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Figure 1.  Flow of Patient Enrollment, Randomization, and Follow-up
Flow of Patient Enrollment, Randomization, and Follow-up

FAS indicates full analysis set; PPS, per-protocol set, and UDCA, ursodeoxycholic acid.

Figure 2.  Cumulative Probability of Gallstone Formation According to Ursodeoxycholic Acid (UDCA) Dosage (Full Analysis Set)
Cumulative Probability of Gallstone Formation According to Ursodeoxycholic Acid (UDCA) Dosage (Full Analysis Set)

Tic marks indicate censored data.

Table 1.  Baseline Characteristics of Patientsa
Baseline Characteristics of Patientsa
Table 2.  Primary Outcome: Proportion of Patients Developing Gallstones Within 12 Months After Gastrectomy
Primary Outcome: Proportion of Patients Developing Gallstones Within 12 Months After Gastrectomy
Table 3.  Adverse Drug Reactionsa
Adverse Drug Reactionsa
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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    Original Investigation
    June 17, 2020

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

    Author Affiliations
    • 1Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
    • 2Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
    • 3Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
    • 4Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
    • 5Department of Surgery, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea
    • 6Department of Surgery, Kyoungpook National University Chilgok Hospital, Daegu, Republic of Korea
    • 7Department of Surgery, Ajou University Hospital, Suwon, Republic of Korea
    • 8Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea
    • 9Department of Surgery, Boramae Medical Center, Seoul, Republic of Korea
    • 10Department of Surgery, Yonsei University Severance Hospital, Seoul, Republic of Korea
    • 11Department of Surgery, Catholic University of Seoul St Mary’s Hospital, Seoul, Republic of Korea
    • 12Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
    • 13Department of Surgery, Chungnam National University Hospital, Daejeon, Republic of Korea
    • 14Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
    • 15Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
    • 16Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
    • 17Department of Surgery and Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
    JAMA Surg. Published online June 17, 2020. doi:10.1001/jamasurg.2020.1501
    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

    Introduction

    The incidence of gallstones, which has been reported to be higher in patients who have undergone gastrectomy than in the general population, varies from 6.1% to 25.7% depending on the report.1-4 Symptomatic gallstone disease accounts for approximately 5% of gallstone cases.2,3,5 Despite the small fraction of symptomatic gallstones, cholecystectomy is more challenging after gastrectomy because of an increased risk of conversion, bile duct injuries, and longer operating times.6,7 An endoscopic approach is also more challenging owing to difficult intubation and cannulation associated with altered anatomy and a high failure rate.8 Therefore, preventing gallstone formation after gastrectomy is needed to avoid burdensome surgical procedures.

    Gallstones after bariatric surgery are mainly caused by rapid weight loss,9 whereas gallstones after gastrectomy in patients with gastric cancer arise from various mechanisms. Vagal nerve resection during gastrectomy has a major influence on the gallbladder’s contractile ability. Previous studies have shown that gastrectomy abolishes phasic contraction of the gallbladder, increasing the propensity for bile salt precipitation and gallstone formation.10,11 Another proposed mechanism is lymph node dissection, specifically in the hepatoduodenal ligament, which results in the dissection of nerve fibers near the gallbladder.12 In addition, nonphysiological reconstruction of the gastrointestinal tract13,14 and an altered response to and secretion of cholecystokinin15 are possible mechanisms of gallstone formation. Cholestasis due to decreased gallbladder contraction16 for various reasons can be summarized as the main mechanism of gallstone formation after gastrectomy.

    There have been several studies of prophylactic cholecystectomy during gastrectomy owing to the high incidence of gallstone formation, especially in patients with obesity undergoing bariatric surgery. However, the benefit of concomitant prophylactic cholecystectomy remains unclear because most patients with gallstones are asymptomatic.4,17-19 Furthermore, there is increasing evidence that cholecystectomy has abnormal metabolic consequences, including nonalcoholic fatty liver disease,20 and concomitant cholecystectomy during bariatric surgery can be more difficult and may be associated with a higher incidence of complications.21 Thus, prophylactic cholecystectomy for future gallstones is not justified. However, some studies have revealed that ursodeoxycholic acid (UDCA) administration can prevent gallstone formation after bariatric surgery.22-27 Ursodeoxycholic acid can improve gallbladder contractility28 by decreasing cholesterol content in the plasma membrane of muscle cells29 and can stimulate biliary secretion, leading to relieved cholestasis.30 Moreover, other mechanisms of action, such as protection of damaged cholangiocytes and stimulation of detoxification of hydrophobic bile acids, may contribute to UDCA’s effect.31 Therefore, UDCA can be a good and safe alternative to prophylactic cholecystectomy.

    Thus, it is necessary to verify the efficacy of UDCA for patients who have undergone gastrectomy owing to gastric cancer. However, to our knowledge, there have been few studies of UDCA regarding the prevention of gallstone formation after gastrectomy. This multicenter, randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of UDCA in preventing gallstone formation after gastrectomy in patients with gastric cancer.

    Methods
    Study Design

    This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in 12 institutions in Korea. Participants were enrolled between May 26, 2015, and January 9, 2017; follow-up ended January 8, 2018. All participants, including those receiving adjuvant chemotherapy, provided written informed consent before enrollment. The study protocol was approved by the institutional review boards at all of the participating institutions (Seoul National University Bundang Hospital, Asan Medical Center, Pusan National University Yangsan Hospital, Chonnam National University Hwasun Hospital, Kyoungpook National University Chilgok Hospital, Ajou University Hospital, National Cancer Center, Boramae Medical Center, Yonsei University Severance Hospital, Catholic University Seoul St. Mary’s Hospital, Samsung Medical Center, and Chungnam National University Hospital; trial protocol in Supplement 1) and was conducted in accordance with provisions of the Declaration of Helsinki.32 An independent data and safety monitoring board reviewed the progress of the study.

    Study Population

    Patients 19 years of age or older, with a diagnosis of gastric cancer, who underwent total, distal, or proximal gastrectomy were eligible to participate. Before taking part in the trial, all of the surgeons had performed more than 200 gastrectomies, and their respective hospitals regularly performed at least 100 gastrectomies per year. The hepatic branch of the vagus nerve was routinely removed during full lymph node dissection. Patients with pathological stage II or higher gastric cancer received adjuvant chemotherapy. Patients were thoroughly monitored for the administration of chemotherapeutic agents to assess any safety issues. Major inclusion criteria included D1+ or D2 lymph node dissection, an Eastern Cooperative Oncology Group performance status of 1 or lower,33 and a patient life expectancy of at least 3 months. Major exclusion criteria were biliary infection or obstruction, a previous cholecystectomy, preexisting gallstones, pylorus-preserving gastrectomy, active gastrointestinal inflammation (ulcer, pancreatitis, colitis, or enteritis), liver dysfunction, body mass index (calculated as weight in kilograms divided by height in meters squared) greater than 37, uncontrolled type 2 diabetes, hypersensitivity to bile acid or UDCA, and cancers of another organ within 5 years prior to enrollment.

    Randomization

    Individuals who met all inclusion criteria and who had no exclusion criteria at screening were randomly assigned (by the investigators) to receive 300 mg of UDCA, 600 mg of UDCA, or placebo at a ratio of 1:1:1, after written informed consent (from participants) within 2 weeks after gastrectomy. An independent statistician generated a random allocation sequence based on stratification factors; thus, a stratified block randomization method was used to randomly assign participants at each study site. The proc plan procedure in SAS, version 9.4 (SAS Institute Inc) (stratification factors were lymph node dissection range and type of gastrectomy) was used for randomization at each site, and participants were assigned by the investigators via an interactive web-response system. Neither participants nor relevant investigators were aware of these assignments.

    Interventions

    After randomization, 300 mg of UDCA, 600 mg of UDCA, and placebo were administered daily for 52 weeks. To maintain blindness, all capsules were made in the same shape and administered twice daily after breakfast and dinner (one 300-mg capsule once daily and 1 placebo capsule once daily for the 300-mg group, one 300-mg capsule twice daily for the 600-mg group, and 1 placebo capsule twice daily for the placebo group). Drug adherence was checked at every visit. If adherence was 85% or less, the investigator retrained the participant.

    At screening, all participants underwent abdominal ultrasonography to discover preexisting gallstones, if results were not available from the previous 6 weeks. Abdominal ultrasonography was then performed every 3 months up to 12 months to confirm gallstone formation. At each visit, participants were evaluated for drug adherence. Any participant with confirmed gallstone formation during treatment was removed from the study at the time of confirmation. Safety assessments were based on adverse events, laboratory test results (hematology, blood chemistry, and urinalysis), physical examinations, and vital signs at each visit.

    Confirmation of gallstone formation was based primarily on ultrasonography results, supplemented by abdominal computed tomography scans. Criteria for gallstone diagnosis by abdominal ultrasonography were as follows: highly reflective echo, posterior acoustic shadowing, and gravitational dependence.34 To ensure reliability of the results of abdominal ultrasonography and computed tomography scans, all images obtained were reevaluated by 3 independent blinded evaluators. The presence of gallstones not visible on computed tomography scans but visible on ultrasonographic images was also determined by these evaluators. Only diagnoses agreed on by 2 or more evaluators were accepted. Biliary sludge visible on computed tomography scans or ultrasonographic images was not regarded as gallstones.

    Outcomes

    The primary end point was the proportion of patients developing gallstones within 12 months after gastrectomy. Adverse drug reactions during the study period were evaluated as the secondary end point.

    Statistical Analysis

    The study was designed to demonstrate that 300 mg or 600 mg of UDCA was superior to placebo regarding gallstone prevention. Assuming that the primary end point was 7% in the UDCA groups35 and 18% in the placebo group,3,36 the minimum sample size necessary to detect a difference with 80% statistical power (α = .05; 2-sided test) was 138 per group (not considering the multiplicity adjustment of α using a fixed-sequence method: 600 mg of UDCA vs placebo, and 300 mg of UDCA vs placebo).37

    Efficacy was evaluated by both the full analysis set (FAS, based on the intention-to-treat principle) and the per-protocol set (PPS); FAS findings were interpreted as the main results. The FAS comprised participants who underwent at least 1 evaluation of gallstone formation after randomization and did not violate the inclusion or exclusion criteria. The PPS comprised participants who completed the trial without any significant protocol deviations that could affect efficacy. Observed-case analysis included those with missing data, which were not imputed for missing values. To determine the superiority of UDCA vs placebo in preventing gallstone formation, sequential multiple testing was performed for each dose group according to the fixed-sequence method: step 1, superiority testing for 600 mg of UDCA vs placebo (5% significance level); step 2, superiority testing for 300 mg of UDCA vs placebo (5% significance level). The step 2 test was performed only if results of the step 1 test were statistically significant. The test in each step used the logistic regression model with treatment group as a factor and with range of lymph node dissections and type of gastrectomy as covariates; test results were presented (by treatment group) as odds ratios and corresponding 95% CIs for participants who developed gallstones within 12 months.

    Data on time to gallstone formation after administration of the study product were analyzed using Kaplan-Meier plots and the Cox proportional hazards regression model, with treatment groups as the factor and with range of lymph node dissections and type of gastrectomy as covariates. Clinical data were collected and validated using the Rave Electronic Data Capture system (Medidata Institute). All statistical analyses were performed with SAS, version 9.4.

    Results
    Study Participants

    A total of 625 patients were identified as eligible for the study from 12 institutions in the Republic of Korea between May 4, 2015, and January 9, 2017; follow-up ended January 8, 2018. After exclusion of 104 patients, including 33 who declined to participate, 521 were randomized (175 received 300 mg of UDCA, 178 received 600 mg of UDCA, and 168 received placebo) (Figure 1). After follow-up, the FAS comprised 151 patients in the 300-mg group, 164 patients in the 600-mg group, and 150 patients in the placebo group. The baseline characteristics for the 3 groups are shown in Table 1 (the results of PPS analysis are shown in eTable 1 in Supplement 2). The 3 groups were equally randomized and did not show any significant differences regarding age, sex, body mass index, smoking, drinking, stage of gastric cancer, and surgical factors.

    Outcomes

    In the FAS (311 men; median age, 56.0 years [interquartile range, 48.0-64.0 years]), the proportions of patients developing gallstones within 12 months after gastrectomy were 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. The odds ratios (vs placebo) 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 (Table 2). The differences in proportions between the 2 UDCA groups compared with the placebo group were significant at −11.4% (95% CI, −18.3% to −4.4%) for the 300-mg group and −12.4% (95% CI, −19.1% to −5.7%) for the 600-mg group (results for the PPS are shown in eTable 2 in Supplement 2). All of the gallstones detected were gallbladder stones. No bile duct or intrahepatic duct stones were detected during the study period.

    The proportions of patients developing gallstones at each time point (3, 6, and 9 months after gastrectomy) are shown in eTable 3 in Supplement 2 (results for the PPS are shown in eTable 4 in Supplement 2). The preventive effects of UDCA on gallstone formation were observed 3 months after administration. Figure 2 indicates the time to gallstone formation after administration of the investigational product and the cumulative probability of gallstone formation with a Kaplan-Meier plot. A Cox proportional hazards regression model revealed hazard ratios (vs placebo) of 0.3 (95% CI, 0.1-0.7) in the 300-mg group and 0.2 (95% CI, 0.1-0.5) in the 600-mg group. In subgroup analysis of patients with a D2 lymph node dissection, the proportions of patients developing gallstones within 12 months were significantly lower in the treatment groups vs placebo group (6 of 85 [7.1%] in the 300-mg group, 4 of 97 [4.1%] in the 600-mg group, and 13 of 86 [15.1%] in the placebo group). Compared with the placebo group, odds ratios for gallstone formation were 0.39 (95% CI, 0.14-1.10; P = .07) in the 300-mg group and 0.23 (95% CI, 0.07-0.74; P = .01) in the 600-mg group. Gallstone complications occurred in 4 patients (1 case of acute cholangitis and 3 of cholecystitis) during the study period, all of whom were in the placebo group.

    Adverse Drug Reactions

    The safety set included 516 patients who received at least 1 dose of investigational product after randomization. No statistically significant differences in the incidence of adverse drug reactions were noted among the 3 groups (Table 3). The most common symptom was nausea (4 of 516 [0.8%]), followed by skin rash (3 of 516 [0.6%]). No serious adverse drug reactions were reported during the study period. Two patients died during the study period: one in the 600-mg group and the other in the placebo group. Both deaths were associated with cancer recurrence, regardless of adverse drug reactions.

    Discussion

    Previous research on UDCA for the prevention of gallstone formation after gastric surgery was performed mostly for patients with obesity who underwent bariatric surgery. There were several randomized clinical trials from the 1990s to 2000s, and results showed that gallstone formation was significantly reduced in the UDCA vs placebo groups.24-26,35 Taken together, these studies indicate that UDCA administration after bariatric surgery can significantly reduce the risk of gallstone formation by approximately 57%.23 However, these studies were limited by small sample sizes and short durations of UDCA administration (mostly 6 months). Two recent studies also revealed the protective effect of UDCA, but both studies had the disadvantage of being retrospective.22,27 To demonstrate the effectiveness of UDCA more clearly, a large-scale randomized clinical trial on the use of UDCA for preventing symptomatic gallstone disease after bariatric surgery has been under way in recent years.38 To our knowledge, our study is the first large-scale randomized clinical study for patients with gastric cancer, and it differs from previous studies in that rapid weight loss is not the main mechanism of gallstone formation. Cholestasis due to decreased gallbladder contraction is considered to be the major mechanism of gallstone formation after gastric cancer surgery.10-16 Therefore, we excluded patients with a body mass index greater than 37 because of the rapid weight loss expected after surgery. Although bariatric surgical procedures include several other types of surgery (ie, vertical banded gastroplasty and gastric bypass surgery) besides gastrectomy, all surgical procedures for patients with gastric cancer are gastrectomies. Therefore, the patients in our study were more uniform. In addition, our study revealed the effectiveness of UDCA by introducing 2 different UDCA dose groups and a longer duration of administration (12 months).

    In our study, gallstone formation was observed in 40 (8.6%) of the 465 patients in the FAS. The age of these patients was similar to that of a previous Korean study,39 but the proportion of male participants in our study was higher (28 of 40 [70.0%]), which is owing to a greater participation by men in our study. Fukagawa et al3 reported that formation of gallstones was observed in 25.7% (173 of 672) of patients who underwent gastrectomy, and 64.7% (112 of 173) developed gallstones within 1 year after gastrectomy. Thus, we planned to administer the trial drug for 1 year, while assuming that most gallstones occur during the early postoperative period. In our study, the incidence of gallstones within 1 year after gastrectomy in the placebo group was 16.7% (25 of 150), which was relatively higher than in previous studies. This result indicates that most gallstones are likely to develop at an early stage after gastrectomy, considering the high incidence in 1 year. Therefore, the planned UDCA treatment duration of 1 year in this study is considered an appropriate design. In addition, we administered UDCA for a longer period than in previous studies,22-27 which typically administered the drug for only 6 months. After gastrectomy, anemia, weight loss, and malnutrition occur most frequently within 1 year after surgery.40 In advanced gastric cancer, adjuvant chemotherapy is performed within 1 year after surgery. Therefore, it is important to prevent gallstones and associated complications for 1 year after surgery.

    Not all gallstones need to be surgically treated. Gallstones requiring surgical treatment are those in patients with symptoms or complications (ie, acute cholecystitis, cholangitis, or gallstone pancreatitis).41 Previous studies have reported that only 4% to 7% of patients with gallstones require treatment.2,3,5 Therefore, it has been suggested that prophylactic cholecystectomy is unnecessary because of the low incidence of complications.4,17 However, despite this low incidence, once gallstone complications occur, there are difficulties with subsequent treatments, such as cholecystectomy6 and endoscopic retrograde cholangiopancreatography.8 Thus, it is necessary to actively consider simple preventive measures, such as UDCA administration, especially for patients with early gastric cancer who are expected to be long-term survivors. In our study, gallstone complications occurred in only 4 patients in the placebo group. Ursodeoxycholic acid may reduce not only the incidence of gallstones but also the number of gallstone complications.

    Limitations

    There are several limitations in this study. First, because of the short study period, we could not confirm how many cholecystectomies were prevented by UDCA therapy; for such confirmation, larger sample sizes and longer observation periods are needed. In addition, it has not been evaluated whether taking UDCA for 1 year affects gallstone formation after 1 year. Our primary end point was the incidence of gallstones within 1 year, but some complications were reported during the short study period. Therefore, further analysis of long-term follow-up data, including the occurrence of gallstones or acute cholecystitis after stopping UDCA treatment, as well as the cost-effectiveness of treatment, may be meaningful. The administration of UDCA may actually reduce the number gallstone complications, such as biliary pain and acute cholecystitis,42 although an investigation of this possibility was not a principal feature of our study design. As a second limitation, this study was conducted in the Republic of Korea, where the incidence of gastric cancer is relatively high, so it may be difficult to generalize the study findings to other regions of the world. However, the mechanism involved in gallstone development after gastrectomy is no different for other racial/ethnic groups, and the efficacy of UDCA in preventing gallstones had already been proven, regardless of race/ethnicity.23 Despite these limitations, our study showed statistically significant efficacy for UDCA against the primary end point in an adequate number of patients.

    Conclusions

    This randomized clinical trial showed that 12 months of UDCA administration significantly reduced the incidence of gallstones after gastrectomy for gastric cancer. All reported adverse reactions were mild and tolerable, as reported in the previous literature.43 Although it is difficult to make any definitive conclusions, we suggest that gallstone formation and its complications may be prevented by the use of UDCA rather than prophylactic cholecystectomy. In the future, studies comprising a larger number of patients with long-term follow-up are needed to confirm whether the use of UDCA can reduce the number of patients undergoing subsequent cholecystectomy.

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    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.

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