Early surgery first for painful chronic pancreatitis with dilated main pancreatic duct: evidence awaiting integration into practice

Early surgery first for painful chronic pancreatitis (CP) with dilated main pancreatic duct: evidence awaiting integration into practice

The optimal management of CP has been a matter of long-standing controversy. About a year ago, the Dutch Pancreatitis Study Group published a follow-up analysis of the ESCAPE randomized clinical trial (RCT), focusing on long-term outcomes of early surgery versus endoscopy-first in patients with painful CP and a dilated main pancreatic duct (1). The trial was designed more than a decade ago (2), and the first publication of outcomes after a follow-up period of 18 months took place in 2020 (3). That first publication set the ground for changes in practice, demonstrating a superiority of an early surgery-first approach when compared with endoscopy-first in terms of pain scores (3). Nevertheless, the long-term sustainability of any superior outcomes with early surgery remained in question in the absence of long-term follow-up. Traditionally, the first line of treatment for pain is opioids, and if these are insufficiently successful, endoscopic therapy comes next, with surgery being considered the last resort. Nevertheless, early surgery has been proposed as a potentially successful alternative in managing pain, and improving quality of life and pancreatic function (4,5). The recently published follow-up analysis of the ESCAPE RCT is therefore very important, despite some limitations, firstly because of the publication of long-term outcomes on a clinically very important topic where data on these are otherwise scarce, but also for a number of other reasons, particularly in the presence of great existing controversy and several uncertainties.

The study recruited 88 patients with severely painful CP and a dilated main pancreatic duct, in 30 hospitals in the Netherlands, from April 2011 to September 2018. Eligible patients had recently started opioids owing to progressive pain despite receiving non-opioid pain medication. In the 2 years prior to inclusion, the maximum period of opioid use had to be 6 months for weak opioids and 2 months for strong opioids. Patients were randomised to undergo early surgery or a step-up endoscopy-first approach as part of the ESCAPE RCT (3). The initial publication reported outcomes after an initial 18-month follow-up (3), while the recently published follow-up analysis of the trial presented long-term clinical data collected until June 2022, accounting for approximately 8 years of follow-up (1).

Outcomes from the initial ESCAPE longitudinal 18-month follow-up showed no benefit of surgery when complete ductal clearance was achieved by means of endoscopy (3). This, along with the fact that endoscopy is less invasive than surgical management, prompted many centres to follow an endoscopy-first approach (1). In line with this, conventionally, when complete endoscopic ductal clearance is considered achievable, patients are usually advised to undergo endoscopy as a first line of treatment (1). However, the long-term outcomes of this approach had been largely unknown. Furthermore, it is important to be mindful of the fact that a long enough duration of pain may lead to its centralisation and a very significant reduction in the potential benefits from future surgical intervention.

The follow-up analysis of the ESCAPE trial compared the long-term outcomes of patients with painful CP and a dilated pancreatic duct, randomized to either early surgery or an endoscopy-first approach. The primary end point of the follow-up analysis was pain, assessed by the Izbicki pain score, while secondary end points included patient-reported complete pain relief and satisfaction. Furthermore, analysis was undertaken in predefined subgroups of patients who progressed to surgery after endoscopy and patients with complete endoscopic ductal clearance. The authors also assessed the trends in pain scores with time progression. All analyses followed the intention-to-treat principle (1).

In the endoscopy-first step-up approach group, patients proceeded to endoscopic management, if medical pain management was unsuccessful, and proceeded to surgical intervention if endoscopic management was unsuccessful. In the early surgery group, a surgical drainage operation was performed by an expert surgeon within 6 weeks after randomization. A longitudinal pancreaticojejunostomy was undertaken in patients with nonenlarged pancreatic head (6), while in patients with an enlarged pancreatic head a Frey procedure or a Beger procedure was undertaken (7,8). In both treatment groups all interventions were undertaken in 7 predefined CP expert centres, by specialist multidisciplinary teams (3). It has to be noted, at this point, that it would be difficult to completely rule out any cases of central pain having developed until the time of endoscopic or surgical intervention. It also has to be mentioned that, as described in the follow-up analysis, any additional treatments/interventions as well as the timing for them were chosen by the treating medical team, in the absence of particular follow-up criteria to guide treatment decisions.

Nevertheless, a number of important observations from this study came to light (1):

• At the end of long-term follow-up, pain scores and rates of patient-reported complete pain relief were superior in the early surgery group, where more patients were “very satisfied” with their treatment (71% vs. 33%) and would recommend their treatment to family members or friends [87% vs. 47%; P<0.001].
• A single procedure was sufficient to adequately treat the pain in 60% of patients in the early surgery group, compared with 12% in the endoscopy-first group.
• After the initial 18-month follow-up, reinterventions were required in 26% of patients in the early surgery group and 44% of patients in the endoscopy-first group. Those who required surgery after endoscopy-first had significantly worse pain scores compared to the early surgery group.
• Importantly, obtaining endoscopic ductal clearance did not improve outcomes, as at the end of long-term follow-up, the pain scores, complete pain relief, interventions per patient and quality of life, did not differ significantly between patients with and without ductal clearance in the endoscopy-first group.
• Compared to patients with ductal clearance in the endoscopy-first group, patients in the early surgery group had improved outcomes, but these only reached statistical significance for visual analogue scale (VAS) score. This and the previous observation are very important and opposite to the initial report. While the initial report might encourage an initial attempt at endoscopic clearance as a purpose and achievable goal of an endoscopy-first approach, the results of the follow-up analysis defy the rationale of this concept and point toward the opposite direction.
• In the endoscopy-first group, the treatment-related complication rate was significantly higher, as was the total number of required additional procedures.
• At the end of long-term follow-up, the rates of exocrine and endocrine insufficiency were not statistically different between the 2 groups. Importantly, this also indicates that surgery did not confer a higher risk of exocrine and endocrine insufficiency.
• Notably, in the group of patients who progressed to surgery after endoscopy first, the rate of complete pain relief was 12% as opposed to 55% in the early surgery group. This is a very important observation, that strongly supports an early surgical treatment first, to avoid centralisation of the pain which consequently limits the benefits of surgery.
• Additionally, in the early surgery group pain scores remained similar at 18-month follow-up and at the end of long-term follow-up, while they worsened over time in the endoscopy-first group.
• Ultimately, as an important conclusion, in this group of patients with painful CP and a dilated main pancreatic duct, after almost 8 years of follow-up, early surgery showed clear superiority to an endoscopy-first approach in terms of pain scores and patient satisfaction.

The results of the ESCAPE trial follow-up analysis are in line with two earlier RCTs from 2003 (9) and 2011 (10), also reporting better outcomes with surgical management compared to endoscopic management in patients with painful CP, even though both trials enrolled patients at more advanced stages of disease.

Furthermore, in pursuit of optimal long-term pain control, the international consensus guidelines for surgery in CP recommend surgery at an early disease stage compared to surgery at more advanced stages (11). Additionally, a cost-effectiveness analysis in the ESCAPE trial, showed that early surgery was more cost-effective than the endoscopy-first approach (12).

In interpreting the results of the long-term follow-up analysis of the ESCAPE trial, it also needs to be noted that the sample size of 88 patients is relatively small and the design is national, while the recruitment of these patients in 30 participating centres over 7.5 years, accounts for an average of 1 patient every 2.5 years, which is a very small number, potentially indicating a high selection process. In addition, the follow-up was non-standardised, predetermined or structured, and based on a single-point data collection, implying variable follow-up periods, more specifically ≥10 years in 7 patients, 5–10 years in 65 patients, and <5 years in 14 patients. Furthermore, the latest advances in endoscopic techniques may have not been utilised in full, while the study may not reflect the standards of practice and outcomes of high-volume endoscopic units with advanced expertise in pancreatic interventions. Moreover, of the 88 patients with CP in the initial ESCAPE trial, 23 died after the initial 18-month follow-up period, while 2 patients did not return the questionnaire. Notably, the recent SCHOKE trial compared combined extracorporeal shock-wave lithotripsy (ESWL) undertaken under epidural ropivacaine anaesthesia, preceding endoscopic retrograde pancreatography (ERP), with sham procedures. Complete stone fragmentation was defined as the fragmentation of all stones to 3 mm or less, therefore the endoscopic procedure on the day after ESWL was aimed at removing stone fragments, and where this was not achieved during the initial ESWL session, additional sessions were performed on subsequent days. Complete pancreatic duct clearance was defined as a more than 90% reduction in the initial stone volume based on the fluoroscopic view of the stone density during the ESWL and subsequent ERP procedure, and was achieved in 88% with this combined approach (13).

Based on the findings of the study in the context of the accumulating evidence, a number of points can be drawn.

Firstly, in the presence of long-standing controversies, it is important that any new evidence is perceived clearly, therefore it has to be underlined that the results of the long-term follow-up analysis of the ESCAPE trial apply specifically to patients with painful CP and a dilated main pancreatic duct. Furthermore, in the same spirit, it is of paramount importance to pursue the utilisation of a common robust language that will facilitate utilisation of the evidence. As such, it is important to note that the term “early surgery”, when utilised to promote the evidence and convey a wider message, may to some extent sound vague (even though we are aware from the study design of the ESCAPE trial that patients assigned to the early-surgery group underwent a surgical drainage operation within 6 weeks after randomization). It is therefore essential to underline that the evidence points towards “early surgery first”, which indicates both that surgery is undertaken early after diagnosis and that it is the first intervention, leaving no room for misinterpretation. On the other hand, the term “surgery-first” alone would mean that surgical treatment was the first intervention but not necessarily undertaken early. As such the term “early surgery first” appears to be complete and accurate and aligns with the need to establish the notion of early surgery first in the mindset of specialist practitioners.

The approach of early surgery first has not been uniformly followed so far, which is a fact that warrants reflection. Firstly, the previous uncertainty and hesitation relating to the actual sustainability of benefits of early surgery in the long term, have been plausible. Moreover, when the comparison involves a significant pancreatic operation versus an endoscopic procedure with the aim of treating pain, particularly with the initial analysis of the ESCAPE trial at 18 months of follow-up showing no clear benefit of surgery against complete endoscopic ductal clearance (3), opting for the least aggressive treatment to start with, would not be unexpected. Additionally, there may be a degree of difficulty among pancreatic surgeons to accept pain alone as a sufficient indication to offer major surgery for a non-cancerous and non-life threatening situation, despite the fact that this pain may not be conservatively manageable and may have a massive negative effect on patients’ quality of life. Perhaps, it has not been widely perceived that postponing a timely surgical intervention can lead to irreversible development of opioid dependence and neuropathic pain.

There is therefore a clear need to overcome stereotypes and the new evidence from the follow-up analysis of the ESCAPE trial is an important step in this direction. Looking at daily practice, one has to explore who orchestrates and makes the decisions about the management of patients with painful CP. Could it be that patients seen by gastroenterologists as a first point of referral, are more easily offered endoscopic options first? Does the fact that, surgeons will naturally always take seriously into account the risk of major complications from major pancreatic surgery against those of endoscopy first, especially for benign disease, have a major impact on clinical practice (14)? Nevertheless, the evidence is available, specific, and should be used upon counselling patients for their preferred treatment and provision of informed consent. Notably, the Dutch Pancreatitis Study Group has more recently published a further nationwide multicenter retrospective study of 381 patients who underwent surgical treatment for symptomatic CP (15). Three distinct categories of surgical techniques were compared, namely (I) surgical drainage procedures [including lateral pancreaticojejunostomy (LPJ), extended LPJ, Partington-Rochelle, and Puestow procedures], (II) duodenum-preserving pancreatic head resections (including Frey, Beger, and Bern procedures), and (III) standard pancreatic resections (including pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy) (15). The overall surgical outcomes were good and surgical drainage procedures displayed the best safety profile with 0% 90-day mortality, 0% postoperative pancreatic fistula, major morbidity of 12% and excellent functional outcomes, providing a strong argument in support of tailoring surgery based on pancreatic morphology and using the least extensive procedure required, in accordance with the international consensus guidelines (11,15). The results of this study are in line with previous reports (16-20) and underscore the importance of centralization of pancreatic surgery.

Another parameter to consider is that patients with CP are a small cohort among all patients referred to pancreatic surgeons, while among pancreatic surgeons a minority only have significant expertise or specialist interest in the overall and surgical management of CP. Nevertheless, the evidence dictates that these patients could benefit, where possible, from highly-specialised services, such as specialist pancreatitis clinics employing a multidisciplinary approach supported by specialist hepatopancreatobiliary radiologists, with the involvement of expert surgeons, gastroenterologists/interventional endoscopists, dieticians, devoted to utilising the available evidence (21). That being said, medical treatment should not be restricted to simple and strong analgesics, but also include neuromodulators such as gabapentinoids, serotonin-and norepinephrine reuptake inhibitors, and electrical neuromodulation. And not less importantly, as there may also be a degree of difficulty for the patients to opt for early surgery first compared to endoscopy first, it is of paramount importance to achieve effective communication in conveying the evidence. When a patient asks “what do I have to lose from an endoscopy first which is a much less aggressive intervention?”, there is a list of arguments to utilise from the recent evidence, as highlighted earlier. Nevertheless, it has to be remembered that the role of the clinician is to inform the patient about the available options and existing evidence, in order to help them make decisions that are most suitable to them.

All in all, while there is room for further research to address specific points in pursuit of optimising and individualising management, there is already considerable evidence in favour of early surgical treatment in the discussed group of patients before any other intervention, and this evidence is now awaiting integration into practice.

This evidence and the guidelines of the recent years (11,22,23) are expected to act in synergy and promote the role of early surgery first for patients with painful CP and a dilated main pancreatic duct.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-88/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-88/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. van Veldhuisen CL, Kempeneers MA, de Rijk FEM, et al. Long-Term Outcomes of Early Surgery vs Endoscopy First in Chronic Pancreatitis: Follow-Up Analysis of the ESCAPE Randomized Clinical Trial. JAMA Surg 2025;160:126-33. Erratum in: JAMA Surg 2025;160:234. [Crossref] [PubMed]
2. Ahmed Ali U, Issa Y, Bruno MJ, et al. Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial. BMC Gastroenterol 2013;13:49. [Crossref] [PubMed]
3. Issa Y, Kempeneers MA, Bruno MJ, et al. Effect of Early Surgery vs Endoscopy-First Approach on Pain in Patients With Chronic Pancreatitis: The ESCAPE Randomized Clinical Trial. JAMA 2020;323:237-47. [Crossref] [PubMed]
4. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007;356:676-84. [Crossref] [PubMed]
5. Drewes AM, Kempeneers MA, Andersen DK, et al. Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons! Gut 2019;68:1343-51. [Crossref] [PubMed]
6. PARTINGTON PF. ROCHELLE RE. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960;152:1037-43. [Crossref] [PubMed]
7. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987;2:701-7. [Crossref] [PubMed]
8. Beger HG, Krautzberger W, Bittner R, et al. Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery 1985;97:467-73.
9. Díte P, Ruzicka M, Zboril V, et al. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553-8. [Crossref] [PubMed]
10. 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;141:1690-5. [Crossref] [PubMed]
11. Kempeneers MA, Issa Y, Ali UA, et al. International consensus guidelines for surgery and the timing of intervention in chronic pancreatitis. Pancreatology 2020;20:149-57. [Crossref] [PubMed]
12. Kempeneers MA, Issa Y, Bruno MJ, et al. Cost-effectiveness of Early Surgery Versus Endoscopy-first Approach for Painful Chronic Pancreatitis in the ESCAPE Trial. Ann Surg 2023;277:e878-84. [Crossref] [PubMed]
13. Talukdar R, Olesen SS, Unnisa M, et al. Extracorporeal Shock-Wave Lithotripsy and Endoscopy for the Treatment of Pain in Chronic Pancreatitis : A Sham-Controlled, Randomized Trial. Ann Intern Med 2024;177:749-58. [Crossref] [PubMed]
14. Mavroeidis VK, Russell TB, Clark J, et al. Pancreatoduodenectomy for suspected malignancy: nonmalignant histology confers increased risk of serious morbidity. Ann R Coll Surg Engl 2023;105:446-54. [Crossref] [PubMed]
15. Van Veldhuisen CL, Leseman CA, De Rijk FEM, et al. Nationwide Outcome of Tailored Surgery for Symptomatic Chronic Pancreatitis Based on Pancreatic Morphology: Validation of the International Guidelines. Ann Surg 2025;281:655-63. [Crossref] [PubMed]
16. Riediger H, Adam U, Fischer E, et al. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg 2007;11:949-59; discussion 959-60. [Crossref] [PubMed]
17. van der Gaag NA, van Gulik TM, Busch OR, et al. Functional and medical outcomes after tailored surgery for pain due to chronic pancreatitis. Ann Surg 2012;255:763-70.
18. van der Geest LG, van Rijssen LB, Molenaar IQ, et al. Volume-outcome relationships in pancreatoduodenectomy for cancer. HPB (Oxford) 2016;18:317-24. [Crossref] [PubMed]
19. Benzing C, Hau HM, Atanasov G, et al. Surgical therapy of chronic pancreatitis: clinical results and health-related quality of life. Z Gastroenterol 2018;56:1354-64. [Crossref] [PubMed]
20. Ghorbani P, Dankha R, Brisson R, et al. Surgical Outcomes and Trends for Chronic Pancreatitis: An Observational Cohort Study from a High-Volume Centre. J Clin Med 2022;11:2105. [Crossref] [PubMed]
21. Mavroeidis VK, Knapton J, Saffioti F, et al. Pancreatic surgery and tertiary pancreatitis services warrant provision for support from a specialist diabetes team. World J Diabetes 2024;15:598-605. [Crossref] [PubMed]
22. Löhr JM, Dominguez-Munoz E, Rosendahl J, et al. United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J 2017;5:153-99. [Crossref] [PubMed]
23. Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Updated August 2018. Endoscopy 2019;51:179-93. [Crossref] [PubMed]