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Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage
Digestive and Liver Disease 36 (2004) 412–418
Digestive Endoscopy
Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage H. Gerke a,∗ , R. White c , M.F. Byrne a , H. Stiffler a , R.M. Mitchell a , H.I. Hurwitz b , M.A. Morse b , M.S. Branch a , P.S. Jowell a , B. Czito d , B. Clary c , T.N. Pappas c , D.S. Tyler c , J. Baillie a a
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Box 3189, Durham, NC 27710, USA b Division of Hematology/Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA c Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA d Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA Received 1 October 2003; accepted 26 January 2004
Abstract Background. It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy. Aims. The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer. Patients. One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002. Methods. The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded. Results. Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage. Conclusions. Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Cholangiopancreatography, endoscopic retrograde; Jaundice; Neoadjuvant therapy; Pancreatic neoplasms; Pancreaticoduodenectomy
1. Introduction Recent efforts to improve survival after pancreaticoduodenectomy for periampullary malignancies include neoadjuvant chemoradiation [1–6]. In most jaundiced patients undergoing neoadjuvant chemoradiation, biliary decom∗ Corresponding author. Tel.: +1-919-684-3894; fax: +1-919-684-4695. E-mail address: [email protected] (H. Gerke).
pression is used to palliate symptoms (e.g. pruritus) associated with jaundice during the preoperative period and to avoid adverse effects on the metabolism of chemotherapeutic drugs. However, there is ongoing controversy about the safety of preoperative biliary drainage. Obstructive jaundice is suspected of being associated with increased morbidity and mortality after major surgical procedures [7–9], which might be due to adverse effects on metabolic functions, immunity, nutritional status and wound healing [10–16]. Initial observational studies [17–21] and a randomised trial
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H. Gerke et al. / Digestive and Liver Disease 36 (2004) 412–418
[22] suggested a beneficial effect of biliary decompression on complications of subsequent operations. However, several further studies [23–31] and a recent meta-analysis [32] failed to demonstrate an advantage of preoperative biliary drainage. On the other hand, retrospective data from Povoski et al. have gone so far as to suggest that preoperative endoscopic stenting might increase mortality and morbidity after pancreaticoduodenectomy [33]. The aim of this study was to analyse complications related to endoscopic biliary stents (EBS) and the impact of prosthetic biliary drainage on postoperative morbidity and mortality of pancreaticoduodenectomy in patients who undergo neoadjuvant chemoradiation prior to resection for their periampullary neoplasms.
2. Patients and methods One hundred and eighty-four patients with non-metastatic periampullary neoplasms were prospectively selected for neoadjuvant chemoradiation therapy (CRT) between February 1995 and October 2002. The histologic diagnosis was
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pancreatic adenocarcinoma in 153 patients, ampullary cancer in 11 patients, cholangiocarcinoma in 13 patients, duodenal carcinoma in 4 patients and neuroendocrine tumour in 3 patients. In 160 patients, CRT consisted of a planned dose of 4500 cGy of daily external beam radiation therapy (EBRT) and concomitant 5-fluorouracil (5-FU)-based chemotherapy. EBRT was delivered in 180 cGy fractions, 5 days a week, with or without a boost dose of 540 cGy to the tumour bed. The patients received either 5-FU alone (n = 126), 5-FU plus bolus mitomycin-C on day 3 (n = 17), 5-FU plus infusional cisplatin (n = 3), or a combination of 5-FU, mitomycin-C and cisplatin (n = 14). Twelve patients received a planned dose of 3000 cGy given in 150 cGy fractions delivered twice a day over 2 weeks and concomitant Gemcitabine chemotherapy. The median total dose of EBRT received was 4500 cGy (range: 900–5040 cGy). Three patients did not receive chemoradiation because of contraindications (urosepsis in one patient, severe nausea and cholangitis due to a malfunctioning percutaneous biliary drain (PBD) in one patient, cholangitis secondary to endoscopic biliary stenting and pathologic vertebral fracture in one patient).
184 pts Insufficient data or lost to follow up
9 pts Prior surgical biliary bypass
7 pts
168 pts (male 97, median 65 years, 31-83 years) Died prior to restaging
3 pts: cholangitis 2 (PBD 1, EBS 1 *), myocardial infarction 1 165 pts (162 pts received CRT **)
Radical Resection
75
Surgical Bypass 45
Other
45 #
Pancreaticoduodenectomy 72
Biliary bypass
12
Xlap only
Duodenectomy
1
Gastrojejunostomy
14
Laparoscopy only
Mid-pancreas resection
1
Double Bypass @
19
No Surgery
Pancreatic tail resection
1
*
15 2 28
PBD = percutaneous biliary drain; EBS = endoscopic biliary stent
**
3 patients never received CRT because of contraindications
@
Double bypass = biliary bypass + gastrojejunostomy
#
Xlap = exploratory laparotomy
Fig. 1. Patients (pts) included in the study for CRT in non-metastatic periampullary tumours.
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Indication for biliary drainage was obstructive jaundice. Endoscopic biliary drainage was either performed at the Duke University Medical Center or at a referring institution. Stent failure was defined as cholangitis or recurrent jaundice requiring stent exchange. The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of EBS and morbidity of pancreaticoduodenectomy. Sufficient data were available for 175 patients. Seven patients who had undergone a previous surgical biliary bypass were excluded, leaving 168 for analysis. Seventy-two patients finally underwent pancreaticoduodenectomy (Fig. 1). Complications occurring during the same admissions or within 1 month of discharge were considered as postoperative complications. Wound infections were identified by purulent discharge and/or wound changes requiring re-operation, early removal of staples or sutures or initiation of antibiotic therapy. A two-tailed Chi-squared test was used to analyse data for statistical differences. Endoscopic stent survival was defined as the time from stent insertion to stent failure. This was analysed by the method of Kaplan and Meier and log rank test using a commercial computer software program (SPSS 10.0 for Windows, SPSS Inc., Chicago, IL, USA). The censored date was the date of surgery or—in patients not undergoing surgery—the date of radiological re-staging.
3. Results Out of 168 patients, 119 had an EBS. In 62 patients, the stent was inserted at the Duke University Medical Center; in the other 57 patients, it was inserted at the referring institution. Adequate information about the EBS was available in 65 patients, of whom 64 received a plastic stent. The stent size was 7 French (Fr) in 4 patients; 8.5 Fr in 4 patients, 10 Fr in 53 patients and 11.5 Fr in 3 patients. In one patient, the initial biliary drain was a self-expandable 30 Fr metal mesh stent. Eighteen patients had a PBD and 31 did not require any biliary drainage procedure (Table 1). The median interval between initial prosthetic biliary drainage and radiological re-staging was 93 days (range: 32–403 days). In those patients who underwent surgery, the median interval between prosthetic biliary drainage and surgery was 117 days (range: 26–356 days). Preoperative
Table 1 Preoperative biliary drainage Biliary drain EBS PBD No preoperative drainage
119 18 31
Total
168
Table 2 Characteristics of patients undergoing pancreaticoduodenectomy with and without preoperative biliary drain Biliary drain
Male (%) Median age (years) (range) Median preoperative Serum bilirubin (mg/dl) (range) White blood count (×109 l−1 ) (range)
Yes (n = 58)
No (n = 14)
60 63 (31–80)
43 63 (49–77)
0.6 (0.2–14.2)
0.4 (0.2–2.2)
5.6 (3.3–12.4)
6.3 (3.6–8.2)
Comorbidity (%) Cardiovascular disease Diabetes mellitus
13 (22) 13 (22)
0 3 (21)
Preoperative stage (%)a Resectable Locally advanced Unknown
46 (79) 7 (12) 5 (9)
12 (86) 2 (14) 0
Histology Pancreatic adenocarcinoma Ampullary cancer Cholangiocarcinoma Duodenal carcinoma Neuroendocrine tumour
45 5 7 0 1
10 2 0 2 0
a
Resectable: no evidence of direct invasion of the superior mesenteric artery (SMA) or celiac axis (CA) and patent superior mesenteric vein (SMV) and portal vein (PV). Locally advanced: presence of soft tissue abutting or encircling the SMA or CA or occlusion of the SMV or PV. Unknown: staging information of preoperative CT scan not available.
serum bilirubin was available in 50 out of the 58 patients who had prosthetic biliary drainage prior to pancreaticoduodenectomy: the median serum bilirubin was 0.6 mg/dl. Only four patients had a preoperative serum bilirubin greater than 1.5 mg/dl. Preoperative serum bilirubin was available in 13 out of the 14 patients without prosthetic drainage and was normal in 12 patients. One patient had a preoperative bilirubin of 2.2 mg/dl. Median preoperative serum bilirubin was 0.4 mg/dl (Table 2). 3.1. Stent-related complications Stent failure prior to surgery or—in those who did not undergo surgery—prior to the date of the re-staging CT occurred in 41 of the 119 patients (34%) who received an EBS. Stent failure presented with signs and symptoms of cholangitis in 16 patients (13%) and 1 patient died (0.8%). Thirty-three patients required a single stent exchange; seven patients had two or more stent exchanges. One patient had narrowing of a metal stent due to a tight stricture, which was balloon dilated. Eighteen patients (15%) were hospitalised for stent-related complications. The median length of hospital stay was 4 days (range: 2–18 days). In 19 out of the 119 patients (16%), stent failure occurred within 30 days of stent insertion. In 21 patients, stent failure occurred prior to initiation of CRT.
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One hundred and seventeen of the 119 patients with EBS received CRT. In 12 of those 117 patients, stent failure occurred during CRT. One patient died from biliary sepsis; in six patients, chemotherapy was discontinued due to biliary complications. Chemotherapy was resumed in four patients after 4, 6, 6 and 11 days, respectively, and discontinued in one patient due to a large duodenal ulcer and in another patient due to recurrent stent failure. Overall, CRT was discontinued early in 11 of 172 patients. In only one patient, this was attributed to a malfunctioning EBS. Kaplan–Meier analysis revealed a median stent survival of 190 days (95% confidence interval: 106–274 days) and a mean stent survival of 138 days (95% confidence interval: 124–152 days). Log rank testing did not show a significant difference in stent survival with respect to age (<60 or >60 years), preoperative staging, gender or histology; however, due to low statistical power these cannot be excluded. 3.2. Morbidity and mortality of pancreaticoduodenectomy One hundred and twenty patients underwent either tumour resection (75 patients) or palliative surgery (45 patients) (Fig. 1). Out of the 72 patients who underwent pancreaticoduodenectomy, 53 had received an EBS, 5 had received a PBD and 14 did not have any preoperative biliary drainage. The characteristics of the patients with and without pros-
Table 3 Postoperative complications of pancreaticoduodenectomya Any complication Complications requiring an invasive interventionb Death Surgical wound infection (SWI) Intra-abdominal abscess (IAA) Sterile fluid collection requiring drainage Intra-abdominal bleeding Gastric outlet obstruction Pancreatic fistula Chylous fistula Enterocutaneous fistula Delayed gastric emptying Portal vein thrombosis Pneumatosis intestinalis leading to re-explorationc Clostridium difficile colitis Gastrointestinal bleeding Port-a-cath infection Urinary tract infection Pneumonia Arrhythmia
48 15 3 20 9 3 2 3 2 2 1 5 1
(67) (21) (4) (28) (13) (4) (4)
(7)
1 4 (6) 2 1 2 2 4 (6)
Data is presented as number (%). Late complications not listed in the table include late enterocutaneous fistulas (n = 2) requiring re-operation after 4 and 8 months, respectively, and a late cologastrojejunal fistula (n = 1) requiring surgical repair after 4 months. a Occurring during the same admission or within 1 month of discharge. b Laparotomy or drainage procedure. c Two patients had intestinal pneumatosis on CT scan that resolved spontaneously and was not counted as a complication.
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Table 4 Postoperative complications after pancreaticoduodenectomy in patients with and without preoperative biliary drain Biliary drain
Wound infection Intra-abdominal abscess Invasive interventiona Any complication Postoperative death
Yes (n = 58)
No (n = 14)
17 7 13 41 3
3 2 2 7 0
(29) (12) (22) (71) (5)
(21) (14) (14) (50)
ns ns ns ns ns
Data is presented as number (%); ns = not significant. a Complications requiring laparotomy or a drainage procedure.
thetic biliary drainage (EBS and PBD) are summarised in Table 2. Postoperative complications occurred in 67% of the patients after pancreaticoduodenectomy (Tables 3 and 4). The mortality was 4%. Complication rates were not statistically different between patients with and without preoperative biliary drainage (Table 4).
4. Discussion Combined modality therapy improves survival in patients with pancreatic cancer. Yet, one-fourth of eligible patients do not receive postoperative chemoradiation due to delayed recovery from surgery [6]. This problem has been overcome by delivering chemoradiation prior to surgery. Moreover, neoadjuvant treatment might allow better selection of patients who benefit from pancreaticoduodenectomy, since patients with rapidly progressive disease or evident metastases after chemoradiation are not subjected to radical surgery. Another advantage of preoperative chemoradiation is potential downstaging of locally advanced tumours. However, neoadjuvant therapy requires biliary drainage in most patients, which raises concerns about morbidity related to biliary stent occlusion and increased surgical complications. The operative morbidity of pancreaticoduodenectomy (Whipple procedure) is high [9], and there is ongoing controversy about the impact of preoperative biliary drainage. A hypothetical benefit of preoperative biliary stenting did not translate into a lower operative morbidity in clinical studies [32], and retrospective data from the Memorial Sloan-Kettering Center (MSKC), New York, suggested an increased risk of infectious complication [33,34] as well as overall morbidity and mortality of pancreaticoduodenectomy after biliary stenting. Similar microbiological profiles of intraoperative bile cultures and cultures from the infection site support the hypothesis that these surgical infections arise from the biliary tree [35]. Bacteria are introduced into the biliary tree by endoscopic or transhepatic percutaneous manipulation and plastic stents provide a breeding ground for bacteria, which encourages sludge formation. Karsten et al. [27] demonstrated bacterial contamination of bile in 112 of the 119 patients (94%) who had a preoperative
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EBS compared to 34% of the patients without preoperative drainage (P < 0.001). Infections were more common in patients whose bile grew pathogens, and cultures from the infectious focus were likely to match the intraoperative bile cultures. On the other hand, the high incidence of contaminated bile did not result in an increased risk of infectious complications after pancreaticoduodenectomy in this series. Early randomised trials of preoperative biliary decompression via percutaneous transhepatic drains failed to demonstrate a reduced operative morbidity [29–31]. Since external bile loss might outweigh the advantages of biliary decompression, more favourable outcomes were expected with internal biliary drainage by endoscopic stenting [25]. The results of two randomised controlled trials (RCT) [22,28] of preoperative endsocopic biliary stenting were mixed. In a study by Lygidakis et al. [22], 38 patients were randomised to either EBS or no biliary drainage prior to pancreaticoduodenectomy. The postoperative morbidity was significantly lower in the drainage group (16% versus 74%). In a study by Lai et al. [28], 87 patients were randomly assigned to either early elective surgery or preoperative biliary drainage. The authors included patients who underwent palliative surgery. There was no difference in the morbidity and mortality rates between the drainage and the non-drainage group (39 and 15% versus 41 and 14%, respectively). In a meta-analysis, the combined data of these two RCT showed a tendency in favour of preoperative endoscopic stenting, although this failed to reach statistical significance [32]. While two retrospective studies suggested an increased risk of minor infectious complications due to preoperative biliary drainage, they did not confirm the increased operative morbidity and mortality suggested by the data from MSKC reported by Povoski et al. [33]. Pisters et al. [36] reviewed a prospective data cohort of 300 patients who underwent pancreaticoduodenectomy. Preoperative prosthetic biliary drainage was associated with an increased incidence of wound infections; however, this did not translate into an increased overall morbidity or mortality. Sohn et al. [37] analysed data from 567 patients and found an increased incidence of pancreatic fistulas and wound infections in patients with preoperative biliary drains, but no increased overall morbidity or mortality. Martignoni et al. did not find a difference in postoperative complications after pancreaticoduodenectomy between those patients who underwent preoperative biliary drainage and those who did not [24]. Unlike the present study, previous studies have not assessed the impact of preoperative biliary drainage on postoperative complications in the setting of neoadjuvant chemotherapy. In the present study, there was no statistically significant difference in the incidence of wound infections (29% versus 21%) and intra-abdominal abscesses (12% versus 14%) between patients with and without prosthetic biliary drainage who underwent pancreaticoduodenectomy. Interpretation of the results is hampered by lack of randomised controls and low statistical power, due to the small sample size. Yet, it is noteworthy
that both wound infections and intra-abdominal abscesses were commonly observed in the no-drainage group. Previously published data show that the contribution, if any, of preoperative prosthetic biliary drainage to the incidence of infectious surgical complications is small. The present study suggests that this remains true in the setting of CRT. Most studies evaluating postoperative complications and preoperative drainage did not account for stent-related complications; one might fear that these might be increased in the setting of neoadjuvant chemoradiation due to immunosuppression. In the present study, stent failure prior to surgery or re-staging occurred in 34% of the patients with preoperative EBS. Sixteen percent of the patients with endoscopic stents had early stent failure within 30 days of stent insertion. In more than half of the patients, stent failure occurred before the neoadjuvant therapy was initiated. Two large series from Amsterdam reported similar stent failure rates of 33 and 34%, respectively, in patients with preoperative drainage prior to pancreaticoduodenectomy who did not undergo neoadjuvant therapy [25,27]. Pisters et al. [38] reported stent malfunction (occlusion or migration) in 15% of the patients with pancreatic cancer in the setting of neoadjuvant chemoradiation. Only stent failure that occurred after initiation chemoradiation was taken into account, which explains the lower stent failure rates compared to the present study. Lofts et al. [39] retrospectively analysed stent occlusion rates in 47 patients with adenocarcinoma of the pancreas, bile ducts or gall bladder. Stent occlusion rates did not differ between patients who received chemotherapy and those who did not (37 and 39%, respectively), and the mean duration of patency was not shortened by chemotherapy (105 days in the chemotherapy group versus 119 days in the non-chemotherapy group). In the present study, the median and mean durations of EBS patency were 190 and 138 days, respectively, according to Kaplan–Meier analysis. We accept that this is a rough estimate because stent patency was only followed until surgery or radiological re-staging, and stent occlusion occurred in only 34% of the patients during that observation period. The duration of stent patency in the present study compares to that of historical controls, who did not undergo chemoradiation: mean duration of EBS patency in malignancy has been reported as 2–6 months [40–50]. Thus, we believe that chemoradiation does not shorten stent patency. In the present study, stent occlusion was typically managed by an outpatient stent exchange. However, 18 of the 41 patients with malfunctioning EBS required hospitalisation for a median of 4 days. This underlines the importance of following these patients closely at centres with experience in interventional ERCP. The impact of EBS-related complications on CRT was low in the present study. One hundred and seventeen of the 119 patients with EBS received CRT. Of those patients, treatment was discontinued due to stent-related complications in six patients (5%) and resumed in four patients after a median of 6 days. Another patient with EBS died from cholangitis
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during CRT. Overall, CRT was terminated early in 11 out of 172 patients; this was due to a malfunctioning biliary stent in one patient only. Pisters et al. [38] reported treatment interruption due to stent occlusion in 4 of the 154 patients (2.6%), with treatment breaks of 2 and 3 days in two patients and early treatment termination in two patients. We conclude that interruption of chemoradiation due to a malfunctioning EBS is uncommon, and treatment can usually be continued after stent exchange. It has been argued that preoperative biliary drainage has no advantage over immediate pancreaticoduodenectomy. On the other hand, it has been shown that patients treated at centres with a higher volume of pancreaticoduodenectomies have lower mortality rates [51]. Many patients are diagnosed and evaluated at regional centres; in these patients, palliative biliary decompression allows time for preoperative work-up and referral to a specialised centre. Furthermore, biliary drainage of jaundiced patients is a “sine qua non” for CRT. We feel that the potential benefits of preoperative biliary drainage and neoadjuvant therapy outweigh any excess of preoperative morbidity related to endoscopic or percutaneous biliary drainage. It is important that the patients have access to centres that can provide prompt therapy for stent-related complications. Conflict of interest statement None declared.
List of abbreviations CRT, neoadjuvant chemoradiation therapy; EBRT, external beam radiation therapy; EBS, endoscopic biliary stent; PBD, percutaneous biliary drain; RCT, randomised controlled trial.
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[39] Lofts FJ, Evans TR, Mansi JL, Glees JP, Knight MJ. Bile duct stents: is there an increased rate of complications in patients receiving chemotherapy? Eur J Cancer 1997;33:209–13. [40] Speer AG, Cotton PB, Russell RC, Mason RR, Hatfield AR, Leung JW, et al. Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 1987;2:57– 62. [41] Terruzzi V, Comin U, De Grazia F, Toti GL, Zambelli A, Beretta S, et al. Prospective randomized trial comparing Tannenbaum Teflon and standard polyethylene stents in distal malignant biliary stenosis. Gastrointest Endosc 2000;51:23–7. [42] Siegel JH, Pullano W, Kodsi B, Cooperman A, Ramsey W. Optimal palliation of malignant bile duct obstruction: experience with endoscopic 12 French prostheses. Endoscopy 1988;20:137– 41. [43] Matsuda Y, Shimakura K, Akamatsu T. Factors affecting the patency of stents in malignant biliary obstructive disease: univariate and multivariate analysis. Am J Gastroenterol 1991;86:843– 9. [44] Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K. Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 19921992;340: 1488–92. [45] De Ledinghen V, Person B, Legoux JL, Le Sidaner A, Desaint B, Greef M, et al. Prevention of biliary stent occlusion by ursodeoxycholic acid plus norfloxacin: a multicenter randomized trial. Dig Dis Sci 2000;45:145–50. [46] van Berkel AM, Boland C, Redekop WK, Bergman JJ, Groen AK, Tytgat GN, et al. A prospective randomized trial of Teflon versus polyethylene stents for distal malignant biliary obstruction. Endoscopy 1998;30:681–6. [47] Sung JJ, Chung SC, Tsui CP, Co AL, Li AK. Omitting side-holes in biliary stents does not improve drainage of the obstructed biliary system: a prospective randomized trial. Gastrointest Endosc 1994; 40:321–5. [48] Huibregtse K, Katon RM, Coene PP, Tytgat GN. Endoscopic palliative treatment in pancreatic cancer. Gastrointest Endosc 1986;32:334– 8. [49] Kadakia SC, Starnes E. Comparison of 10 French gauge stent with 11.5 French gauge stent in patients with biliary tract diseases. Gastrointest Endosc 1992;38:454–9. [50] Knyrim K, Wagner HJ, Pausch J, Vakil N. A prospective, randomized, controlled trial of metal stents for malignant obstruction of the common bile duct. Endoscopy 1993;25:207–12. [51] Birkmeyer JD, Finlayson SR, Tosteson AN, Sharp SM, Warshaw AL, Fisher ES. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 1999;125:250–6.
Digestive Endoscopy
Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage H. Gerke a,∗ , R. White c , M.F. Byrne a , H. Stiffler a , R.M. Mitchell a , H.I. Hurwitz b , M.A. Morse b , M.S. Branch a , P.S. Jowell a , B. Czito d , B. Clary c , T.N. Pappas c , D.S. Tyler c , J. Baillie a a
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Box 3189, Durham, NC 27710, USA b Division of Hematology/Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA c Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA d Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA Received 1 October 2003; accepted 26 January 2004
Abstract Background. It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy. Aims. The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer. Patients. One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002. Methods. The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded. Results. Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage. Conclusions. Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Cholangiopancreatography, endoscopic retrograde; Jaundice; Neoadjuvant therapy; Pancreatic neoplasms; Pancreaticoduodenectomy
1. Introduction Recent efforts to improve survival after pancreaticoduodenectomy for periampullary malignancies include neoadjuvant chemoradiation [1–6]. In most jaundiced patients undergoing neoadjuvant chemoradiation, biliary decom∗ Corresponding author. Tel.: +1-919-684-3894; fax: +1-919-684-4695. E-mail address: [email protected] (H. Gerke).
pression is used to palliate symptoms (e.g. pruritus) associated with jaundice during the preoperative period and to avoid adverse effects on the metabolism of chemotherapeutic drugs. However, there is ongoing controversy about the safety of preoperative biliary drainage. Obstructive jaundice is suspected of being associated with increased morbidity and mortality after major surgical procedures [7–9], which might be due to adverse effects on metabolic functions, immunity, nutritional status and wound healing [10–16]. Initial observational studies [17–21] and a randomised trial
1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.01.024
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[22] suggested a beneficial effect of biliary decompression on complications of subsequent operations. However, several further studies [23–31] and a recent meta-analysis [32] failed to demonstrate an advantage of preoperative biliary drainage. On the other hand, retrospective data from Povoski et al. have gone so far as to suggest that preoperative endoscopic stenting might increase mortality and morbidity after pancreaticoduodenectomy [33]. The aim of this study was to analyse complications related to endoscopic biliary stents (EBS) and the impact of prosthetic biliary drainage on postoperative morbidity and mortality of pancreaticoduodenectomy in patients who undergo neoadjuvant chemoradiation prior to resection for their periampullary neoplasms.
2. Patients and methods One hundred and eighty-four patients with non-metastatic periampullary neoplasms were prospectively selected for neoadjuvant chemoradiation therapy (CRT) between February 1995 and October 2002. The histologic diagnosis was
413
pancreatic adenocarcinoma in 153 patients, ampullary cancer in 11 patients, cholangiocarcinoma in 13 patients, duodenal carcinoma in 4 patients and neuroendocrine tumour in 3 patients. In 160 patients, CRT consisted of a planned dose of 4500 cGy of daily external beam radiation therapy (EBRT) and concomitant 5-fluorouracil (5-FU)-based chemotherapy. EBRT was delivered in 180 cGy fractions, 5 days a week, with or without a boost dose of 540 cGy to the tumour bed. The patients received either 5-FU alone (n = 126), 5-FU plus bolus mitomycin-C on day 3 (n = 17), 5-FU plus infusional cisplatin (n = 3), or a combination of 5-FU, mitomycin-C and cisplatin (n = 14). Twelve patients received a planned dose of 3000 cGy given in 150 cGy fractions delivered twice a day over 2 weeks and concomitant Gemcitabine chemotherapy. The median total dose of EBRT received was 4500 cGy (range: 900–5040 cGy). Three patients did not receive chemoradiation because of contraindications (urosepsis in one patient, severe nausea and cholangitis due to a malfunctioning percutaneous biliary drain (PBD) in one patient, cholangitis secondary to endoscopic biliary stenting and pathologic vertebral fracture in one patient).
184 pts Insufficient data or lost to follow up
9 pts Prior surgical biliary bypass
7 pts
168 pts (male 97, median 65 years, 31-83 years) Died prior to restaging
3 pts: cholangitis 2 (PBD 1, EBS 1 *), myocardial infarction 1 165 pts (162 pts received CRT **)
Radical Resection
75
Surgical Bypass 45
Other
45 #
Pancreaticoduodenectomy 72
Biliary bypass
12
Xlap only
Duodenectomy
1
Gastrojejunostomy
14
Laparoscopy only
Mid-pancreas resection
1
Double Bypass @
19
No Surgery
Pancreatic tail resection
1
*
15 2 28
PBD = percutaneous biliary drain; EBS = endoscopic biliary stent
**
3 patients never received CRT because of contraindications
@
Double bypass = biliary bypass + gastrojejunostomy
#
Xlap = exploratory laparotomy
Fig. 1. Patients (pts) included in the study for CRT in non-metastatic periampullary tumours.
414
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Indication for biliary drainage was obstructive jaundice. Endoscopic biliary drainage was either performed at the Duke University Medical Center or at a referring institution. Stent failure was defined as cholangitis or recurrent jaundice requiring stent exchange. The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of EBS and morbidity of pancreaticoduodenectomy. Sufficient data were available for 175 patients. Seven patients who had undergone a previous surgical biliary bypass were excluded, leaving 168 for analysis. Seventy-two patients finally underwent pancreaticoduodenectomy (Fig. 1). Complications occurring during the same admissions or within 1 month of discharge were considered as postoperative complications. Wound infections were identified by purulent discharge and/or wound changes requiring re-operation, early removal of staples or sutures or initiation of antibiotic therapy. A two-tailed Chi-squared test was used to analyse data for statistical differences. Endoscopic stent survival was defined as the time from stent insertion to stent failure. This was analysed by the method of Kaplan and Meier and log rank test using a commercial computer software program (SPSS 10.0 for Windows, SPSS Inc., Chicago, IL, USA). The censored date was the date of surgery or—in patients not undergoing surgery—the date of radiological re-staging.
3. Results Out of 168 patients, 119 had an EBS. In 62 patients, the stent was inserted at the Duke University Medical Center; in the other 57 patients, it was inserted at the referring institution. Adequate information about the EBS was available in 65 patients, of whom 64 received a plastic stent. The stent size was 7 French (Fr) in 4 patients; 8.5 Fr in 4 patients, 10 Fr in 53 patients and 11.5 Fr in 3 patients. In one patient, the initial biliary drain was a self-expandable 30 Fr metal mesh stent. Eighteen patients had a PBD and 31 did not require any biliary drainage procedure (Table 1). The median interval between initial prosthetic biliary drainage and radiological re-staging was 93 days (range: 32–403 days). In those patients who underwent surgery, the median interval between prosthetic biliary drainage and surgery was 117 days (range: 26–356 days). Preoperative
Table 1 Preoperative biliary drainage Biliary drain EBS PBD No preoperative drainage
119 18 31
Total
168
Table 2 Characteristics of patients undergoing pancreaticoduodenectomy with and without preoperative biliary drain Biliary drain
Male (%) Median age (years) (range) Median preoperative Serum bilirubin (mg/dl) (range) White blood count (×109 l−1 ) (range)
Yes (n = 58)
No (n = 14)
60 63 (31–80)
43 63 (49–77)
0.6 (0.2–14.2)
0.4 (0.2–2.2)
5.6 (3.3–12.4)
6.3 (3.6–8.2)
Comorbidity (%) Cardiovascular disease Diabetes mellitus
13 (22) 13 (22)
0 3 (21)
Preoperative stage (%)a Resectable Locally advanced Unknown
46 (79) 7 (12) 5 (9)
12 (86) 2 (14) 0
Histology Pancreatic adenocarcinoma Ampullary cancer Cholangiocarcinoma Duodenal carcinoma Neuroendocrine tumour
45 5 7 0 1
10 2 0 2 0
a
Resectable: no evidence of direct invasion of the superior mesenteric artery (SMA) or celiac axis (CA) and patent superior mesenteric vein (SMV) and portal vein (PV). Locally advanced: presence of soft tissue abutting or encircling the SMA or CA or occlusion of the SMV or PV. Unknown: staging information of preoperative CT scan not available.
serum bilirubin was available in 50 out of the 58 patients who had prosthetic biliary drainage prior to pancreaticoduodenectomy: the median serum bilirubin was 0.6 mg/dl. Only four patients had a preoperative serum bilirubin greater than 1.5 mg/dl. Preoperative serum bilirubin was available in 13 out of the 14 patients without prosthetic drainage and was normal in 12 patients. One patient had a preoperative bilirubin of 2.2 mg/dl. Median preoperative serum bilirubin was 0.4 mg/dl (Table 2). 3.1. Stent-related complications Stent failure prior to surgery or—in those who did not undergo surgery—prior to the date of the re-staging CT occurred in 41 of the 119 patients (34%) who received an EBS. Stent failure presented with signs and symptoms of cholangitis in 16 patients (13%) and 1 patient died (0.8%). Thirty-three patients required a single stent exchange; seven patients had two or more stent exchanges. One patient had narrowing of a metal stent due to a tight stricture, which was balloon dilated. Eighteen patients (15%) were hospitalised for stent-related complications. The median length of hospital stay was 4 days (range: 2–18 days). In 19 out of the 119 patients (16%), stent failure occurred within 30 days of stent insertion. In 21 patients, stent failure occurred prior to initiation of CRT.
H. Gerke et al. / Digestive and Liver Disease 36 (2004) 412–418
One hundred and seventeen of the 119 patients with EBS received CRT. In 12 of those 117 patients, stent failure occurred during CRT. One patient died from biliary sepsis; in six patients, chemotherapy was discontinued due to biliary complications. Chemotherapy was resumed in four patients after 4, 6, 6 and 11 days, respectively, and discontinued in one patient due to a large duodenal ulcer and in another patient due to recurrent stent failure. Overall, CRT was discontinued early in 11 of 172 patients. In only one patient, this was attributed to a malfunctioning EBS. Kaplan–Meier analysis revealed a median stent survival of 190 days (95% confidence interval: 106–274 days) and a mean stent survival of 138 days (95% confidence interval: 124–152 days). Log rank testing did not show a significant difference in stent survival with respect to age (<60 or >60 years), preoperative staging, gender or histology; however, due to low statistical power these cannot be excluded. 3.2. Morbidity and mortality of pancreaticoduodenectomy One hundred and twenty patients underwent either tumour resection (75 patients) or palliative surgery (45 patients) (Fig. 1). Out of the 72 patients who underwent pancreaticoduodenectomy, 53 had received an EBS, 5 had received a PBD and 14 did not have any preoperative biliary drainage. The characteristics of the patients with and without pros-
Table 3 Postoperative complications of pancreaticoduodenectomya Any complication Complications requiring an invasive interventionb Death Surgical wound infection (SWI) Intra-abdominal abscess (IAA) Sterile fluid collection requiring drainage Intra-abdominal bleeding Gastric outlet obstruction Pancreatic fistula Chylous fistula Enterocutaneous fistula Delayed gastric emptying Portal vein thrombosis Pneumatosis intestinalis leading to re-explorationc Clostridium difficile colitis Gastrointestinal bleeding Port-a-cath infection Urinary tract infection Pneumonia Arrhythmia
48 15 3 20 9 3 2 3 2 2 1 5 1
(67) (21) (4) (28) (13) (4) (4)
(7)
1 4 (6) 2 1 2 2 4 (6)
Data is presented as number (%). Late complications not listed in the table include late enterocutaneous fistulas (n = 2) requiring re-operation after 4 and 8 months, respectively, and a late cologastrojejunal fistula (n = 1) requiring surgical repair after 4 months. a Occurring during the same admission or within 1 month of discharge. b Laparotomy or drainage procedure. c Two patients had intestinal pneumatosis on CT scan that resolved spontaneously and was not counted as a complication.
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Table 4 Postoperative complications after pancreaticoduodenectomy in patients with and without preoperative biliary drain Biliary drain
Wound infection Intra-abdominal abscess Invasive interventiona Any complication Postoperative death
Yes (n = 58)
No (n = 14)
17 7 13 41 3
3 2 2 7 0
(29) (12) (22) (71) (5)
(21) (14) (14) (50)
ns ns ns ns ns
Data is presented as number (%); ns = not significant. a Complications requiring laparotomy or a drainage procedure.
thetic biliary drainage (EBS and PBD) are summarised in Table 2. Postoperative complications occurred in 67% of the patients after pancreaticoduodenectomy (Tables 3 and 4). The mortality was 4%. Complication rates were not statistically different between patients with and without preoperative biliary drainage (Table 4).
4. Discussion Combined modality therapy improves survival in patients with pancreatic cancer. Yet, one-fourth of eligible patients do not receive postoperative chemoradiation due to delayed recovery from surgery [6]. This problem has been overcome by delivering chemoradiation prior to surgery. Moreover, neoadjuvant treatment might allow better selection of patients who benefit from pancreaticoduodenectomy, since patients with rapidly progressive disease or evident metastases after chemoradiation are not subjected to radical surgery. Another advantage of preoperative chemoradiation is potential downstaging of locally advanced tumours. However, neoadjuvant therapy requires biliary drainage in most patients, which raises concerns about morbidity related to biliary stent occlusion and increased surgical complications. The operative morbidity of pancreaticoduodenectomy (Whipple procedure) is high [9], and there is ongoing controversy about the impact of preoperative biliary drainage. A hypothetical benefit of preoperative biliary stenting did not translate into a lower operative morbidity in clinical studies [32], and retrospective data from the Memorial Sloan-Kettering Center (MSKC), New York, suggested an increased risk of infectious complication [33,34] as well as overall morbidity and mortality of pancreaticoduodenectomy after biliary stenting. Similar microbiological profiles of intraoperative bile cultures and cultures from the infection site support the hypothesis that these surgical infections arise from the biliary tree [35]. Bacteria are introduced into the biliary tree by endoscopic or transhepatic percutaneous manipulation and plastic stents provide a breeding ground for bacteria, which encourages sludge formation. Karsten et al. [27] demonstrated bacterial contamination of bile in 112 of the 119 patients (94%) who had a preoperative
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EBS compared to 34% of the patients without preoperative drainage (P < 0.001). Infections were more common in patients whose bile grew pathogens, and cultures from the infectious focus were likely to match the intraoperative bile cultures. On the other hand, the high incidence of contaminated bile did not result in an increased risk of infectious complications after pancreaticoduodenectomy in this series. Early randomised trials of preoperative biliary decompression via percutaneous transhepatic drains failed to demonstrate a reduced operative morbidity [29–31]. Since external bile loss might outweigh the advantages of biliary decompression, more favourable outcomes were expected with internal biliary drainage by endoscopic stenting [25]. The results of two randomised controlled trials (RCT) [22,28] of preoperative endsocopic biliary stenting were mixed. In a study by Lygidakis et al. [22], 38 patients were randomised to either EBS or no biliary drainage prior to pancreaticoduodenectomy. The postoperative morbidity was significantly lower in the drainage group (16% versus 74%). In a study by Lai et al. [28], 87 patients were randomly assigned to either early elective surgery or preoperative biliary drainage. The authors included patients who underwent palliative surgery. There was no difference in the morbidity and mortality rates between the drainage and the non-drainage group (39 and 15% versus 41 and 14%, respectively). In a meta-analysis, the combined data of these two RCT showed a tendency in favour of preoperative endoscopic stenting, although this failed to reach statistical significance [32]. While two retrospective studies suggested an increased risk of minor infectious complications due to preoperative biliary drainage, they did not confirm the increased operative morbidity and mortality suggested by the data from MSKC reported by Povoski et al. [33]. Pisters et al. [36] reviewed a prospective data cohort of 300 patients who underwent pancreaticoduodenectomy. Preoperative prosthetic biliary drainage was associated with an increased incidence of wound infections; however, this did not translate into an increased overall morbidity or mortality. Sohn et al. [37] analysed data from 567 patients and found an increased incidence of pancreatic fistulas and wound infections in patients with preoperative biliary drains, but no increased overall morbidity or mortality. Martignoni et al. did not find a difference in postoperative complications after pancreaticoduodenectomy between those patients who underwent preoperative biliary drainage and those who did not [24]. Unlike the present study, previous studies have not assessed the impact of preoperative biliary drainage on postoperative complications in the setting of neoadjuvant chemotherapy. In the present study, there was no statistically significant difference in the incidence of wound infections (29% versus 21%) and intra-abdominal abscesses (12% versus 14%) between patients with and without prosthetic biliary drainage who underwent pancreaticoduodenectomy. Interpretation of the results is hampered by lack of randomised controls and low statistical power, due to the small sample size. Yet, it is noteworthy
that both wound infections and intra-abdominal abscesses were commonly observed in the no-drainage group. Previously published data show that the contribution, if any, of preoperative prosthetic biliary drainage to the incidence of infectious surgical complications is small. The present study suggests that this remains true in the setting of CRT. Most studies evaluating postoperative complications and preoperative drainage did not account for stent-related complications; one might fear that these might be increased in the setting of neoadjuvant chemoradiation due to immunosuppression. In the present study, stent failure prior to surgery or re-staging occurred in 34% of the patients with preoperative EBS. Sixteen percent of the patients with endoscopic stents had early stent failure within 30 days of stent insertion. In more than half of the patients, stent failure occurred before the neoadjuvant therapy was initiated. Two large series from Amsterdam reported similar stent failure rates of 33 and 34%, respectively, in patients with preoperative drainage prior to pancreaticoduodenectomy who did not undergo neoadjuvant therapy [25,27]. Pisters et al. [38] reported stent malfunction (occlusion or migration) in 15% of the patients with pancreatic cancer in the setting of neoadjuvant chemoradiation. Only stent failure that occurred after initiation chemoradiation was taken into account, which explains the lower stent failure rates compared to the present study. Lofts et al. [39] retrospectively analysed stent occlusion rates in 47 patients with adenocarcinoma of the pancreas, bile ducts or gall bladder. Stent occlusion rates did not differ between patients who received chemotherapy and those who did not (37 and 39%, respectively), and the mean duration of patency was not shortened by chemotherapy (105 days in the chemotherapy group versus 119 days in the non-chemotherapy group). In the present study, the median and mean durations of EBS patency were 190 and 138 days, respectively, according to Kaplan–Meier analysis. We accept that this is a rough estimate because stent patency was only followed until surgery or radiological re-staging, and stent occlusion occurred in only 34% of the patients during that observation period. The duration of stent patency in the present study compares to that of historical controls, who did not undergo chemoradiation: mean duration of EBS patency in malignancy has been reported as 2–6 months [40–50]. Thus, we believe that chemoradiation does not shorten stent patency. In the present study, stent occlusion was typically managed by an outpatient stent exchange. However, 18 of the 41 patients with malfunctioning EBS required hospitalisation for a median of 4 days. This underlines the importance of following these patients closely at centres with experience in interventional ERCP. The impact of EBS-related complications on CRT was low in the present study. One hundred and seventeen of the 119 patients with EBS received CRT. Of those patients, treatment was discontinued due to stent-related complications in six patients (5%) and resumed in four patients after a median of 6 days. Another patient with EBS died from cholangitis
H. Gerke et al. / Digestive and Liver Disease 36 (2004) 412–418
during CRT. Overall, CRT was terminated early in 11 out of 172 patients; this was due to a malfunctioning biliary stent in one patient only. Pisters et al. [38] reported treatment interruption due to stent occlusion in 4 of the 154 patients (2.6%), with treatment breaks of 2 and 3 days in two patients and early treatment termination in two patients. We conclude that interruption of chemoradiation due to a malfunctioning EBS is uncommon, and treatment can usually be continued after stent exchange. It has been argued that preoperative biliary drainage has no advantage over immediate pancreaticoduodenectomy. On the other hand, it has been shown that patients treated at centres with a higher volume of pancreaticoduodenectomies have lower mortality rates [51]. Many patients are diagnosed and evaluated at regional centres; in these patients, palliative biliary decompression allows time for preoperative work-up and referral to a specialised centre. Furthermore, biliary drainage of jaundiced patients is a “sine qua non” for CRT. We feel that the potential benefits of preoperative biliary drainage and neoadjuvant therapy outweigh any excess of preoperative morbidity related to endoscopic or percutaneous biliary drainage. It is important that the patients have access to centres that can provide prompt therapy for stent-related complications. Conflict of interest statement None declared.
List of abbreviations CRT, neoadjuvant chemoradiation therapy; EBRT, external beam radiation therapy; EBS, endoscopic biliary stent; PBD, percutaneous biliary drain; RCT, randomised controlled trial.
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