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Efficacy and Safety of Ursodeoxycholic Acid for the Prevention of Gallstone Formation After Gastrectomy in Patients With Gastric CancerThe PEGASUS-D Randomized Clinical Trial

Educational Objective To identify if the use of ursodeoxycholic acid following gastrectomy is safe and effective for the prevention of gallstone formation.
1 Credit CME
Key Points

Question  Can ursodeoxycholic acid administration prevent gallstone formation after gastrectomy in patients with gastric cancer?

Findings  In this randomized clinical trial of 521 adults, the use of 300 mg or 600 mg of ursodeoxycholic acid, compared with placebo, resulted in a significantly decreased proportion of patients developing gallstones within 12 months after gastrectomy (5.3% in the 300-mg group, 4.3% in the 600-mg group, and 16.7% in the placebo group).

Meaning  Ursodeoxycholic acid administration may prevent gallstone formation after gastrectomy in patients with gastric cancer.

Abstract

Importance  The incidence of gallstones has been reported to increase after gastrectomy. However, few studies have been conducted on the prevention of gallstone formation in patients who have undergone gastrectomy.

Objective  To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) in preventing gallstone formation after gastrectomy in patients with gastric cancer.

Design, Setting, and Participants  The PEGASUS-D study (Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study) was a randomized, double-blind, placebo-controlled clinical trial conducted at 12 institutions in the Republic of Korea. Adults (aged ≥19 years) with a diagnosis of gastric cancer who underwent total, distal, or proximal gastrectomy were enrolled between May 26, 2015, and January 9, 2017; follow-up ended January 8, 2018. Efficacy was evaluated by both the full analysis set, based on the intention-to-treat principle, and the per-protocol set; full analysis set findings were interpreted as the main results.

Interventions  Eligible participants were randomly assigned to receive 300 mg of UDCA, 600 mg of UDCA, or placebo at a ratio of 1:1:1. Ursodeoxycholic acid and placebo were administered daily for 52 weeks.

Main Outcomes and Measures  Gallstone formation was assessed with abdominal ultrasonography every 3 months for 12 months. Randomization and allocation to trial groups were carried out by an interactive web-response system. The primary end point was the proportion of patients developing gallstones within 12 months after gastrectomy.

Results  A total of 521 patients (175 received 300 mg of UDCA, 178 received 600 mg of UDCA, and 168 received placebo) were randomized. The full analysis set included 465 patients (311 men; median age, 56.0 years [interquartile range, 48.0-64.0 years]), with 151 patients in the 300-mg group, 164 patients in the 600-mg group, and 150 patients in the placebo group. The proportion of patients developing gallstones within 12 months after gastrectomy was 8 of 151 (5.3%) in the 300-mg group, 7 of 164 (4.3%) in the 600-mg group, and 25 of 150 (16.7%) in the placebo group. Compared with the placebo group, odds ratios for gallstone formation were 0.27 (95% CI, 0.12-0.62; P = .002) in the 300-mg group and 0.20 (95% CI, 0.08-0.50; P < .001) in the 600-mg group. No significant adverse drug reactions were detected among the enrolled patients.

Conclusions and Relevance  Administration of UDCA for 12 months significantly reduced the incidence of gallstones after gastrectomy for gastric cancer. These findings suggest that UDCA administration prevents gallstone formation after gastrectomy in patients with gastric cancer.

Trial Registration  ClinicalTrials.gov Identifier: NCT02490111

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: March 13, 2020.

Published Online: June 17, 2020. doi:10.1001/jamasurg.2020.1501

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Lee SH et al. JAMA Surgery.

Corresponding Author: Do Joong Park, MD, PhD, Department of Surgery and Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea (djparkmd@snu.ac.kr).

Author Contributions: Dr D. J. Park had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: S. H. Lee, Jang, Yoo, Ryu, Y.S. Park, D. J. Park.

Acquisition, analysis, or interpretation of data: S. H. Lee, Jang, Yoo, Hwang, Ryu, Kwon, Hur, Yoon, Eom, H. S. Ahn, Son, Song, H. H. Lee, Choi, An, S.-I. Lee, K. H. Lee, S. Ahn, D. J. Park.

Drafting of the manuscript: S. H. Lee, Jang, Ryu, D. J. Park.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: S. H. Lee, H. S. Ahn, K. H. Lee, S. Ahn, D. J. Park.

Obtained funding: S. H. Lee, Ryu, D. J. Park.

Administrative, technical, or material support: S. H. Lee, Jang, Yoo, Ryu, Eom, H. S. Ahn, An, K. H. Lee, Y. S. Park, D. J. Park.

Supervision: S. H. Lee, Ryu, Song, An, D. J. Park.

Conflict of Interest Disclosures: Dr S.H. Lee reported receiving speaker honoraria and grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr Yoo reported receiving grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr Y. S. Park reported receiving grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr D. J. Park reported receiving speaker honoraria from Daewoong Pharmaceutical Co Ltd during the conduct of the study; and a research grant from Medtronic outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by a research grant from Daewoong Pharmaceutical Co Ltd.

Role of the Funder/Sponsor: The funding source, with guidance from the steering committee, was involved in the study design, data collection and analysis, and manuscript preparation process.

Group Information: The Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study (PEGASUS-D) Group members are Do Joong Park (principal investigator [PI]), Sang Hyub Lee (co-PI), Moon-Won Yoo, Sun-Hwi Hwang, Seong-Yeob Ryu, Oh Kyoung Kwon, Hoon Hur, Hong Man Yoon, Bang Wool Eom, Hye Seong Ahn, Taeil Son, Kyo Young Song, Han Hong Lee, Min-Gew Choi, Ji Yeong An, Sang-Il Lee (all site PIs), Dong Kee Jang, Kyung Ho Lee, Young Suk Park (all investigators), and Soyeon Ahn (principal biostatistician).

Meeting Presentation: This paper was presented at the Lecture Presentation of Research Forum of the Digestive Disease Week; May 18, 2019; San Diego, California; at the International Gastric Cancer Congress; May 10, 2019; Prague, Czech Republic; and at the 39th Congress of the European Society of Surgical Oncology; October 10, 2019; Rotterdam, the Netherlands.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and their families for participating in the trial. Kyung Won Kim, MD, PhD, Asan Medical Center; Jee Hyun Baek, MD, Human Medical Imaging and Intervention Center; Hyun Sik Woo, MD, Boramae Medical Center; and Eun Sun Lee, MD, PhD, Chung-Ang University Hospital provided consultation regarding radiologic criteria. They were compensated for their contributions. Hyung-Ho Kim, MD, PhD, and Sang-Hoon Ahn, MD, Seoul National University Bundang Hospital; Beom-Su Kim, MD, PhD, and In Seob Lee, MD, PhD, Asan Medical Center; and Ji Yoen Park, MD, Kyoungpook National University Hospital were investigators for each institute. They were not compensated for their contributions. Hyun Ju Shin, BS, Daewoong Pharmaceutical Co Ltd, was clinical project leader and Bobae Jo, MS, Daewoong Pharmaceutical Co Ltd, was the statistician. They were not compensated for their contributions.

References
1.
Park  DJ , Kim  KH , Park  YS , Ahn  SH , Park  DJ , Kim  HH .  Risk factors for gallstone formation after surgery for gastric cancer.   J Gastric Cancer. 2016;16(2):98-104. doi:10.5230/jgc.2016.16.2.98 PubMedGoogle ScholarCrossref
2.
Kobayashi  T , Hisanaga  M , Kanehiro  H , Yamada  Y , Ko  S , Nakajima  Y .  Analysis of risk factors for the development of gallstones after gastrectomy.   Br J Surg. 2005;92(11):1399-1403. doi:10.1002/bjs.5117 PubMedGoogle ScholarCrossref
3.
Fukagawa  T , Katai  H , Saka  M , Morita  S , Sano  T , Sasako  M .  Gallstone formation after gastric cancer surgery.   J Gastrointest Surg. 2009;13(5):886-889. doi:10.1007/s11605-009-0832-8 PubMedGoogle ScholarCrossref
4.
Kimura  J , Kunisaki  C , Takagawa  R ,  et al.  Is routine prophylactic cholecystectomy necessary during gastrectomy for gastric cancer?   World J Surg. 2017;41(4):1047-1053. doi:10.1007/s00268-016-3831-4 PubMedGoogle ScholarCrossref
5.
Li  VK , Pulido  N , Martinez-Suartez  P ,  et al.  Symptomatic gallstones after sleeve gastrectomy.   Surg Endosc. 2009;23(11):2488-2492. doi:10.1007/s00464-009-0422-6 PubMedGoogle ScholarCrossref
6.
Fraser  SA , Sigman  H .  Conversion in laparoscopic cholecystectomy after gastric resection: a 15-year review.   Can J Surg. 2009;52(6):463-466.PubMedGoogle Scholar
7.
Sasaki  A , Nakajima  J , Nitta  H , Obuchi  T , Baba  S , Wakabayashi  G .  Laparoscopic cholecystectomy in patients with a history of gastrectomy.   Surg Today. 2008;38(9):790-794. doi:10.1007/s00595-007-3726-y PubMedGoogle ScholarCrossref
8.
Moreels  TG .  ERCP in the patient with surgically altered anatomy.   Curr Gastroenterol Rep. 2013;15(9):343. doi:10.1007/s11894-013-0343-3 PubMedGoogle ScholarCrossref
9.
Iglézias Brandão de Oliveira  C , Adami Chaim  E , da Silva  BB .  Impact of rapid weight reduction on risk of cholelithiasis after bariatric surgery.   Obes Surg. 2003;13(4):625-628. doi:10.1381/096089203322190862 PubMedGoogle ScholarCrossref
10.
Ura  K , Sarna  SK , Condon  RE .  Antral control of gallbladder cyclic motor activity in the fasting state.   Gastroenterology. 1992;102(1):295-302. doi:10.1016/0016-5085(92)91813-J PubMedGoogle ScholarCrossref
11.
Rehnberg  O , Haglund  U .  Gallstone disease following antrectomy and gastroduodenostomy with or without vagotomy.   Ann Surg. 1985;201(3):315-318. doi:10.1097/00000658-198503000-00010 PubMedGoogle ScholarCrossref
12.
Yi  SQ , Ohta  T , Tsuchida  A ,  et al.  Surgical anatomy of innervation of the gallbladder in humans and Suncus murinus with special reference to morphological understanding of gallstone formation after gastrectomy.   World J Gastroenterol. 2007;13(14):2066-2071. doi:10.3748/wjg.v13.i14.2066 PubMedGoogle ScholarCrossref
13.
Pezzolla  F , Lantone  G , Guerra  V ,  et al.  Influence of the method of digestive tract reconstruction on gallstone development after total gastrectomy for gastric cancer.   Am J Surg. 1993;166(1):6-10. doi:10.1016/S0002-9610(05)80573-2 PubMedGoogle ScholarCrossref
14.
Takahashi  T , Yamamura  T , Yokoyama  E ,  et al.  Impaired contractile motility of the gallbladder after gastrectomy.   Am J Gastroenterol. 1986;81(8):672-677.PubMedGoogle Scholar
15.
Inoue  K , Fuchigami  A , Hosotani  R ,  et al.  Release of cholecystokinin and gallbladder contraction before and after gastrectomy.   Ann Surg. 1987;205(1):27-32.PubMedGoogle Scholar
16.
Portincasa  P , Altomare  DF , Moschetta  A ,  et al.  The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study.   Am J Gastroenterol. 2000;95(12):3444-3451. doi:10.1111/j.1572-0241.2000.03282.x PubMedGoogle ScholarCrossref
17.
Bencini  L , Marchet  A , Alfieri  S ,  et al; Italian Research Group for Gastric Cancer (GIRCG).  The Cholegas trial: long-term results of prophylactic cholecystectomy during gastrectomy for cancer—a randomized-controlled trial.   Gastric Cancer. 2019;22(3):632-639. doi:10.1007/s10120-018-0879-x PubMedGoogle ScholarCrossref
18.
Dakour-Aridi  HN , El-Rayess  HM , Abou-Abbass  H , Abu-Gheida  I , Habib  RH , Safadi  BY .  Safety of concomitant cholecystectomy at the time of laparoscopic sleeve gastrectomy: analysis of the American College of Surgeons National Surgical Quality Improvement Program database.   Surg Obes Relat Dis. 2017;13(6):934-941. doi:10.1016/j.soard.2016.12.012 PubMedGoogle ScholarCrossref
19.
Yardimci  S , Coskun  M , Demircioglu  S , Erdim  A , Cingi  A .  Is concomitant cholecystectomy necessary for asymptomatic cholelithiasis during laparoscopic sleeve gastrectomy?   Obes Surg. 2018;28(2):469-473. doi:10.1007/s11695-017-2867-3 PubMedGoogle ScholarCrossref
20.
Ruhl  CE , Everhart  JE .  Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population.   Am J Gastroenterol. 2013;108(6):952-958. doi:10.1038/ajg.2013.70 PubMedGoogle ScholarCrossref
21.
Ammori  BJ , Vezakis  A , Davides  D , Martin  IG , Larvin  M , McMahon  MJ .  Laparoscopic cholecystectomy in morbidly obese patients.   Surg Endosc. 2001;15(11):1336-1339. doi:10.1007/s004640000019 PubMedGoogle ScholarCrossref
22.
Coupaye  M , Calabrese  D , Sami  O , Msika  S , Ledoux  S .  Evaluation of incidence of cholelithiasis after bariatric surgery in subjects treated or not treated with ursodeoxycholic acid.   Surg Obes Relat Dis. 2017;13(4):681-685. doi:10.1016/j.soard.2016.11.022 PubMedGoogle ScholarCrossref
23.
Uy  MC , Talingdan-Te  MC , Espinosa  WZ , Daez  ML , Ong  JP .  Ursodeoxycholic acid in the prevention of gallstone formation after bariatric surgery: a meta-analysis.   Obes Surg. 2008;18(12):1532-1538. doi:10.1007/s11695-008-9587-7 PubMedGoogle ScholarCrossref
24.
Miller  K , Hell  E , Lang  B , Lengauer  E .  Gallstone formation prophylaxis after gastric restrictive procedures for weight loss: a randomized double-blind placebo-controlled trial.   Ann Surg. 2003;238(5):697-702. doi:10.1097/01.sla.0000094305.77843.cf PubMedGoogle ScholarCrossref
25.
Wudel  LJ  Jr , Wright  JK , Debelak  JP , Allos  TM , Shyr  Y , Chapman  WC .  Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study.   J Surg Res. 2002;102(1):50-56. doi:10.1006/jsre.2001.6322 PubMedGoogle ScholarCrossref
26.
Williams  C , Gowan  R , Perey  BJ .  A double-blind placebo-controlled trial of ursodeoxycholic acid in the prevention of gallstones during weight loss after vertical banded gastroplasty.   Obes Surg. 1993;3(3):257-259. doi:10.1381/096089293765559278 PubMedGoogle ScholarCrossref
27.
Abdallah  E , Emile  SH , Elfeki  H ,  et al.  Role of ursodeoxycholic acid in the prevention of gallstone formation after laparoscopic sleeve gastrectomy.   Surg Today. 2017;47(7):844-850. doi:10.1007/s00595-016-1446-x PubMedGoogle ScholarCrossref
28.
van de Heijning  BJ , van de Meeberg  PC , Portincasa  P ,  et al.  Effects of ursodeoxycholic acid therapy on in vitro gallbladder contractility in patients with cholesterol gallstones.   Dig Dis Sci. 1999;44(1):190-196. doi:10.1023/A:1026635124115 PubMedGoogle ScholarCrossref
29.
Guarino  MP , Cong  P , Cicala  M , Alloni  R , Carotti  S , Behar  J .  Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones.   Gut. 2007;56(6):815-820. doi:10.1136/gut.2006.109934 PubMedGoogle ScholarCrossref
30.
Jazrawi  RP , de Caestecker  JS , Goggin  PM ,  et al.  Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid.   Gastroenterology. 1994;106(1):134-142. doi:10.1016/S0016-5085(94)94899-2 PubMedGoogle ScholarCrossref
31.
Paumgartner  G , Beuers  U .  Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.   Hepatology. 2002;36(3):525-531. doi:10.1053/jhep.2002.36088 PubMedGoogle ScholarCrossref
32.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle ScholarCrossref
33.
Oken  MM , Creech  RH , Tormey  DC ,  et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group.   Am J Clin Oncol. 1982;5(6):649-655. doi:10.1097/00000421-198212000-00014 PubMedGoogle ScholarCrossref
34.
Bortoff  GA , Chen  MY , Ott  DJ , Wolfman  NT , Routh  WD .  Gallbladder stones: imaging and intervention.   Radiographics. 2000;20(3):751-766. doi:10.1148/radiographics.20.3.g00ma16751 PubMedGoogle ScholarCrossref
35.
Sugerman  HJ , Brewer  WH , Shiffman  ML ,  et al.  A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass–induced rapid weight loss.   Am J Surg. 1995;169(1):91-96. doi:10.1016/S0002-9610(99)80115-9 PubMedGoogle ScholarCrossref
36.
Inoue  K , Fuchigami  A , Higashide  S ,  et al.  Gallbladder sludge and stone formation in relation to contractile function after gastrectomy: a prospective study.   Ann Surg. 1992;215(1):19-26. doi:10.1097/00000658-199201000-00002 PubMedGoogle ScholarCrossref
37.
Sakamaki  K , Kamiura  T , Morita  Y ,  et al.  Current practice on multiplicity adjustment and sample size calculation in multi-arm clinical trials: an industry survey in Japan.   Ther Innov Regul Sci. 2016;50(6):846-852. doi:10.1177/2168479016651660 PubMedGoogle ScholarCrossref
38.
Boerlage  TCC , Haal  S , Maurits de Brauw  L ,  et al.  Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial).   BMC Gastroenterol. 2017;17(1):164. doi:10.1186/s12876-017-0674-x PubMedGoogle ScholarCrossref
39.
Park  YH , Park  SJ , Jang  JY ,  et al.  Changing patterns of gallstone disease in Korea.   World J Surg. 2004;28(2):206-210. doi:10.1007/s00268-003-6879-x PubMedGoogle ScholarCrossref
40.
Kim  KH , Park  DJ , Park  YS , Ahn  SH , Park  DJ , Kim  HH .  Actual 5-year nutritional outcomes of patients with gastric cancer.   J Gastric Cancer. 2017;17(2):99-109. doi:10.5230/jgc.2017.17.e12 PubMedGoogle ScholarCrossref
41.
Warttig  S , Ward  S , Rogers  G ; Guideline Development Group.  Diagnosis and management of gallstone disease: summary of NICE guidance.   BMJ. 2014;349:g6241. doi:10.1136/bmj.g6241 PubMedGoogle ScholarCrossref
42.
Tomida  S , Abei  M , Yamaguchi  T ,  et al.  Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: a cohort analysis.   Hepatology. 1999;30(1):6-13. doi:10.1002/hep.510300108PubMedGoogle ScholarCrossref
43.
Hempfling  W , Dilger  K , Beuers  U .  Systematic review: ursodeoxycholic acid—adverse effects and drug interactions.   Aliment Pharmacol Ther. 2003;18(10):963-972. doi:10.1046/j.1365-2036.2003.01792.xPubMedGoogle ScholarCrossref
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