Langenbecks Arch Surg DOI 10.1007/s00423-017-1590-9
ORIGINAL ARTICLE
Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study Ekaterina Petrova 1 & Felix Rückert 2 & Sebastian Zach 2 & YinFeng Shen 1,3 & Jürgen Weitz 4 & Robert Grützmann 4,5 & Uwe A. Wittel 6 & Frank Makowiec 6 & Ulrich T. Hopt 6 & Peter Bronsert 7 & Florian Kühn 8 & Bettina M. Rau 8 & Roman E. Izrailov 9 & Igor E. Khatkov 9 & Hryhoriy Lapshyn 1 & Louisa Bolm 1 & Dirk Bausch 1 & Tobias Keck 1 & Ulrich F. Wellner 1 & Gabriel Seifert 6
Received: 17 January 2017 / Accepted: 9 May 2017 # Springer-Verlag Berlin Heidelberg 2017
Abstract Purpose Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. Methods Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were
used to identify prognostic factors for postoperative mortality and overall survival. Results N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51–19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13–12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25–14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12–14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29–3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13–2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13–
Ekaterina Petrova and Felix Rückert contributed equally to the manuscript and share primary authorship. Ulrich F. Wellner and Gabriel Seifert contributed equally to the manuscript and share senior authorship. * Tobias Keck
[email protected]
1
Clinic of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
2
Department of Surgery, University Medical Center Mannheim, Mannheim, Germany
3
Department of Surgery, Hubei Hospital of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan 430061, People’s Republic of China
4
Department for Visceral, Thoracic and Vascular Surgery at the University Hospital, Technical University Dresden, Dresden, Germany
5
Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
6
Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany
7
Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
8
Department of General, Thoracic, Vascular and Transplantation Surgery, Rostock University Hospital, Rostock, Germany
9
Moscow Clinical Scientific Center, Moscow, Russia
Langenbecks Arch Surg
2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21–5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04–2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. Conclusion Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible. Keywords Distal bile duct carcinoma . Pancreatoduodenectomy . Pancreatic surgery . Distal cholangiocarcinoma . Periampullary carcinomaEkaterina Petrova and Felix Rückert contributed equally to the manuscript and share primary authorship.Ulrich F. Wellner and Gabriel Seifert contributed equally to the manuscript and share senior authorship.
Introduction Carcinomas arising from the biliary tree are grouped according to the current WHO classification into intrahepatic, perihilar, and distal bile duct carcinomas accounting for the difference in location, pathogenesis, and therapeutic approach to these tumors [1]. Distal bile duct carcinomas (DBDC) are defined by their primary site of origin in the segment between the confluence of the cystic and common bile ducts and the ampulla. It is a rare tumor with an annual incidence in western countries of 1–2 per 100,000 population [2], with the majority of patients in the seventh decade and male [3]. As for all periampullary carcinoma, including pancreatic head carcinoma, ampullary carcinoma, DBDC, and duodenal carcinoma, the only established curative therapy for DBDC is surgical resection, usually performed as pancreatoduodenectomy. Due to their location in the pancreatic head, common embryological origin, and similar histomorphology, differentiation between periampullary carcinoma is challenging and not always definitive [4]. In many aspects, like prognosis [5, 6], response to chemotherapy [7, 8], or incidence of postoperative pancreatic fistula [9, 10], there are differences between these tumors, which warrant an effort to make an accurate diagnosis and to study them separately. Due to the rarity of the disease, data on outcome after resection of DBDC is scarce, especially from western countries, and single-center studies are often underpowered due to the small number of patients. We report an analysis of outcome, risk, and prognostic factors in patients undergoing pancreatoduodenectomy for DBDC in the setting of a multicenter, retrospective, observational study.
Patients and methods Patients Approval for the study was obtained from the institutional ethics committee of the University of Lübeck (Ref 14037A). Patients who underwent pancreatoduodenectomy for DBDC were identified from institutional databases of each of the following five German and one Russian high-volume centers for pancreatic surgery in the corresponding time periods: University Medical Center Mannheim (1998–2013); University Medical Center Freiburg (1994–2012); University Hospital Technical University of Dresden (1994– 2014); Rostock University Hospital (2003–2014); University Hospital Schleswig-Holstein, Campus Lübeck (2013–2015); and Moscow Clinical Scientific Center, Russia (2012–2014). Study parameters The following parameters were analyzed: year of operation grouped in four time intervals (1994–2000, 2001–2005, 2006–2010, 2011–2015); patient characteristics (sex, age at the time of operation, body mass index (BMI)); total bilirubin serum level as measured prior to operation in mg/dl; operation features (type of resection (Whipple versus PPPD), with or without segmental portal vein resection (PVR), operative time (incision to skin closure)); postoperative complications (postoperative pancreatic fistula (POPF), postpancreatectomy hemorrhage (PPH), delayed gastric emptying (DGE), reoperation, in-hospital death); postoperative hospital stay (defined as the number of days from the first postoperative day till discharge); histological parameters (T, N, and M categories according to AJCC/UICC Classification 7th edition, grade of differentiation, margin status); overall survival follow-up as from the date of surgery, and long-term survival follow-up as from the day of hospital discharge. POPF, PPH, and DGE were defined and graded according to the International Study Group for Pancreatic Surgery (ISGPS) [11–13]; cases prior to the introduction of those definitions in 2005 were defined and classified retrospectively based on the patients’ records. Resection margin was considered positive (R1), whenever tumor cells were detected at the resection margin. Overall and long-term survival was defined as time in months till death of any cause after the operation and after hospital discharge. Statistical analysis For the statistical analysis, IBM SPSS Statistics for Windows, Version 22.0, and R version 3.3.1 were used. There were 29 (0.64%) missing data entries in 24 cases in 7 variables
Langenbecks Arch Surg
(operative time (8), BMI (6), bilirubin (4), margin status (2), DGE (5), grade (2), reoperation (2)). Multiple imputation [14] with the fully conditional specification method as implemented in SPSS was performed with center, time interval, age, sex, type of resection, PVR, T, N, M, log survival, survival status, in-hospital death, BMI, bilirubin, grade, operative time, resection margin, reoperation, and DGE included in the imputation model. A total of 20 imputations were performed. Median, 1-year, 3-year, and 5-year overall and longterm survival estimates were determined via the KaplanMeier method. For the further statistical analysis, variables were recoded in the following way: the continuous variables age and operative time were dichotomized with the median as cutoff; bilirubin level >4.5 mg/dl was compared with bilirubin level ≤4.5 mg/dl. This cutoff value was based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 of the National Cancer Institute [15], where bilirubin >4.5 mg/dl is the combined grade 3 and grade 4 hyperbilirubinemia. According to the WHO classification of obesity and overweight, patients with BMI ≥30 kg/m 2 (obese) and those with BMI 68 Sex 0 Female 1 Male BMI [kg/m2] 0 4.5 OP Type 0 PPPD 1 Whipple OP Time [min] 0 ≤377 1 >377 PVR 0 No 1 Yes Reoperation 0 No 1 Yes PPH 0 None/grade A 1 Grade B/C POPF 0 None/grade A 1 Grade B/C DGE 0 None/grade A 1 Grade B/C Time interval 0 1994–2000 1 2001–2005 2 2006–2010 3 2011–2015 Center Dresden Lübeck Mannheim Rostock Moscow Freiburg Total
117 102
6 12
5.1 11.8
76 143
8 10
10.5 7.0
183–186 42–45
13 5
7.0–7.1 11.1–11.9
160–163 65–68
12 6
7.4–7.5 8.8–9.2
181 38
14 4
7.7 10.5
113–116 112–115
7 11
6.0–6.2 9.6–9.8
186 27
12 6
6.5 18.2
183–187 41–45
6 12
3.2–3.3 26.7–29.3
186 33
8 10
4.3 30.3
160 59
6 12
3.8 20.3
184–187 41–44
11–12 6–7
5.9–6.5 14.0–16.7
45 70 59 54
3 6 2 7
6.7 8.6 3.4 13.0
83 6 32 51 3 53 228
9 0 2 3 0 4 18
10.8 0 6.3 5.9 0 7.6 7.8
p
Odds ratio
Upper
95% CI
p
Lower
Upper
1.12
14.03
0.033
2.47
0.89
6.86
0.083
4.00
0.64
0.24
1.70
0.367
NI
1.71
0.57
5.12
0.338
NI
1.23
0.44
3.44
0.695
NI
1.38
0.43
4.47
0.589
NI
1.66
0.61
4.47
0.316
NI
3.00
1.04
8.65
0.042
2.66
0.72
9.92
0.143
12.25
4.23
35.49
377 PVR 0 No 1 Yes T 0 T1 1 T2 2 T3/4 N 0 N0 1 N1 M 0 M0 1 M1/x R 0 R0 1 R+ G 0 G1/2 1 G3/4 Grade C complications 0 No 1 Yes Time interval 0 1994–2000 1 2001–2005 2 2006–2010 3 2011–2015 Total
116 94
75 51
41 43
29.3 29.1
71 139
45 81
26 58
29.6 29.3
170–173 37–40
108–110 16–17
61–63 21–23
28.3–28.7 33.7–46.4
148–150 60–62
93–95 30–33
55–56 28–29
28.7–29.6 29.1–29.3
174 36
99 27
75 9
29.6 28.2
106–109 101–104
48–50 76–78
57–60 24–27
36.5–37.4 24.5–25.5
180 30
108 18
72 12
30.5 15.2
9 38 163
4 20 102
5 18 61
82.3 31.7 27.5
100 110
48 78
52 32
41.1 22.2
198 12
117 9
81 3
29.8 14.2
166–168 42–44
90–92 34–36
76 8
33.7–36.5 15.2–15.6
109–110 100–101
62–63 63–64
47 37
38.4 17.5
167–169 41–43
94–95 31–32
72–74 10–11
30.0–31.7 24.6–25.5
42 64 57 47 210
28 48 34 16 126
14 16 23 31 84
24.6 29.6 31.7 29.3 29.3
95% CI
p
Lower Upper
0.98
0.68
1.42
0.929
NI
1.00
0.68
1.44
0.950
NI
0.86
0.50
1.47
0.580
NI
1.17
0.75
1.83
0.483
NI NI
1.59
0.99
2.56
0.056
1.37
0.75
2.49
0.301
1.76
1.12
2.76
0.014
1.15
0.68
1.97
0.598
1.74
1.02
2.96
0.043
1.21
0.67
2.17
0.530
3.11 4.46 2.06
0.90 1.38 1.40
10.74 14.35 3.03
0.073 0.012
