximal part (1 cm in length and 1.5 cm in diameter).
Clinical evaluation The clinical study was performed at the Eastern Hepatobiliary Hospital. The study protocol was approved by the Institutional Review Board for Human Research of the 144 GASTROINTESTINAL ENDOSCOPY
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Metal stents that prevent duodenobiliary reflux have not been reported upon. In this pilot study, newly designed antireflux metal stents were successfully deployed with fewer complications of cholangitis in 23 patients who had unresectable malignant biliary obstruction. The median duration of stent patency and patient survival was 14 months and 7.9 months, respectively.
Eastern Hepatobiliary Hospital, and each of the patients gave informed consent to participate in the study. Consecutive patients with malignant stricture involving the distal or middle common bile duct (CBD) were enrolled in the study. All patients had obstructive jaundice with pathologic or imaging evidence characteristic of malignant lesions. Exclusion criteria included resectable lesions, previous stenting, previous bile duct surgery, and duodenal obstruction. Between August 2007 and April 2009, a total of 23 patients with unresectable nonhilar malignant CBD obstruction underwent ARMS placement. There were 11 men and 12 women, with a mean age of 65.4 years (range, 31-84 years). The indications for endoscopic stenting included pancreatic carcinoma in 13 patients, cholangiocarcinoma in 4, ampullary tumor in 2, gallbladder cancer in 2, and liver cancer with extrahepatic duct invasion in 2. Most patients had pathologic confirmation of malignancy through previous surgery, brush cytology, or FNA sampling. Some patients had imaging evidence of tumor with distal metastasis. The mean ⫾ SD serum bilirubin level before stenting was 216.9 ⫾ 134.6 mol/L (range, 32.6 – 406.2 mol/L). The preparation was similar to that for general ERCP procedures. A standard endoscope (JF-260V; Olympus Optical, Tokyo, Japan) with a working channel of 3.7 mm in diameter was used. When nonhilar bile duct stricture was confirmed on cholangiography, a guidewire (Jagwire; Boston Scientific, Natick, Mass, USA) was introduced through the stricture. No sphincterotomy was routinely performed, and temporary dilation was done using a 10F catheter dilator (Cook Endoscopy, Winston-Salem, NC, USA). The ARMS was advanced into the bile duct with the proximal end located ⱖ2 cm above the upper level of the bile duct obstruction. The stent was then released under fluoroscopic guidance, leaving the distal end with the antireflux valve outside the duodenal papilla. Any technical difficulty encountered was noted. Drainage of bile was confirmed before withdrawal of the endoscope. All patients were followed clinically, and liver function tests were repeated within the first week after stenting. Subsequent follow-up was conducted at 1- to 2-month intervals, with either clinic visits or telephone calls. Any changes in symptom and laboratory tests were recorded. www.giejournal.org
Hu et al
Preliminary experience with biliary antireflux metal stent
TABLE 1. Characteristics and clinical outcome of patients treated with ARMSs Patient Gender/age (y)
Diagnosis
Stent type Stent patency (mo) Cause of occlusion Adjuvant therapy Survival (mo)
1
F/31
Pancreatic Ca
OS, UC
4⫹
—
—
4
2
F/76
Pancreatic Ca
OS, UC
6⫹
—
—
6
3
F/84
Bile duct Ca
OS, UC
1
IG
—
3
4
M/43
Liver Ca
OS, C
3
MIG
CT
8
5
F/46
Pancreatic Ca
OS, C
5⫹
—
CT
5
6
F/58
Ampulla Ca
OS, C
14⫹
—
—
14
7
F/67
Gallbladder Ca
OS, C
2.5
OG
RT
3.5
8
F/80
Bile duct Ca
OS, C
3
MIG
—
9
9
M/67
Pancreatic Ca
OS, C
1⫹
—
—
1
10
F/68
Ampulla Ca
OS, C
12⫹
—
RT
12
11
M/50
Pancreatic Ca
OS, C
1.5⫹
—
—
1.5
12
M/74
Pancreatic Ca
OS, C
9
OG
CT
10
13
F/72
Pancreatic Ca
OS, C
3.7
MIG
—
7
14
M/73
Pancreatic Ca
MS, C
15
M/38
Pancreatic Ca
MS, C
6.5⫹
—
TACE
6.5⫹
16
M/68
Pancreatic Ca
MS, C
6⫹
—
—
6
17
F/74
Pancreatic Ca
MS, C
8⫹
—
GJ
8
18
F/70
Bile duct Ca
MS, C
3⫹
—
RT
3⫹
19
M/79
Pancreatic Ca
MS, C
6⫹
—
—
6
20
M/61
Liver Ca
MS, C
8⫹
—
—
8⫹
21
M/59
Bile duct Ca
MS, C
6⫹
—
—
6
22
F/70
Gallbladder Ca
MS, C
6⫹
—
—
6⫹
23
M/67
Pancreatic Ca
MS, C
6⫹
—
—
6⫹
LF
C, Covered; Ca, cancer; CT, chemotherapy; GJ, gastrojejunostomy; IG, ingrowth; LF, lost to follow-up; MIG, migration; MS, modified stent; OG, overgrowth; OS, original stent; RT, radiotherapy; TACE, transcatheter arterial chemoembolization; UC, uncovered.
Stent occlusion was suspected if the patient had worsening liver function test results or symptoms of cholangitis. Immediate endoscopic intervention was then performed, and a plastic stent was inserted through the previously placed metal stent. Stent occlusion was defined as worsening jaundice and/or cholangitis, with improvement after the second stent insertion. The duration of stent patency measured from endoscopic stenting to onset of stent occlusion and patient survival measured from endoscopic stenting to death were recorded. The end point of this study was stent occlusion or patient death.
Statistical analyses The results are given in mean ⫾ SD unless stated otherwise. Cumulative survival and stent patency duration were plotted by using the Kaplan-Meier method. www.giejournal.org
RESULTS ARMSs were successfully placed in all 23 patients in a single attempt (Table 1). Two patients received 6-cm stents and the others 8-cm stents. A 9F deployment system with a similar release mechanism was used, and the technical difficulty encountered during stent placement was similar to that of ordinary SEMSs. The mean time taken for endoscopic stenting was 28.6 ⫾ 16.3 minutes. ARMSs with the original design were used in 13 patients (3 were uncovered stents), and the modified stents were used in the remaining 10 patients. After stent placement, bile could be seen flowing out easily through the antireflux valve (Video 1, available online at www.giejournal.org). There were no significant procedure-related complications except for 1 patient in whom mild GI bleeding developed because of Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY
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Figure 3. Kaplan-Meier curve showing the cumulative survival of patients and patency of the ARMS. Figure 2. The antireflux valve remained intact without debris collection in 1 patient 3 months after ARMS placement.
DISCUSSION an underlying duodenal tumor. The bleeding was controlled with hemostasis medications and blood transfusion. No acute cholangitis or pancreatitis was observed. Clinical follow-up information was available for 22 patients; 1 patient was lost to follow-up after discharge. Jaundice improved in all patients after stent placement, and the serum bilirubin levels returned to normal within 1 month in 20 patients. All patients remained asymptomatic before the onset of stent occlusion. Five patients agreed to undergo repeat endoscopy to check the function of the stent and integrity of the valve between 1 and 5 months after ARMS placement. All 5 valves were found to be intact without collection of food residue inside the stents (Fig. 2). Up to the time of reporting, 6 stent malfunctions occurred in the original ARMS group, and endoscopic reinterventions were performed. The causes of stent malfunction included tumor ingrowth in 1 (at 34 days after placement of an uncovered ARMS), tumor overgrowth in 2 (at 113 and 270 days, respectively), and stent migration in 3 (at 86, 92, and 111 days, respectively). No complication was found, as of the time of writing, among the patients who received the improved-design stent. The remaining patients were well until death or final follow-up. At the time of analysis (November 2009), 17 patients had died without evidence of biliary obstruction, with a median survival of 7.9 months (range, 1-14 months). Five patients remained alive without biliary symptoms. The causes of death included advanced cancer in 11 patients, GI bleeding in 2, cardiac failure in 1, and renal failure in 1. The stent patency and patient survival curves were shown by using the Kaplan-Meier method (Fig. 3). The median duration of ARMS patency was 14 months with 3-, 6-, and 12-month patency rates of 95.1%, 74.2%, and 55.9%, respectively. The overall survival rates at 3, 6, and 12 months were 91.0%, 81.3%, and 17.2%, respectively, with a median survival of 7.9 months. 146 GASTROINTESTINAL ENDOSCOPY
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The sphincter of Oddi functions like a “gatekeeper” for the biliary tract, allowing outflow of bile into the duodenum and preventing ascending duodenal biliary reflux. When a stent is placed across the ampulla of Vater, this barrier function is compromised. The presence of pneumobilia after biliary stent placement suggests occurrence of duodenal biliary reflux. Several studies have reported the presence of plant fibers in the bile ducts and blocked plastic stents as a result of reflux of food material.10-12 In a recent study using scanning electron microscopy, van Berkel et al13 confirmed reflux of material from the gut along the entire length of the stent, often combined with microorganisms. The refluxed material together with bacterial adhesion was believed to be the primary cause of plastic stent occlusion.14-16 In 2007, Dua et al14 reported a modified plastic biliary stent with an antireflux function. In their study, a 4-cm long windsock-shaped valve was attached to the distal end of the stent in the duodenum. The stent could withstand a retrograde pressure gradient of more than 320 mm Hg. A subsequent randomized clinical trial comparing this new stent with conventional plastic stents was conducted in 60 consecutive patients with nonhilar malignant CBD strictures. The median duration of patency of the plastic antireflux stent was significantly longer compared with the conventional stent (145 days vs 101 days). That is the only study demonstrating the benefits of an antireflux biliary stent with a longer stent patency duration.17 SEMSs are preferable to plastic stents for the palliation of unresectable biliary malignancies and are more costeffective if the patient survival is likely to be ⬎6 months.18-23 SEMSs have a longer median duration of patency compared with plastic stents, and the cause of stent blockage may be tissue ingrowth, overgrowth, or sludge formation. Although duodenal biliary reflux may not be the primary cause of SEMS occlusion, the occurrence of such reflux no doubt exists whenever an SEMS is being placed www.giejournal.org
Hu et al
across the duodenal papilla.4 SEMSs have a larger lumen and are theoretically more susceptible to reflux of duodenal contents. It is not uncommon to see that patients with SEMSs have reported episodes of unexplained fever or cholangitis, as seen in approximately one-third of our patients previously treated with SEMSs. In a study reported by Okamoto et al,24 cholangitis occurred in 12 of 108 patients (11.1%), but more frequently in the subgroup with transpapillary stent placement (21.6%). The authors concluded that SEMS placement across the main papilla may predispose patients to cholangitis because of disruption of the sphincter mechanism. In another study, Misra and Dwivedi4 noted that cholangitis occurred in 2 patients with an SEMS blocked only at the duodenal end by a large amount of food debris, and the authors believed that reflux of duodenal contents played a role in the blockage of the SEMS. To the best of our knowledge, there is no earlier report on antireflux biliary SEMSs. Many questions remain unanswered, such as the technical feasibility of making an SEMS with an antireflux valve, the difficulty involved in deployment, whether the presence of the antireflux valve interferes with bile flow, the ideal design, and how long such a valve can last. In the present study, we found that making an antireflux SEMS using available medical-grade material is technically possible. There was no additional difficulty in placing such a stent compared with the conventional SEMS. The mean time for ARMS placement procedures was 28.6 ⫾ 16.3 minutes, which is very similar to that for the placement of ordinary SEMSs. After stent deployment, bile could be seen flowing easily through the valve outlet. All of the patients showed a rapid improvement in jaundice, and the serum bilirubin level returned to normal in 20 of 22 patients within the first month. Several patients underwent endoscopic surveillance of the ARMSs, and the valves were found to remain intact for as long as 5 months. More importantly, we did not find any collection of duodenal contents at the orifice of the stent, which is a common phenomenon observed in ordinary SEMSs. Among the 6 patients with stent malfunction, tumor ingrowth was found in 1 patient with an uncovered ARMS. Symptoms resolved with placement of a covered ARMS. However, stent migration occurred in 3 patients with covered ARMSs at 86 to 111 days after stent placement. To overcome this problem, a further modification was made by adding an enlarged proximal part (diameter of 1.5 cm) without membrane cover to enhance anchorage of the ARMS and to prevent downward stent migration. It is unclear whether ARMSs can prolong stent patency and patient survival compared with conventional SEMSs. In earlier reports, conventional SEMSs had a median duration of stent patency of 4.8 to 10 months, and the patients treated with SEMSs had a median survival of 4.5 to 6.5 months.1-3,22,24 A more recent study involving transpapillary SEMS placement revealed a mean life expectancy of only 5 months in 100 patients, with a mean survival in patients with gallbladder cancer, pancreatic cancer, and www.giejournal.org
Preliminary experience with biliary antireflux metal stent
cholangiocarcinoma of 3, 5.9, and 8.5 months, respectively.4 Our results appeared to be superior to the earlier report, with a median duration of stent patency of 14 months and a median patient survival of 7.9 months. The limitation of our study is the small number of patients in a pilot observational study with different pathologies causing bile duct obstruction. In conclusion, our preliminary experience suggests that it is feasible to develop SEMSs with a durable antireflux valve. The efficacy and safety of such a stent in human use are evident. The new antireflux SEMS has the potential benefit of prolonging stent patency and patient survival with fewer complications of cholangitis. Further randomized controlled trials comparing ARMSs with ordinary SEMSs are necessary to confirm the benefits of the antireflux mechanism. ACKNOWLEDGMENTS The authors thank Professor Joseph Leung of the University of California, Davis, for his help with the manuscript. REFERENCES 1. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic drainage method for inoperable malignant stricture of the common bile duct. Gastrointest Endosc 1998;47:1-7. 2. Davids PH, Groen AK, Rauws EA, et al. Randomized trial of selfexpanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992;340:1488-92. 3. Knyrim K, Wagner HJ, Pausch J, et al. A prospective, randomized, controlled trial of metal stents for malignant obstruction of the common bile duct. Endoscopy 1993;25:207-12. 4. Misra SP, Dwivedi M. Reflux of duodenal contents and cholangitis in patients undergoing self-expanding metal stent placement. Gastrointest Endosc 2009;70:317-21. 5. Nicholson AA, Royston CMS. Palliation of inoperable biliary obstruction with self-expanding metallic endoprostheses: a review of 77 patients. Clin Radiol 1993;47:245-50. 6. Stoker J, Lameris JS, Jeekel J. Percutaneously placed Wallstent endoprosthesis in patients with malignant distal biliary obstruction. Br J Surg 1993;80:1185-7. 7. Boguth L, Tatalovic S, Antonucci F, et al. Malignant biliary obstruction: clinical and histopathologic correlation after treatment with selfexpanding metallic prostheses. Radiology 1994;192:669-74. 8. Stocker J, Lameris JS. Complications of percutaneously inserted biliary Wallstent. J Vasc Interv Radiol 1993;4:767-72. 9. Hatzidakis AA, Tsetis D, Chrysou E, et al. Nitinol stents for palliative treatment of malignant obstructive jaundice: should we stent the sphincter of Oddi in every case? Cardiovasc Intervent Radiol 2001;24:245-8. 10. Weickert U, Venzke T, Konig J, et al. Why do bilioduodenal plastic stents become occluded? A clinical and pathological investigation on 100 consecutive patients. Endoscopy 2001;33:786-90. 11. DowidarN,KolmosHJ,LyonH,etal.Cloggingofbiliaryendoprostheses.Amorphologic and bacteriologic study. Scand J Gastroenterol 1991;26:1137-44. 12. Groen AK, Out T, Huibregtse K, et al. Characterization of the content of occluded biliary endoprostheses. Endoscopy 1987;19:57-9. 13. van Berkel AM, van Marle J, Groen AK, et al. Mechanisms of biliary stent clogging: confocal laser scanning and scanning electron microscopy. Endoscopy 2005;37:729-34. 14. Dua KS, Reddy ND, Rao VG, et al. Impact of reducing duodenobiliary reflux on biliary stent patency: an in vitro evaluation and a prospective randomized clinical trial that used a biliary stent with an antireflux valve. Gastrointest Endosc 2007;65:819-28.
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Preliminary experience with biliary antireflux metal stent 15. Yu JL, Andersson R, Parsson H, et al. A bacteriologic and scanning electron microscope study after implantation of foreign bodies in the biliary tract in rats. Scand J Gastroenterol 1996;31:175-81. 16. Sung JY, Shaffer EA, Lam K, et al. Hydrophobic bile salt inhibits bacterial adhesion on biliary stent material. Dig Dis Sci 1994;39:999-1006. 17. Kahaleh M. Antireflux biliary stents: is it time to go with the flow? Gastrointest Endosc 2007;65;829-31. 18. Arguedas MR, Heudebert GH, Stinnett AA, et al. Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a costeffectiveness analysis. Am J Gastroenterol 2002;97:898-904. 19. van Laethem JL, De Broux S, Eisendrath P, et al. Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum. Am J Gastroenterol 2003;98:1271-7.
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Hu et al 20. Wasan SM, Ross WA, Staerkel GA, et al. Use of expandable metallic biliary stents in resectable pancreatic cancer. Am J Gastroenterol 2005;100:2056-61. 21. Yeoh KG, Zimmerman MJ, Cunningham JT, et al. Comparative costs of metal versus plastic biliary stent strategies for malignant obstructive jaundice by decision analysis. Gastrointest Endosc 1999;49:466-71. 22. Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003;57:178-82. 23. Stern N, Sturgess R. Endoscopic therapy in the management of malignant biliary obstruction. Eur J Surg Oncol 2008;34:313-7. 24. Okamoto T, Fujioka S, Yanagisawa S, et al. Placement of a metallic stent across the main duodenal papilla may predispose to cholangitis. Gastrointest Endosc 2006;63:792-6.
www.giejournal.org
Background: Antireflux stents that prevent duodenal biliary reflux may improve biliary drainage and prolong stent patency. However, the use of antireflux metal stents (ARMSs) in the human biliary system has not been reported. Objective: To evaluate the safety and efficacy of ARMSs for the palliation of unresectable distal biliary malignancies. Design and Setting: A retrospective case series in a tertiary referral center. Patients: From August 2007 to April 2009, a total of 23 patients with unresectable nonhilar malignant biliary obstruction. Intervention: Endoscopic placement of an ARMS. Main Outcome Measurements: Technical success and early complications with follow-up of stent patency and patient survival. Results: Placement of an ARMS was successful on the first attempt in all patients. There were no procedurerelated complications. Follow-up was obtained in 22 cases. Serum bilirubin level returned to normal within 1 month of stenting in 20 patients. Six stent malfunctions occurred as a result of tumor ingrowth (1 patient), tumor overgrowth (2 patients), and stent migration (3 patients). The remaining patients were free of biliary symptoms until death or final follow-up. The median duration of stent patency of ARMSs was 14 months, with cumulative patency rates at 3, 6, and 12 months of 95%, 74%, and 56%, respectively. The median survival of the patients was 7.9 months (range, 1-14 months). Limitations: Small number of patients in single endoscopy center. Conclusions: Endoscopic insertion of an ARMS is technically feasible, safe, and effective in patients with distal malignant biliary obstruction. The impact of ARMSs in prolonging stent patency and life expectancy deserves further randomized evaluation.
Endoscopic placement of a self-expandable metal stent (SEMS) is an established palliative treatment for unresectable pancreaticobiliary tumors. The fully expanded SEMS with a large diameter of 30F provides longer stent patency duration compared with the smaller-caliber plas-
tic stents.1-3 However, an SEMS placed across the major papilla predisposes to duodenal biliary reflux and ascending infection. In a recent study using barium examination, free reflux was demonstrated through the SEMSs in all patients.4 It is not uncommon for fever or colic to develop
Abbreviations: ARMS, antireflux metal stent; CBD, common bile duct; SEMS, self-expandable metal stent.
doi:10.1016/j.gie.2010.08.048
DISCLOSURE: The following author disclosed the following financial relationship relevant to this publication: Dr Hu is the inventor of the ARMS and has worked in collaboration with Micro-Tech (Nanjing) Co, Nanjing, China, in developing the stent. The stents used in this study were provided free of charge by the company. The other authors disclosed no financial relationships relevant to this publication. Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00
www.giejournal.org
Received April 27, 2010. Accepted August 28, 2010. Current affiliations: Department of Endoscopy, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China. Presented at Gastro 2009/United European Gastroenterology Federation, London, United Kingdom, November 21-25, 2009 (Endoscopy 2009;41(Suppl 1):A395). Reprint requests: Bing Hu, MD, PhD, 225 Changhai Road, Shanghai 200438, China.
Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY
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Preliminary experience with biliary antireflux metal stent
Hu et al
Take-home Message ●
Figure 1. The metal biliary stent with antireflux valve.
in patients with an SEMS in situ, and cholangitis is a major complication after SEMS placement that affects the patient’s quality of life. The frequency of cholangitis after SEMS placement ranges from 6.5% to 22% in reported series.5-9 We hypothesize that SEMSs with an antireflux valve will prevent duodenal biliary reflux and improve bile drainage. To the best of our knowledge, there has been no report on antireflux metal biliary stents in the literature, and the feasibility of such a stent remains unknown. This study was designed as a pilot feasibility study. The aim was to develop a new antireflux SEMS and assess its safety and efficacy in the palliation of nonhilar biliary malignancies.
PATIENTS AND METHODS Design of an antireflux metal stent A new antireflux metal stent (ARMS) was braided with nitinol wire with or without a membrane cover. A hemispheric silicon valve with a cross-shaped outlet was attached to its distal (duodenal) end. In an uncovered ARMS, a silicon membrane (2 cm in length) was added on the duodenal side. A recent modification included the addition of 4 slim wires attached to the valve to maintain its shape and a proximal enlarged bare wire part for anchorage to reduce the risk of stent migration (Fig. 1). The diameter of the ARMS was 10 mm, and its length was 6 or 8 cm for biliary obstructions at different locations. The modified ARMS was a covered stent with the exception of its proximal part (1 cm in length and 1.5 cm in diameter).
Clinical evaluation The clinical study was performed at the Eastern Hepatobiliary Hospital. The study protocol was approved by the Institutional Review Board for Human Research of the 144 GASTROINTESTINAL ENDOSCOPY
Volume 73, No. 1 : 2011
Metal stents that prevent duodenobiliary reflux have not been reported upon. In this pilot study, newly designed antireflux metal stents were successfully deployed with fewer complications of cholangitis in 23 patients who had unresectable malignant biliary obstruction. The median duration of stent patency and patient survival was 14 months and 7.9 months, respectively.
Eastern Hepatobiliary Hospital, and each of the patients gave informed consent to participate in the study. Consecutive patients with malignant stricture involving the distal or middle common bile duct (CBD) were enrolled in the study. All patients had obstructive jaundice with pathologic or imaging evidence characteristic of malignant lesions. Exclusion criteria included resectable lesions, previous stenting, previous bile duct surgery, and duodenal obstruction. Between August 2007 and April 2009, a total of 23 patients with unresectable nonhilar malignant CBD obstruction underwent ARMS placement. There were 11 men and 12 women, with a mean age of 65.4 years (range, 31-84 years). The indications for endoscopic stenting included pancreatic carcinoma in 13 patients, cholangiocarcinoma in 4, ampullary tumor in 2, gallbladder cancer in 2, and liver cancer with extrahepatic duct invasion in 2. Most patients had pathologic confirmation of malignancy through previous surgery, brush cytology, or FNA sampling. Some patients had imaging evidence of tumor with distal metastasis. The mean ⫾ SD serum bilirubin level before stenting was 216.9 ⫾ 134.6 mol/L (range, 32.6 – 406.2 mol/L). The preparation was similar to that for general ERCP procedures. A standard endoscope (JF-260V; Olympus Optical, Tokyo, Japan) with a working channel of 3.7 mm in diameter was used. When nonhilar bile duct stricture was confirmed on cholangiography, a guidewire (Jagwire; Boston Scientific, Natick, Mass, USA) was introduced through the stricture. No sphincterotomy was routinely performed, and temporary dilation was done using a 10F catheter dilator (Cook Endoscopy, Winston-Salem, NC, USA). The ARMS was advanced into the bile duct with the proximal end located ⱖ2 cm above the upper level of the bile duct obstruction. The stent was then released under fluoroscopic guidance, leaving the distal end with the antireflux valve outside the duodenal papilla. Any technical difficulty encountered was noted. Drainage of bile was confirmed before withdrawal of the endoscope. All patients were followed clinically, and liver function tests were repeated within the first week after stenting. Subsequent follow-up was conducted at 1- to 2-month intervals, with either clinic visits or telephone calls. Any changes in symptom and laboratory tests were recorded. www.giejournal.org
Hu et al
Preliminary experience with biliary antireflux metal stent
TABLE 1. Characteristics and clinical outcome of patients treated with ARMSs Patient Gender/age (y)
Diagnosis
Stent type Stent patency (mo) Cause of occlusion Adjuvant therapy Survival (mo)
1
F/31
Pancreatic Ca
OS, UC
4⫹
—
—
4
2
F/76
Pancreatic Ca
OS, UC
6⫹
—
—
6
3
F/84
Bile duct Ca
OS, UC
1
IG
—
3
4
M/43
Liver Ca
OS, C
3
MIG
CT
8
5
F/46
Pancreatic Ca
OS, C
5⫹
—
CT
5
6
F/58
Ampulla Ca
OS, C
14⫹
—
—
14
7
F/67
Gallbladder Ca
OS, C
2.5
OG
RT
3.5
8
F/80
Bile duct Ca
OS, C
3
MIG
—
9
9
M/67
Pancreatic Ca
OS, C
1⫹
—
—
1
10
F/68
Ampulla Ca
OS, C
12⫹
—
RT
12
11
M/50
Pancreatic Ca
OS, C
1.5⫹
—
—
1.5
12
M/74
Pancreatic Ca
OS, C
9
OG
CT
10
13
F/72
Pancreatic Ca
OS, C
3.7
MIG
—
7
14
M/73
Pancreatic Ca
MS, C
15
M/38
Pancreatic Ca
MS, C
6.5⫹
—
TACE
6.5⫹
16
M/68
Pancreatic Ca
MS, C
6⫹
—
—
6
17
F/74
Pancreatic Ca
MS, C
8⫹
—
GJ
8
18
F/70
Bile duct Ca
MS, C
3⫹
—
RT
3⫹
19
M/79
Pancreatic Ca
MS, C
6⫹
—
—
6
20
M/61
Liver Ca
MS, C
8⫹
—
—
8⫹
21
M/59
Bile duct Ca
MS, C
6⫹
—
—
6
22
F/70
Gallbladder Ca
MS, C
6⫹
—
—
6⫹
23
M/67
Pancreatic Ca
MS, C
6⫹
—
—
6⫹
LF
C, Covered; Ca, cancer; CT, chemotherapy; GJ, gastrojejunostomy; IG, ingrowth; LF, lost to follow-up; MIG, migration; MS, modified stent; OG, overgrowth; OS, original stent; RT, radiotherapy; TACE, transcatheter arterial chemoembolization; UC, uncovered.
Stent occlusion was suspected if the patient had worsening liver function test results or symptoms of cholangitis. Immediate endoscopic intervention was then performed, and a plastic stent was inserted through the previously placed metal stent. Stent occlusion was defined as worsening jaundice and/or cholangitis, with improvement after the second stent insertion. The duration of stent patency measured from endoscopic stenting to onset of stent occlusion and patient survival measured from endoscopic stenting to death were recorded. The end point of this study was stent occlusion or patient death.
Statistical analyses The results are given in mean ⫾ SD unless stated otherwise. Cumulative survival and stent patency duration were plotted by using the Kaplan-Meier method. www.giejournal.org
RESULTS ARMSs were successfully placed in all 23 patients in a single attempt (Table 1). Two patients received 6-cm stents and the others 8-cm stents. A 9F deployment system with a similar release mechanism was used, and the technical difficulty encountered during stent placement was similar to that of ordinary SEMSs. The mean time taken for endoscopic stenting was 28.6 ⫾ 16.3 minutes. ARMSs with the original design were used in 13 patients (3 were uncovered stents), and the modified stents were used in the remaining 10 patients. After stent placement, bile could be seen flowing out easily through the antireflux valve (Video 1, available online at www.giejournal.org). There were no significant procedure-related complications except for 1 patient in whom mild GI bleeding developed because of Volume 73, No. 1 : 2011 GASTROINTESTINAL ENDOSCOPY
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Hu et al
Figure 3. Kaplan-Meier curve showing the cumulative survival of patients and patency of the ARMS. Figure 2. The antireflux valve remained intact without debris collection in 1 patient 3 months after ARMS placement.
DISCUSSION an underlying duodenal tumor. The bleeding was controlled with hemostasis medications and blood transfusion. No acute cholangitis or pancreatitis was observed. Clinical follow-up information was available for 22 patients; 1 patient was lost to follow-up after discharge. Jaundice improved in all patients after stent placement, and the serum bilirubin levels returned to normal within 1 month in 20 patients. All patients remained asymptomatic before the onset of stent occlusion. Five patients agreed to undergo repeat endoscopy to check the function of the stent and integrity of the valve between 1 and 5 months after ARMS placement. All 5 valves were found to be intact without collection of food residue inside the stents (Fig. 2). Up to the time of reporting, 6 stent malfunctions occurred in the original ARMS group, and endoscopic reinterventions were performed. The causes of stent malfunction included tumor ingrowth in 1 (at 34 days after placement of an uncovered ARMS), tumor overgrowth in 2 (at 113 and 270 days, respectively), and stent migration in 3 (at 86, 92, and 111 days, respectively). No complication was found, as of the time of writing, among the patients who received the improved-design stent. The remaining patients were well until death or final follow-up. At the time of analysis (November 2009), 17 patients had died without evidence of biliary obstruction, with a median survival of 7.9 months (range, 1-14 months). Five patients remained alive without biliary symptoms. The causes of death included advanced cancer in 11 patients, GI bleeding in 2, cardiac failure in 1, and renal failure in 1. The stent patency and patient survival curves were shown by using the Kaplan-Meier method (Fig. 3). The median duration of ARMS patency was 14 months with 3-, 6-, and 12-month patency rates of 95.1%, 74.2%, and 55.9%, respectively. The overall survival rates at 3, 6, and 12 months were 91.0%, 81.3%, and 17.2%, respectively, with a median survival of 7.9 months. 146 GASTROINTESTINAL ENDOSCOPY
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The sphincter of Oddi functions like a “gatekeeper” for the biliary tract, allowing outflow of bile into the duodenum and preventing ascending duodenal biliary reflux. When a stent is placed across the ampulla of Vater, this barrier function is compromised. The presence of pneumobilia after biliary stent placement suggests occurrence of duodenal biliary reflux. Several studies have reported the presence of plant fibers in the bile ducts and blocked plastic stents as a result of reflux of food material.10-12 In a recent study using scanning electron microscopy, van Berkel et al13 confirmed reflux of material from the gut along the entire length of the stent, often combined with microorganisms. The refluxed material together with bacterial adhesion was believed to be the primary cause of plastic stent occlusion.14-16 In 2007, Dua et al14 reported a modified plastic biliary stent with an antireflux function. In their study, a 4-cm long windsock-shaped valve was attached to the distal end of the stent in the duodenum. The stent could withstand a retrograde pressure gradient of more than 320 mm Hg. A subsequent randomized clinical trial comparing this new stent with conventional plastic stents was conducted in 60 consecutive patients with nonhilar malignant CBD strictures. The median duration of patency of the plastic antireflux stent was significantly longer compared with the conventional stent (145 days vs 101 days). That is the only study demonstrating the benefits of an antireflux biliary stent with a longer stent patency duration.17 SEMSs are preferable to plastic stents for the palliation of unresectable biliary malignancies and are more costeffective if the patient survival is likely to be ⬎6 months.18-23 SEMSs have a longer median duration of patency compared with plastic stents, and the cause of stent blockage may be tissue ingrowth, overgrowth, or sludge formation. Although duodenal biliary reflux may not be the primary cause of SEMS occlusion, the occurrence of such reflux no doubt exists whenever an SEMS is being placed www.giejournal.org
Hu et al
across the duodenal papilla.4 SEMSs have a larger lumen and are theoretically more susceptible to reflux of duodenal contents. It is not uncommon to see that patients with SEMSs have reported episodes of unexplained fever or cholangitis, as seen in approximately one-third of our patients previously treated with SEMSs. In a study reported by Okamoto et al,24 cholangitis occurred in 12 of 108 patients (11.1%), but more frequently in the subgroup with transpapillary stent placement (21.6%). The authors concluded that SEMS placement across the main papilla may predispose patients to cholangitis because of disruption of the sphincter mechanism. In another study, Misra and Dwivedi4 noted that cholangitis occurred in 2 patients with an SEMS blocked only at the duodenal end by a large amount of food debris, and the authors believed that reflux of duodenal contents played a role in the blockage of the SEMS. To the best of our knowledge, there is no earlier report on antireflux biliary SEMSs. Many questions remain unanswered, such as the technical feasibility of making an SEMS with an antireflux valve, the difficulty involved in deployment, whether the presence of the antireflux valve interferes with bile flow, the ideal design, and how long such a valve can last. In the present study, we found that making an antireflux SEMS using available medical-grade material is technically possible. There was no additional difficulty in placing such a stent compared with the conventional SEMS. The mean time for ARMS placement procedures was 28.6 ⫾ 16.3 minutes, which is very similar to that for the placement of ordinary SEMSs. After stent deployment, bile could be seen flowing easily through the valve outlet. All of the patients showed a rapid improvement in jaundice, and the serum bilirubin level returned to normal in 20 of 22 patients within the first month. Several patients underwent endoscopic surveillance of the ARMSs, and the valves were found to remain intact for as long as 5 months. More importantly, we did not find any collection of duodenal contents at the orifice of the stent, which is a common phenomenon observed in ordinary SEMSs. Among the 6 patients with stent malfunction, tumor ingrowth was found in 1 patient with an uncovered ARMS. Symptoms resolved with placement of a covered ARMS. However, stent migration occurred in 3 patients with covered ARMSs at 86 to 111 days after stent placement. To overcome this problem, a further modification was made by adding an enlarged proximal part (diameter of 1.5 cm) without membrane cover to enhance anchorage of the ARMS and to prevent downward stent migration. It is unclear whether ARMSs can prolong stent patency and patient survival compared with conventional SEMSs. In earlier reports, conventional SEMSs had a median duration of stent patency of 4.8 to 10 months, and the patients treated with SEMSs had a median survival of 4.5 to 6.5 months.1-3,22,24 A more recent study involving transpapillary SEMS placement revealed a mean life expectancy of only 5 months in 100 patients, with a mean survival in patients with gallbladder cancer, pancreatic cancer, and www.giejournal.org
Preliminary experience with biliary antireflux metal stent
cholangiocarcinoma of 3, 5.9, and 8.5 months, respectively.4 Our results appeared to be superior to the earlier report, with a median duration of stent patency of 14 months and a median patient survival of 7.9 months. The limitation of our study is the small number of patients in a pilot observational study with different pathologies causing bile duct obstruction. In conclusion, our preliminary experience suggests that it is feasible to develop SEMSs with a durable antireflux valve. The efficacy and safety of such a stent in human use are evident. The new antireflux SEMS has the potential benefit of prolonging stent patency and patient survival with fewer complications of cholangitis. Further randomized controlled trials comparing ARMSs with ordinary SEMSs are necessary to confirm the benefits of the antireflux mechanism. ACKNOWLEDGMENTS The authors thank Professor Joseph Leung of the University of California, Davis, for his help with the manuscript. REFERENCES 1. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic drainage method for inoperable malignant stricture of the common bile duct. Gastrointest Endosc 1998;47:1-7. 2. Davids PH, Groen AK, Rauws EA, et al. Randomized trial of selfexpanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992;340:1488-92. 3. Knyrim K, Wagner HJ, Pausch J, et al. A prospective, randomized, controlled trial of metal stents for malignant obstruction of the common bile duct. Endoscopy 1993;25:207-12. 4. Misra SP, Dwivedi M. Reflux of duodenal contents and cholangitis in patients undergoing self-expanding metal stent placement. Gastrointest Endosc 2009;70:317-21. 5. Nicholson AA, Royston CMS. Palliation of inoperable biliary obstruction with self-expanding metallic endoprostheses: a review of 77 patients. Clin Radiol 1993;47:245-50. 6. Stoker J, Lameris JS, Jeekel J. Percutaneously placed Wallstent endoprosthesis in patients with malignant distal biliary obstruction. Br J Surg 1993;80:1185-7. 7. Boguth L, Tatalovic S, Antonucci F, et al. Malignant biliary obstruction: clinical and histopathologic correlation after treatment with selfexpanding metallic prostheses. Radiology 1994;192:669-74. 8. Stocker J, Lameris JS. Complications of percutaneously inserted biliary Wallstent. J Vasc Interv Radiol 1993;4:767-72. 9. Hatzidakis AA, Tsetis D, Chrysou E, et al. Nitinol stents for palliative treatment of malignant obstructive jaundice: should we stent the sphincter of Oddi in every case? Cardiovasc Intervent Radiol 2001;24:245-8. 10. Weickert U, Venzke T, Konig J, et al. Why do bilioduodenal plastic stents become occluded? A clinical and pathological investigation on 100 consecutive patients. Endoscopy 2001;33:786-90. 11. DowidarN,KolmosHJ,LyonH,etal.Cloggingofbiliaryendoprostheses.Amorphologic and bacteriologic study. Scand J Gastroenterol 1991;26:1137-44. 12. Groen AK, Out T, Huibregtse K, et al. Characterization of the content of occluded biliary endoprostheses. Endoscopy 1987;19:57-9. 13. van Berkel AM, van Marle J, Groen AK, et al. Mechanisms of biliary stent clogging: confocal laser scanning and scanning electron microscopy. Endoscopy 2005;37:729-34. 14. Dua KS, Reddy ND, Rao VG, et al. Impact of reducing duodenobiliary reflux on biliary stent patency: an in vitro evaluation and a prospective randomized clinical trial that used a biliary stent with an antireflux valve. Gastrointest Endosc 2007;65:819-28.
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Preliminary experience with biliary antireflux metal stent 15. Yu JL, Andersson R, Parsson H, et al. A bacteriologic and scanning electron microscope study after implantation of foreign bodies in the biliary tract in rats. Scand J Gastroenterol 1996;31:175-81. 16. Sung JY, Shaffer EA, Lam K, et al. Hydrophobic bile salt inhibits bacterial adhesion on biliary stent material. Dig Dis Sci 1994;39:999-1006. 17. Kahaleh M. Antireflux biliary stents: is it time to go with the flow? Gastrointest Endosc 2007;65;829-31. 18. Arguedas MR, Heudebert GH, Stinnett AA, et al. Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a costeffectiveness analysis. Am J Gastroenterol 2002;97:898-904. 19. van Laethem JL, De Broux S, Eisendrath P, et al. Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum. Am J Gastroenterol 2003;98:1271-7.
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Hu et al 20. Wasan SM, Ross WA, Staerkel GA, et al. Use of expandable metallic biliary stents in resectable pancreatic cancer. Am J Gastroenterol 2005;100:2056-61. 21. Yeoh KG, Zimmerman MJ, Cunningham JT, et al. Comparative costs of metal versus plastic biliary stent strategies for malignant obstructive jaundice by decision analysis. Gastrointest Endosc 1999;49:466-71. 22. Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003;57:178-82. 23. Stern N, Sturgess R. Endoscopic therapy in the management of malignant biliary obstruction. Eur J Surg Oncol 2008;34:313-7. 24. Okamoto T, Fujioka S, Yanagisawa S, et al. Placement of a metallic stent across the main duodenal papilla may predispose to cholangitis. Gastrointest Endosc 2006;63:792-6.
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