Preoperative biliary drainage for periampullary tumors causing obstructive jaundice; DR ainage vs. (direct) OP eration (DROP-trial)

Patients with obstructive jaundice caused by a tumor in the pancreatic head area (pancreas, distal bile duct, papilla of Vater), without radiological evidence of irresectability, will undergo an exploration with the intention of resection of the tumor, being the only option for cure [1‐4]. If a resection is not possible due to locoregional irresectability or distant metastases, a biliary and gastric bypass procedure is performed [5‐8]. Surgery in jaundiced patients with a tumor in the pancreatic head area is associated with a higher risk of postoperative complications compared with surgery in non jaundiced patients [9‐11]. These complications primarily consist of septic complications (cholangitis, abscesses, and leakage), haemorrhage, impaired wound healing and renal disorders. The increased risk of surgery in jaundiced patients was recognized already in 1935 by Allen O. Whipple, who proposed a two staged procedure for surgery in deeply jaundiced patients. The first stage consisted of a drainage procedure by a cholecystogastrostomy, to decompress the biliary tract in order to restore normal liver function, followed four weeks later by radical resection of the tumor [12]. Numerous experimental and clinical studies have been performed since, investigating the cause and directed at prevention of complications after surgery in patients with obstructive jaundice.

While the postoperative mortality rate after pancreatoduodenectomy has been reduced from around 20% to 1–5% in experienced centres, the morbidity rate has remained virtually unchanged, ranging from 40 to 60% [5, 6, 8, 9]. Many different etiologic factors for development of complications have been characterized: presence of toxic substances as bilirubin and bile salts, impaired nutritional status, effects of endotoxins, bacterial translocation, modulation of the inflammatory cascade with cytokine release, reduction of cellular immunity and nutritional status [13‐21]. For these etiologic factors different interventions have been undertaken in the past decades, attempting to lower the risk of complications. The current project addresses the issue of preoperative biliary drainage (PBD).

Early studies on external PBD could not demonstrate a reduction in complication rate in humans because this procedure, although relieving the biliary obstruction, does not restore the bile flow to the gut lumen [22]. Internal drainage has been shown in multiple experimental models to improve liver function and nutritional status, to reduce systemic endotoxemia and cytokine release, and subsequently to improve immune response [13‐15, 19‐21]. Finally the mortality was significantly reduced in these animal models[16]. The first non-randomized studies on internal PBD in jaundiced patients reported a reduced mortality and morbidity [22]. However, clinical studies and small randomized trials could not confirm the positive effect of PBD on surgical outcome [23‐27]. Some studies even reported a deleterious effect, partly due to complications associated with the drainage procedure [28‐32]. Despite these results, PBD is generally accepted in The Netherlands. In previous studies we found that around 90% of patients with obstructive jaundice currently undergo preoperative drainage in The Netherlands [28, 29]. The dominance of drainage can be attributed in part to the familiarity of endoscopic retrograde cholangiopancreatography (ERCP), which has been used in the past as the first diagnostic procedure for obstructive jaundice. The time needed for extensive diagnostic workup, including diagnostic laparoscopy (DL), is a logistic explanation for the assumed benefit of PBD. However, the value of DL for periampullary tumors is disputed, especially in the light of improvement of other non-invasive diagnostic procedures [1‐4, 33, 34]. Other important factors that influence the decision to opt for PBD are (local) referral patterns and waiting lists. Current state-of-the-art radiological diagnostic and staging procedures for suspected periampullary tumors require only a minimum of time [1]. These non-invasive radiological procedures have the same diagnostic accuracy as ERCP, an invasive diagnostic procedure, and, moreover, offer the advantage of assessing local tumor extension as well as distant metastases [1‐3]. Therefore, ERCP with subsequent drainage as part of a routine diagnostic workup is outdated.

ERCP and endoscopic sphincterotomy with insertion of biliary and pancreatic stents is a difficult gastrointestinal endoscopic procedure. Complications, such as haemorrhage, pancreatitis, perforation of the duodenal wall, cholangitis and stent occlusion cannot always be avoided and occur in approximately 10 percent of procedures [35, 36]. Mortality as a consequence of the procedure is reported in 0.5%–1% of the cases [36]. The negative side-effects of PBD, such as an increase of infectious complications after surgery, has been the focus of attention in more recent studies [30‐32]. It was concluded that the potential advantages of preoperative drainage fail to outweigh the negative effects [20, 23, 24, 28‐32].

In the light of the ongoing controversy of PBD, a meta-analysis of randomized clinical trials and comparative studies was carried out [37]. The aim of this study was to evaluate the efficacy of drainage in jaundiced patients compared with patients that underwent direct surgical treatment. No difference in mortality could be detected between both strategies, but overall complication rate in patients that underwent PBD was significantly higher compared with direct surgical treatment, 57.3% and 41.9% respectively (level I evidence). The mean overall hospital stay was increased by two weeks in patients that underwent biliary drainage. Unfortunately, most of the studies have methodological flaws (e.g. differences in drainage procedures, duration of drainage, internal vs. external drainage, surgical procedures, small sample size) and do not provide unequivocal treatment recommendations. Therefore, a prospective randomized trial addressing the effects of PBD is indicated. Especially, for the potential consequences of future treatment might be considerable; a shorter workup period, less invasive diagnostic procedures (ERCP) and a shorter time interval to surgery. The study focuses on complication rate (40–60%), the primary endpoint for most past studies.

The concept of PBD has been developed to reduce the postoperative morbidity and mortality in patients with obstructive jaundice, caused by a suspected pancreatic/periampullary malignancy. However, PBD, both endoscopic or percutaneous, is associated with an increased incidence of postoperative morbidity [mostly infectious complications] and postoperative mortality when performed prior to a pancreatoduodenectomy. Furthermore, the techniques used for PBD harbour their own complications. Therefore, the overall conclusion not to routinely perform preoperative biliary drainage seems evident. Nevertheless, still the majority of these patients undergo preoperative drainage, often preceded by a diagnostic endoscopic retrograde cholangiopancreatography (ERCP). Unfortunately, most of the available literature addressing the efficacy of PBD suffers from methodological flaws (e.g. differences in drainage procedures, duration of drainage, internal vs. external drainage, surgical procedures, small sample size) or is outdated.

Therefore, a prospective randomized trial addressing the effects of PBD, and thus solving the longstanding controversy whether or not PBD should be routinely performed in jaundiced patients prior to a pancreatoduodenectomy, is indicated. Especially, for the potential consequences of future treatment might be considerable; a shorter workup period, less invasive diagnostic procedures (ERCP) and a shorter time interval to surgery.