Abstract
Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference −2·3, 95% CI −6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. Funding German Research Foundation (DFG).
| Originalsprache | Englisch |
|---|---|
| Zeitschrift | The Lancet |
| Jahrgang | 390 |
| Ausgabenummer | 10099 |
| Seiten (von - bis) | 1027-1037 |
| Seitenumfang | 11 |
| ISSN | 0140-6736 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 09.09.2017 |
Fördermittel
ChroPac was an investigator-initiated trial funded by the German Research Foundation. The funder had no role in trial design, data collection, data analysis, data interpretation, or writing of the report. MKD, FJH, and MWB had full access to all data and had final responsibility for the decision to submit the manuscript for publication. ChroPac is the first randomised controlled trial to compare partial pancreatoduodenectomy with DPPHR for treatment of chronic pancreatitis in a multicentre setting with a pragmatic design. The results showed that DPPHR was not superior to partial pancreatoduodenectomy in terms of the primary endpoint, long-term postoperative quality of life assessed with the EORTC QLQ-C30 and PAN26 questionnaires. The validity of this result was corroborated by several prespecified sensitivity analyses. Significant improvements in scores of global health status/quality of life and pain scales in both groups showed that both procedures were effective in the treatment of chronic pancreatitis. Four of five previous trials comparing DPPHR with partial pancreatoduodenectomy for chronic pancreatitis provided information about quality of life. 11–13,33 Two of these trials 33,34 found that quality-of-life scores were similar for DPPHR and partial pancreatoduodenectomy, thus agreeing with our results. Farkas and colleagues 12 showed a benefit for quality of life in favour of DPPHR during 1 year follow-up after surgery. The initial report of the trial by Izbicki and colleagues 13 showed superiority for DPPHR over partial pancreatoduodenectomy in terms of quality of life, but the long-term results suggested no significant difference between the two procedures. 35,36 In a quantitative summary, the pooled results of the meta-analysis of trials within this report corroborated the finding that DPPHR and partial pancreatoduodenectomy lead to similar quality of life ( appendix ). In line with the results of this study, both a 2016 Cochrane meta-analysis 37 and a network meta-analysis 38 of DPPHR versus partial pancreatoduodenectomy for the treatment of chronic pancreatitis concluded that there were no differences in medium-term or long-term quality of life between the two procedures. Concerning the secondary endpoints, no differences in mortality, morbidity, and new onset of exocrine insufficiency or diabetes were seen between the two interventions. DPPHR resulted in a shorter operating time than partial pancreatoduodenectomy, as shown in previous smaller trials. 12,13,33 However, other secondary outcomes of this trial favoured partial pancreatoduodenectomy, which might influence future clinical decision making. First, patients treated with DPPHR were more frequently readmitted to hospital because of chronic pancreatitis during the 24 month trial. Second, in the partial pancreatoduodenectomy group, no reoperations due to chronic pancreatitis were necessary at more than 6 months after index surgery. Close inspection of the long-term results of previous trials 34–36 comparing partial pancreatoduodenectomy with DPPHR revealed similar patterns, although statistical significance was not attained owing to low sample sizes. Our meta-analysis of reoperations due to chronic pancreatitis in these three trials led to a significant result in favour of partial pancreatoduodenectomy ( appendix ). Thus, partial pancreatoduodenectomy might be the more definitive treatment for patients with chronic pancreatitis. However, in the interpretation it should be noted that the ChroPac trial was not explicitly powered for these secondary endpoints. The findings concerning quality of life at baseline in this trial correlated well with those of other studies in similar patient populations, 39–41 confirming the external validity of our results. Furthermore, the baseline characteristics of the trial population were typical for the intended patient population. Alcohol consumption and smoking were frequent baseline characteristics and were the presumed primary causes of chronic pancreatitis in the trial population. The representative patient population, together with the multicentre, pragmatic trial design, permit wide generalisability of our results. Although surgical intervention has been shown to be superior to endoscopy for the treatment of chronic pancreatitis, 3–5 and there is increasing evidence that early surgery is effective in reduction of pain and preservation of pancreatic function, 42 most patients treated with surgery have undergone previous endoscopic retrograde cholangiopancreatography, and a large proportion have even undergone pancreatic stenting before being referred for surgical treatment. The results of an ongoing Dutch trial 43 comparing early surgery with a step-up approach might shed more light on the importance of early surgery, with potential implications for clinical practice. Regarding pancreatic function, DPPHR and partial pancreatoduodenectomy did not differ significantly in terms of new onset of exocrine insufficiency or diabetes. However, some patients with exocrine or endocrine insufficiency before surgery had functional improvement after surgery. Previous trials 33–36 with sufficient follow-up also showed similar incidences for exocrine and endocrine insufficiency after partial pancreatoduodenectomy and DPPHR. This finding might indicate that progressive parenchymal destruction in chronic pancreatitis, rather than an individual surgical procedure, is mainly responsible for the impairment of pancreatic function. The strength of this trial is its multicentre, randomised, double-blind design, by which systemic bias was reduced to a minimum. Furthermore, clear definition of endpoints, publication of the protocol, and strict assessment assured high-quality data. Nevertheless, some limitations should be considered when interpreting the results. First, although the secondary endpoints were clearly defined, some of them represented complex conditions (eg, diabetes) that could require more intensive assessment. To investigate those complex conditions in detail, laboratory analyses (eg, glycated haemoglobin) or treatment details (eg, dietary treatment, oral medication, insulin therapy) would be of importance. However, such a detailed analysis would have substantially complicated the conduct of this multinational trial. Therefore, clear and transparent but pragmatic definitions for these complex conditions were used because they only represented secondary endpoints. Hence, the conclusions regarding these outcomes have to be judged with consideration of the applied definitions and that the trial was not powered for these endpoints. Second, the aggregation of modifications of the two surgical techniques in the comparison groups ruled out discrimination between the individual techniques. This approach might be considered a limitation, given that most centres focus on one individual modification. However, this issue was debated intensely during protocol development and it was decided that, because none of the individual techniques showed clear superiority over the others, the aim of the ChroPac trial would be to provide a pragmatic comparison of two surgical strategies (DPPHR and partial pancreatoduodenectomy). The results of this trial could form the baseline for further refinement of the decision of which of the two strategies to follow in individual cases (a tailored approach). The incidental detection of pancreatic cancer in 11 (5%) of 226 patients in the mITT population underlines that this disease is not a rare occurrence in this patient population. If pancreatic cancer cannot be ruled out with certainty, partial pancreatoduodenectomy should be done, because it is an adequate oncological treatment and it avoids the need for reoperation. Conversely, in patients with compression or occlusion of the portal vein system, which occurred in 27 (12%) of 224 patients in this trial ( appendix ), DPPHR should be the procedure of choice to avoid major bleeding and other intraoperative complications. In the remaining cases, surgeons can continue their preferred procedure, because both procedures were similarly effective for treatment of chronic pancreatitis. This trial provides evidence on which to base discussion of the harms and benefits of individual strategies with patients. In conclusion, both partial pancreatoduodenectomy and DPPHR were effective in the treatment of chronic head pancreatitis, with no difference in quality of life, mortality, and morbidity between the interventions. Although DPPHR offered advantages with regard to operating time, partial pancreatoduodenectomy might be the more definitive treatment because it was associated with fewer readmissions. For further individualisation of the available techniques, surgeons need to learn more about the specific reason for readmission or reoperation after DPPHR due to ongoing or recurrent chronic pancreatitis, such as stenosis of the common bile duct or pancreatic duct. Future trials should aim to identify subgroups of patients, on the basis of preoperative clinical and imaging characteristics, who will benefit specifically from a particular procedure. Pancreatic surgeons should be competent in both DPPHR and partial pancreatoduodenectomy to be able to offer the optimal treatment on an individual patient basis. Contributors MKD and MWB conceived and designed the trial, supervised trial conduct, participated in data analysis and interpretation, and prepared and wrote the report. FJH participated in trial design, trial conduct, data analysis and interpretation, and prepared and wrote the report. AU, TH, and CD-H managed the trial and contributed to data interpretation and writing of the manuscript. MD, RG, UAW, RS, H-MH, JW, AK, C-DH, AT, TJW, MB, TBe, TBö, MG, US, FT, ALM, and LS participated in patient recruitment and trial conduct. PK participated in patient recruitment, trial design, and trial conduct. CMH participated in patient recruitment and trial conduct and developed the patient information sheet and consent form for the UK arm of the trial. KT was responsible for onsite monitoring. MK and TBr participated in trial design, data analysis, and data interpretation. All authors have proof-read the manuscript. ChroPac Trial Group ChroPac trial coordination: Writing Committee Markus K Diener, Felix J Hüttner (Study Center of the German Surgical Society, SDGC), Markus W Büchler (coordinating investigator); Trial design Markus K Diener, Felix J Hüttner (SDGC), Markus W Büchler (coordinating investigator), Meinhard Kieser, Thomas Bruckner (Institute of Medical Biometry and Informatics, IMBI); Trial management Inga Rossion, Colette Doerr-Harim, Alexandra Kunz, Evelin Hund (SDGC); Serious adverse event management Markus K Diener, Colette Doerr-Harim (SDGC); Data management Ronald Limprecht (IMBI); Analysis Thomas Bruckner, Meinhard Kieser; Steering committee Markus W Büchler, Meinhard Kieser, Hans Jürgen Schlitt (Department of Surgery, University Medical Centre Regensburg, Regensburg, Germany), Joachim Mössner (Department of Gastroenterology, University Hospital Leipzig, Leipzig, Germany), Christoph M Seiler (Department of General Visceral and Vascular Surgery, Josephs-Hospital Warendorf, Warendorf, Germany); Data safety and monitoring board Gabriele Ihorst (Clinical Trials Unit of the Medical Center, University of Freiburg, Freiburg, Germany), Pierluigi Di Sebastiano (Division of Surgical Oncology, SS Annunziata Hospital, Chieti, Italy); Helmut Witzigmann (Department of General, Visceral, and Thoracic Surgery, Municipal Hospital Dresden-Friedrichstadt, Dresden, Germany). ChroPac trial investigators and participating centres (in alphabetical order of location, including patient recruitment numbers) Fritz Klein (Charité, Department of Surgery, Universitätsmedizin Berlin, Berlin, Germany; five patients); Robert Grützmann, Heike Berthold (Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany; 22 patients); Heike Körnlein (Department of General and Visceral Surgery, Klinikum Esslingen, Esslingen, Germany; one patient); Ulrich Hopt, Olivia Sick, Tobias Keck (Department of General and Visceral Surgery, Medical Centre, University of Freiburg, Freiburg, Germany; 19 patients); Lars Ivo Partecke, Sebastian Peters, Markus M Lerch (Department of General, Visceral, Thoracic and Vascular Surgery and Department of Medicine A, Universitätsmedizin Greifswald, Greifswald, Germany; 13 patients); Barbara Maichle, Birgit Erni (Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; 87 patients); Sabine Bunjes-Schmieger, Sarah Igel (Department for General, Visceral, Vascular, and Paediatric Surgery, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg, Germany; four patients); Svenja Stemmle (Department of General, Visceral, Thoracic, and Trauma Surgery, Krankenhaus der Augustinerinnen, Cologne, Germany; four patients); Hans-Michael Hau (Department of Visceral, Transplantation, Thoracic, and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany; 18 patients); John P Neoptolemos, Michael G T Raraty (NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; seven patients); Miha Petric (Department of Abdominal Surgery, University Medical Centre, Ljubljana, Slovenia; nine patients); Marco Niedergethmann, Claudia Schwarzmeier (Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; seven patients); Bernhard Renz, Brigitte Schreib (Department of General, Visceral, Vascular and Transplantation Surgery, University of Munich, Munich, Germany; 16 patients); Wolfgang E Thasler, Michael H Schoenberg (Department of General and Visceral Surgery, Red Cross Hospital Munich, Munich, Germany; four patients); Helmut Friess, Daniel Reim, Güralp O Ceyhan (Department of Surgery, University Hospital Rechts der Isar, Technical University Munich, Munich, Germany; 19 patients); Monika Diehl-Bein (Department of Surgery, University Medical Centre Regensburg, Regensburg, Germany; four patients); Thomas Simon, Tobias Gehrig, Marion Hoffer (Department of General and Visceral Surgery, GRN-Klinik Sinsheim, Sinsheim, Germany; four patients); Christoph Thomas Germer (Department of General, Visceral, Vascular, and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany; four patients). Declaration of interests We declare no competing interests. Acknowledgments This multicentre trial was funded by a grant from the German Research Foundation (support code DI 1484/2-2). We thank the staff of all participating centres of the ChroPac Trial Group for their outstanding engagement and support of the trial. We also thank the nursing staff and clinical partners (eg, departments of anaesthesiology, gastroenterology, etc) who were not directly involved in the conduct of this trial but without whom successful completion of the trial would not have been possible.
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