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Effect of Early Surgery vs Endoscopy-First Approach on Pain in Patients With Chronic PancreatitisThe ESCAPE Randomized Clinical Trial

Educational Objective
To understand treatment options for chronic pancreatitis.
1 Credit CME
Key Points

Question  For patients with painful chronic pancreatitis, is early surgery more effective than the endoscopy-first approach in reducing pain?

Findings  In this randomized clinical trial that included 88 patients with obstructive painful chronic pancreatitis, early surgery compared with an endoscopy-first approach resulted in significantly less pain over 18 months (area under the curve, 37 vs 49 points measured with the Izbicki pain score (range, 0-100 [increasing score indicates more pain severity]).

Meaning  Although early surgery resulted in less pain over 18 months, because of study limitations, further research is needed to assess persistence of differences over time, as well as to replicate the study findings.

Abstract

Importance  For patients with painful chronic pancreatitis, surgical treatment is postponed until medical and endoscopic treatment have failed. Observational studies have suggested that earlier surgery could mitigate disease progression, providing better pain control and preserving pancreatic function.

Objective  To determine whether early surgery is more effective than the endoscopy-first approach in terms of clinical outcomes.

Design, Setting, and Participants  The ESCAPE trial was an unblinded, multicenter, randomized clinical superiority trial involving 30 Dutch hospitals participating in the Dutch Pancreatitis Study Group. From April 2011 until September 2016, a total of 88 patients with chronic pancreatitis, a dilated main pancreatic duct, and who only recently started using prescribed opioids for severe pain (strong opioids for ≤2 months or weak opioids for ≤6 months) were included. The 18-month follow-up period ended in March 2018.

Interventions  There were 44 patients randomized to the early surgery group who underwent pancreatic drainage surgery within 6 weeks after randomization and 44 patients randomized to the endoscopy-first approach group who underwent medical treatment, endoscopy including lithotripsy if needed, and surgery if needed.

Main Outcomes and Measures  The primary outcome was pain, measured on the Izbicki pain score and integrated over 18 months (range, 0-100 [increasing score indicates more pain severity]). Secondary outcomes were pain relief at the end of follow-up; number of interventions, complications, hospital admissions; pancreatic function; quality of life (measured on the 36-Item Short Form Health Survey [SF-36]); and mortality.

Results  Among 88 patients who were randomized (mean age, 52 years; 21 (24%) women), 85 (97%) completed the trial. During 18 months of follow-up, patients in the early surgery group had a lower Izbicki pain score than patients in the group randomized to receive the endoscopy-first approach group (37 vs 49; between-group difference, −12 points [95% CI, −22 to −2]; P = .02). Complete or partial pain relief at end of follow-up was achieved in 23 of 40 patients (58%) in the early surgery vs 16 of 41 (39%)in the endoscopy-first approach group (P = .10). The total number of interventions was lower in the early surgery group (median, 1 vs 3; P < .001). Treatment complications (27% vs 25%), mortality (0% vs 0%), hospital admissions, pancreatic function, and quality of life were not significantly different between early surgery and the endoscopy-first approach.

Conclusions and Relevance  Among patients with chronic pancreatitis, early surgery compared with an endoscopy-first approach resulted in lower pain scores when integrated over 18 months. However, further research is needed to assess persistence of differences over time and to replicate the study findings.

Trial Registration  ISRCTN Identifier: ISRCTN45877994

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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

Corresponding Author: Marja A. Boermeester, MD, PhD, Department of Surgery, Amsterdam UMC, location AMC, Meibergdreef 9, Ste G4-132.1, 1105AZ Amsterdam, the Netherlands (m.a.boermeester@amsterdamumc.nl).

Accepted for Publication: December 4, 2019.

Author Contributions: Dr Boermeester 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.

Dr Issa and Mr Kempeneers contributed equally as co–first authors.

Concept and design: Issa, Bruno, Fockens, Ahmed Ali, Busch, Dejong, van Eijck, van Goor, Nieuwenhuijs, Witteman, Besselink, van Hooft, Van Santvoort, Dijkgraaf, Boermeester.

Acquisition, analysis, or interpretation of data: Issa, Kempeneers, Bruno, Fockens, Poley, Ahmed Ali, Bollen, Busch, Dejong, van Duijvendijk, van Dullemen, van Eijck, van Goor, Hadithi, Haveman, Keulemans, Nieuwenhuijs, Poen, Tan, Thijs, Timmer, Witteman, Besselink, van Hooft, Van Santvoort, Dijkgraaf, Boermeester.

Drafting of the manuscript: Issa, Kempeneers, Bruno, Ahmed Ali, van Eijck, Nieuwenhuijs, van Hooft, Van Santvoort.

Critical revision of the manuscript for important intellectual content: Issa, Kempeneers, Bruno, Fockens, Poley, Ahmed Ali, Bollen, Busch, Dejong, van Duijvendijk, van Dullemen, van Eijck, van Goor, Hadithi, Haveman, Keulemans, Nieuwenhuijs, Poen, Tan, Thijs, Timmer, Witteman, Besselink, van Hooft, Van Santvoort, Dijkgraaf, Boermeester.

Statistical analysis: Issa, Kempeneers, Ahmed Ali, Van Santvoort, Dijkgraaf, Boermeester.

Obtained funding: Issa, Ahmed Ali, Van Santvoort, Dijkgraaf, Boermeester.

Administrative, technical, or material support: Issa, Kempeneers, Ahmed Ali, Dejong, van Goor, Poen, Timmer, Besselink, van Hooft, Van Santvoort.

Supervision: Issa, Bruno, Poley, Ahmed Ali, Busch, Dejong, van Duijvendijk, van Goor, Haveman, Nieuwenhuijs, Tan, Witteman, Besselink, van Hooft, Van Santvoort, Boermeester.

Conflict of Interest Disclosures: Dr Ahmed Ali reports receipt of grants from ZonMW (governmental agency, nonprofit, Ministry of Health), MLDS (nongovernmental organization, national gastrointestinal disease association, nonprofit), and Alvleeskliervereniging (patient association of pancreatic disease, nongovernmental organization, nonprofit) during the conduct of the study. Dr Boermeester reports receipt of grants from Mylan, Acelity/KCI, Johnson & Johnson, Bard, New Compliance, and Alvleeskliervereniging; and other from Acelity/KCI (speaker, instructor, advisory board), Johnson & Johnson (speaker and advisory board), Bard (speaker), Gore (speaker and instructor), and Smith & Nephew outside the submitted work. Dr Bruno reports receipt of grants for investigator-initiated studies from Cook Medical, Pentax Medical, 3M, and Mylan; grants for industry and investigator-initiated studies from Boston Scientific; and personal fees for consultancies and lectures from Boston Scientific, from Cook Medical, Pentax Medical, 3M, and Mylan outside the submitted work. Dr Fockens reports receipt of grants from Boston Scientific and personal fees from Olympus, Cook, and Ethicon Endosurgery outside the submitted work. Dr Poley reports receipt of personal fees and other from Cook Endoscopy, Boston Scientific, and Pentax outside the submitted work. Dr van Hooft reports receipt of grants from Cook Medical and Abbott and personal fees from Boston Scientific outside the submitted work. No other disclosures were reported.

Funding/Support: The ESCAPE trial was funded by grants from the Netherlands Organization for Health Research and Development (ZonMw; 17110216), and the Dutch Digestive Diseases Foundation (WO10-21, Maag Lever Darm Stichting).

Role of the Funder/Sponsor: The Netherlands Organization for Health Research and Development and the Dutch Digestive Diseases Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: None of the collaborators received compensation for their work for the ESCAPE trial. Department of Gastroenterology, Albert Schweitzer Hospital Dordrecht: Pieter Honkoop, MD, PhD; and Annemieke Y. Thijssen, MD, PhD. Department of Internal Medicine, Alrijne Hospital Leiderdorp: Tessa Kooistra, MD, PhD. Department of Gastroenterology, Amsterdam University Medical Centers, location AMC: Sebastiaan Balkema, MD; Noor Bekkali, MD, PhD; Karam S. Boparai, MD, PhD; Liesbeth M. Kager, MD, PhD; Jaap J. Kloek, MD, PhD; and R. Bart Takkenberg, MD, PhD. Department of Surgery, Amsterdam University Medical Centers, location AMC: Dirk J. Gouma, MD, PhD; Thomas M. van Gulik, MD, PhD; and Willem A. Bemelman, MD, PhD. Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Amsterdam University Medical Centers, location AMC: A. H. (Koos) Zwinderman, PhD. Department of Gastroenterology, Amphia Hospital Breda: Alexander G. L. Bodelier, MD, PhD; and Tom C. J. Seerden, MD, PhD. Department of Gastroenterology, Canisius Wilhelmina Hospital Nijmegen: Conny van Enckevort, MD; and Nienke van Gils, MD. Department of Gastroenterology, Catharina Hospital Eindhoven: Erik Schoon, MD, PhD. Department of Gastroenterology, Deventer Hospital: Lauran Vogelaar, MD, PhD; and Roland S. de Vries, MD. Department of Gastroenterology, Diakonessenhuis Utrecht: Annet M. Voorburg, MD, PhD. Department of Surgery, Elisabeth-Tweesteden Hospital Tilburg: Joos Heisterkamp, MD, PhD. Department of Gastroenterology, Erasmus Medical Center Rotterdam: Geert Bezemer, MD, PhD; Henri Braat, MD, PhD; Paul Didden, MD, PhD; Neda Farahani, MD, PhD; Hajo J. Flink, MD, PhD; Arjun D. Koch, MD, PhD; Cindy Postma, MD, PhD; Paul G. van Putten, MD, PhD; Jurriën G. P. Reijnders, MD, PhD; Robert Roomer, MD, PhD; and Ubbo Wiersema, MD, PhD. Department of Gastroenterology, Gelderse Vallei Hospital Ede: G. Lieneke Homans, MS; Wout G. N. Mares, MD; and Ruby Meiland, MD, PhD. Department of Gastroenterology, Gelre Hospital Apeldoorn: G. Willemien Erkelens, MD, PhD; Hans van Maanen; and Gudrun Muller, MD. Department of Gastroenterology, Haaglanden Medical Center: Erwin van Geenen, MD, PhD; and Lars E. Perk, MD. Department of Internal Medicine, Ijsselland Hospital Capelle a/d Ijssel: Johan de Raaf, MD. Department of Gastroenterology, Isala Hospitals Zwolle: Karin Fransen, MD, PhD; Reinier Hoedemaker, MD; Maarten A. C. Meijssen, MD, PhD; and Dorien Oude Hergelink, MD. Department of Gastroenterology, Jeroen Bosch Hospital ‘s Hertogenbosch: Ivo P. van Munster, MD, PhD; and Tessa E. H. Römkes, MD, PhD. Department of Surgery, Leiden University Medical Center: Andries E. Braat, MD, PhD; and A. F. M. (Sandro) Schaapherder, MD, PhD. Department of Gastroenterology, Maasstad Ziekenhuis Rotterdam: Frank J. G. M. Kubben, MD, PhD. Department of Gastroenterology, Maastricht University Medical Center: Chantal Hoge, MD; and Ad Masclee, MD, PhD. Department of Surgery, Maastricht University Medical Center: Laurents P. S. Stassen, MD, PhD. Department of Gastroenterology, Meander Medical Center Amersfoort: Menno A. Brink, MD, PhD; and Lotte van Vlerken, MD, PhD. Department of Gastroenterology, Medisch Spectrum Twente Enschede: Jeroen J. Kolkman, MD, PhD; and Niels G. Venneman, MD, PhD. Department of Gastroenterology, Noordwest ziekenhuisgroep Alkmaar: A. P. J. (Lex) Houdijk, MD, PhD; and Bas van der Spek, MD, PhD. Department of Gastroenterology, OLVG Amsterdam: Jeroen M. Jansen, MD, PhD; and Olle The, MD, PhD. Department of Surgery, OLVG Amsterdam: Michael F. Gerhards, MD, PhD. Department of Surgery, Radboud University Medical Center Nijmegen: Hein G. Gooszen, MD, PhD. Department of Anesthesiology, Radboud University Medical Center Nijmegen: Oliver Wilder-Smith, MD, PhD. Department of Gastroenterology, Reinier de Graaf Groep Hospital Delft: Jildou Hoekstra, MD, PhD; and Daniëlle F. G. M. Josemanders, MD. Department of Gastroenterology, Rijnstate Hospital Arnhem: B. W. Marcel Spanier, MD, PhD. Department of Gastroenterology, Slingeland Hospital Doetichem: Sybrand Y. de Boer, MD, PhD; and Edith de Vries, MS. Department of Gastroenterology, St Antonius Nieuwegein: Abdulbaqi Al-toma, MD, PhD; Bert van Ramshorst, MD, PhD; and Bas L. A. M. Weusten, MD, PhD. Department of Surgery, St Antonius Nieuwegein: Djamila Boerma, MD, PhD. Department of Gastroenterology, University Medical Center Groningen: A. (Rina) Bijlsma, MD; Eleonora A. M. Festen, MD, PhD; Ilona Kerkhof, MD, PhD; Jan H. Kleibeuker, MD, PhD; and Eva Kouw, MD. Department of Surgery, University Medical Center Groningen: H. Sijbrand Hofker, MD; and R. Ploeg, MD. Department of Anesthesiology, University Medical Center Groningen: Ulrich Beese, MD, PhD. Department of Gastroenterology, University Medical Center Utrecht: Peter D. Siersema, MD, PhD; and Frank P. Vleggaar, MD, PhD. Department of Surgery, University Medical Center Utrecht: I. Quintus Molenaar, MD, PhD. Department of Gastroenterology, Ziekenhuis Groep Twente Almelo: Huseyin Aktas, MD, PhD; and Iris Guchelaar, MD.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We would like to thank all participants and their families. We thank Anneke Roeterdink, BS; Bernadette Schutijser, MS; Steven Groeneveld, BS; Ellen Laluan, BS; Margot van der Hoek, BS; and Vanita Mathura, BS (Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, the Netherlands) for their help as study research nurse/assistants and all the medical and nursing staff at the participating centers. The study research nurses and assistants received financial compensation for their work.

References
1.
Ammann  RW, Muellhaupt  B.  The natural history of pain in alcoholic chronic pancreatitis.  Gastroenterology. 1999;116(5):1132-1140. doi:10.1016/S0016-5085(99)70016-8PubMedGoogle ScholarCrossref
2.
Gardner  TB, Kennedy  AT, Gelrud  A,  et al.  Chronic pancreatitis and its effect on employment and health care experience: results of a prospective American multicenter study.  Pancreas. 2010;39(4):498-501. doi:10.1097/MPA.0b013e3181c5c693PubMedGoogle ScholarCrossref
3.
Drewes  AM, Bouwense  SAW, Campbell  CM,  et al; Working group for the International (IAP–APA–JPS–EPC) Consensus Guidelines for Chronic Pancreatitis.  Guidelines for the understanding and management of pain in chronic pancreatitis.  Pancreatology. 2017;17(5):720-731. doi:10.1016/j.pan.2017.07.006PubMedGoogle ScholarCrossref
4.
Forsmark  CE.  Management of chronic pancreatitis.  Gastroenterology. 2013;144(6):1282-1291 e3. doi:10.1053/j.gastro.2013.02.008PubMedGoogle ScholarCrossref
5.
Löhr  JM, Dominguez-Munoz  E, Rosendahl  J,  et al; HaPanEU/UEG Working Group.  United European gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU).  United European Gastroenterol J. 2017;5(2):153-199. doi:10.1177/2050640616684695PubMedGoogle ScholarCrossref
6.
Cahen  DL, Gouma  DJ, Laramée  P,  et al.  Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis.  Gastroenterology. 2011;141(5):1690-1695. doi:10.1053/j.gastro.2011.07.049PubMedGoogle ScholarCrossref
7.
Clarke  B, Slivka  A, Tomizawa  Y,  et al.  Endoscopic therapy is effective for patients with chronic pancreatitis.  Clin Gastroenterol Hepatol. 2012;10(7):795-802. doi:10.1016/j.cgh.2011.12.040PubMedGoogle ScholarCrossref
8.
Nealon  WH, Matin  S.  Analysis of surgical success in preventing recurrent acute exacerbations in chronic pancreatitis.  Ann Surg. 2001;233(6):793-800. doi:10.1097/00000658-200106000-00009PubMedGoogle ScholarCrossref
9.
Cahen  DL, Gouma  DJ, Nio  Y,  et al.  Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis.  N Engl J Med. 2007;356(7):676-684. doi:10.1056/NEJMoa060610PubMedGoogle ScholarCrossref
10.
Ahmed Ali  U, Nieuwenhuijs  VB, van Eijck  CH,  et al; Dutch Pancreatitis Study Group.  Clinical outcome in relation to timing of surgery in chronic pancreatitis: a nomogram to predict pain relief.  Arch Surg. 2012;147(10):925-932. doi:10.1001/archsurg.2012.1094PubMedGoogle Scholar
11.
Ahmed Ali  U, Pahlplatz  JM, Nealon  WH, van Goor  H, Gooszen  HG, Boermeester  MA.  Endoscopic or surgical intervention for painful obstructive chronic pancreatitis.  Cochrane Database Syst Rev. 2012;1:CD007884. doi:10.1002/14651858.CD007884.pub2PubMedGoogle Scholar
12.
Ke  N, Jia  D, Huang  W,  et al.  Earlier surgery improves outcomes from painful chronic pancreatitis.  Medicine (Baltimore). 2018;97(19):e0651. doi:10.1097/MD.0000000000010651PubMedGoogle Scholar
13.
Maartense  S, Ledeboer  M, Bemelman  WA, Ringers  J, Frolich  M, Masclee  AA.  Effect of surgery for chronic pancreatitis on pancreatic function: pancreatico-jejunostomy and duodenum-preserving resection of the head of the pancreas.  Surgery. 2004;135(2):125-130. doi:10.1016/j.surg.2003.09.004PubMedGoogle ScholarCrossref
14.
Ahmed Ali  U, Issa  Y, Bruno  MJ,  et al; Dutch Pancreatitis Study Group.  Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial.  BMC Gastroenterol. 2013;13:49. doi:10.1186/1471-230X-13-49PubMedGoogle ScholarCrossref
15.
Partington  PF, Rochelle  RE.  Modified Puestow procedure for retrograde drainage of the pancreatic duct.  Ann Surg. 1960;152:1037-1043. doi:10.1097/00000658-196012000-00015PubMedGoogle ScholarCrossref
16.
Frey  CF, Smith  GJ.  Description and rationale of a new operation for chronic pancreatitis.  Pancreas. 1987;2(6):701-707. doi:10.1097/00006676-198711000-00014PubMedGoogle ScholarCrossref
17.
Beger  HG, Krautzberger  W, Bittner  R, Büchler  M, Limmer  J.  Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis.  Surgery. 1985;97(4):467-473.PubMedGoogle Scholar
18.
Dumonceau  JM, Tringali  A, Papanikolaou  IS,  et al.  Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline—updated October 2017.  Endoscopy. 2018;50(9):910-930. doi:10.1055/a-0659-9864PubMedGoogle ScholarCrossref
19.
World Health Organization.  Cancer Pain Relief. Geneva, Switzerland: World Health Organization; 1986.
20.
Izbicki  JR, Bloechle  C, Broering  DC, Kuechler  T, Broelsch  CE.  Longitudinal V-shaped excision of the ventral pancreas for small duct disease in severe chronic pancreatitis: prospective evaluation of a new surgical procedure.  Ann Surg. 1998;227(2):213-219. doi:10.1097/00000658-199802000-00010PubMedGoogle ScholarCrossref
21.
Müller  MW, Friess  H, Martin  DJ, Hinz  U, Dahmen  R, Büchler  MW.  Long-term follow-up of a randomized clinical trial comparing Beger with pylorus-preserving Whipple procedure for chronic pancreatitis.  Br J Surg. 2008;95(3):350-356. doi:10.1002/bjs.5960PubMedGoogle ScholarCrossref
22.
Brazier  JE, Harper  R, Jones  NM,  et al.  Validating the SF-36 health survey questionnaire: new outcome measure for primary care.  BMJ. 1992;305(6846):160-164. doi:10.1136/bmj.305.6846.160PubMedGoogle ScholarCrossref
23.
Demir  IE, Friess  H, Ceyhan  GO.  Neural plasticity in pancreatitis and pancreatic cancer.  Nat Rev Gastroenterol Hepatol. 2015;12(11):649-659. doi:10.1038/nrgastro.2015.166PubMedGoogle ScholarCrossref
24.
Díte  P, Ruzicka  M, Zboril  V, Novotný  I.  A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis.  Endoscopy. 2003;35(7):553-558. doi:10.1055/s-2003-40237PubMedGoogle ScholarCrossref
25.
Issa  Y, van Santvoort  HC, Fockens  P,  et al; Collaborators.  Diagnosis and treatment in chronic pancreatitis: an international survey and case vignette study.  HPB (Oxford). 2017;19(11):978-985. doi:10.1016/j.hpb.2017.07.006PubMedGoogle ScholarCrossref
26.
Nealon  WH, Thompson  JC.  Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression: a longitudinal prospective analysis of the modified puestow procedure.  Ann Surg. 1993;217(5):458-466. doi:10.1097/00000658-199305010-00005PubMedGoogle ScholarCrossref
27.
Lamme  B, Boermeester  MA, Straatsburg  IH,  et al.  Early versus late surgical drainage for obstructive pancreatitis in an experimental model.  Br J Surg. 2007;94(7):849-854. doi:10.1002/bjs.5722PubMedGoogle ScholarCrossref
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