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DOI 10.1007/s00432-012-1371-3
ORIGINAL PAPER
Received: 24 November 2012 / Accepted: 29 December 2012 / Published online: 13 January 2013
Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose CA 19-9 is the only established tumor marker in
pancreatic cancer (PC); the prognostic role of other serum
markers like CEA, CRP, LDH or bilirubin has not yet been
defined.
Methods We pooled pre-treatment data on CA 19-9,
CEA, CRP, LDH and bilirubin levels from two German
multicenter randomized phase II trials together with prospective patient data from one high-volume German Cancer Center. Marker levels were assessed locally before the
start of palliative first-line therapy for advanced PC and
serially during treatment (for CA 19-9 only). Clinical and
M. Haas V. Heinemann D. P. Modest C. Schulz
S. Boeck (&)
Department of Internal Medicine III and Comprehensive Cancer
Center, Klinikum Grosshadern, Ludwig-Maximilians-University
of Munich, Marchioninistr. 15, 81377 Munich, Germany
e-mail: stefan.boeck@med.uni-muenchen.de
F. Kullmann
Department of Medicine I, Gastroenterology/Oncology,
Klinikum Weiden, Weiden, Germany
R. P. Laubender
Institute of Medical Informatics, Biometry and Epidemiology,
Ludwig-Maximilians-University of Munich, Munich, Germany
C. Klose
Institute for Medical Biometry and Informatics,
University of Heidelberg, Heidelberg, Germany
C. J. Bruns
Department of Surgery and Comprehensive Cancer Center,
Klinikum Grosshadern, Ludwig-Maximilians-University of
Munich, Munich, Germany
S. Holdenrieder
Institute of Clinical Chemistry and Clinical Pharmacology,
University Hospital Bonn, Bonn, Germany
Introduction
The diagnosis of pancreatic cancer (PC) is still associated
with a dismal prognosis: only 1015 % of patients initially
present with resectable disease and can undergo curativeintent surgery. However, with a 5-year survival rate of only
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Results
Patient characteristics
Data from 291 PC patients were included into this pooled
multicenter analysis: 116 patients from the LMU Pancreas Center, 122 patients from the Ro96 trial and 53
patients from the GEMOXCET study. Baseline patient
characteristics are summarized within Table 1. At treatment initiation, 243 patients (84 %) had metastatic disease
and 48 patients (16 %) had locally advanced tumors. The
organ most commonly affected by metastases was the liver
(69 %), followed by lung (18 %) and peritoneum (5 %).
The majority of patients treated at the LMU received
gemcitabine-based chemotherapy (61 %) or a capecitabine-based regimen (23 %); only 16 (of the 24 patients
with locally advanced disease) received upfront chemoradiotherapy. Overall, 253 of all patients (87 %) received
treatment within a prospective clinical trial. Median TTP
from treatment initiation in the study cohort was estimated
with 5.1 months; median OS was 9.0 months (Table 1). At
the time of final data analysis, 237 of the 291 PC patients
(81 %) had died.
Univariate analysis of pre-treatment prognostic factors
Univariate analyses of 12 different clinical characteristics
and laboratory parameters were conducted regarding TTP
and OS, respectively (for details see Table 2). Regarding
TTP, the following clinical parameters revealed a statistical
significance: KPS C90 %, tumor grading with good or
median differentiated tumors (G1 ? G2) and age above
64 years (Table 2). Regarding the endpoint OS, locally
advanced tumors, a KPS C90 % and good or median differentiated tumors (G1 ? G2) had an improved survival.
Among laboratory parameters, normal LDH values
(defined as B250 U/l) had a prognostic significance for
both TTP (5.4 vs. 3.4 months, p \ 0.001) and OS (9.9 vs.
5.9 months, p \ 0.001). When LDH was analyzed as
continuous variableafter transformation into the natural
logarithm (log [LDH])and included into a Cox
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Table 1 Patient characteristics
Characteristic
LMU
patients
Ro96
GEMOXCET
Overall
116
122
53
291
Median
63
63
63
63
Range
3978
4075
3175
3178
Age (years)
Gender
Male
73 (63 %)
82 (67 %)
37 (70 %)
192 (66 %)
Female
43 (37 %)
40 (33 %)
16 (30 %)
99 (34 %)
24 (21 %)
24 (20 %)
48 (16 %)
Metastatic
92 (79 %)
98 (80 %)
53 (100 %)
243 (84 %)
29 (25 %)
21 (17 %)
8 (15 %)
58 (20 %)
83 (72 %)
55 (45 %)
31 (59 %)
169 (58 %)
Previous surgery
Karnofsky status (KPS)
90100 %
6080 %
32 (28 %)
66 (54 %)
10 (19 %)
108 (37 %)
Missing
1 (1 %)
1 (1 %)
12 (23 %)
14 (5 %)
G1 ? G2
46 (40 %)
49 (40 %)
22 (42 %)
117 (40 %)
G3 ? G4
59 (51 %)
45 (37 %)
21 (40 %)
125 (43 %)
Missing
11 (9 %)
28 (23 %)
10 (19 %)
49 (17 %)
Tumor grading
Localization of primary
Pancreatic head
72 (62 %)
67 (55 %)
26 (49 %)
165 (57 %)
44 (38 %)
28 (23 %)
19 (36 %)
91 (31 %)
Missing
27 (22 %)
8 (15 %)
35 (12 %)
Histology
Adenocarcinoma
112 (97 %)
122 (100 %)
53 (100 %)
287 (99 %)
4 (3 %)
4 (1 %)
Median
749
1,114
3,461
1,137
Range
881,626
6100,000
8100,000
6100,000
78 (67 %)
122 (100 %)
53 (100 %)
253 (87 %)
Patients deceased
100 (86 %)
97 (80 %)
40 (76 %)
237 (81 %)
4.1
5.5
4.9
5.1
10.1
9.7
7.3
9.0
proportional hazard regression model, the level of significance remained with a HR of 1.65 (95 % CI 1.182.31,
p = 0.004) for TTP and a HR of 1.93 (95 % CI 1.402.65,
p \ 0.001) for OS (Table 2). Measurements of serum CRP
levels at baseline also had a prognostic impact for TTP and
OS: while our pre-defined cutoff of 1.0 mg/dl did not reach
a level of statistical significance for TTP, this could be
observed after transformation into the natural logarithm log
[CRP] (HR 1.24; 95 % CI 1.031.49, p = 0.026).
Regarding OS, both the cutoff of 1.0 mg/dl (11.4 vs.
6.8 months, p = 0.009) and the transformed values log
[CRP] (HR 1.40, 95 % CI 1.161.69, p = 0.001) had a
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Table 2 continued
Variable
Variable
Median
TTP
(months)
Hazard
ratio
(95 % CI)
A: Time-to-progression (TTP)
[4.5 ng/ml
Stage of disease
Locally advanced
Metastatic
log [CEA]
48
243
4.4
5.1
0.868
1
0.97 (0.681.39)
169
5.5
6080 %
108
3.6
G1 ? G2
117
6.1
G3 ? G4
125
4.4
T1 ? T2
48
5.2
T3 ? T4
209
4.7
T (continuous)
256
1
0.004
1.51 (1.142.01)
Tumor grading
101
3.5
<0.001
1.89 (1.352.63)
0.004
1.11 (1.031.19)
0.964
0.99 (0.661.50)
0.351
2.17 (0.4311.12)
0.005
1.63 (1.162.32)
0.037
1.33 (1.021.74)
0.013
1.42 (1.081.88)
203
Hemoglobin
C12 g/dl
\12 g/dl
115
47
log [Hemoglobin]
148
4.1
4.4
0.008
Locally advanced
48
12.9
1.50 (1.102.03)
Metastatic
243
8.3
151
4.2
C64 years
140
5.8
192
4.5
90100 %
169
9.9
0.412
0.85 (0.581.25)
6080 %
108
8.0
0.832
1.02 (0.841.25)
G1 ? G2
117
10.8
G3 ? G4
125
8.3
T1 ? T2
48
8.3
T3 ? T4
209
9.2
99
5.3
1
0.015
0.72 (0.540.94)
1
0.915
1.02 (0.771.34)
Pre-treatment CA 19-9
T (continuous)
256
Age (at study entry)
20
3.8
B63 years
151
9.1
128
6.1
0.76 (0.451.27)
C64 years
140
8.8
[1,000 U/ml
140
4.0
1.11 (0.661.84)
log [age]
291
Pre-treatment CA 19-9
128
6.1
[1,000 U/ml
140
4.0
268
Male
192
8.6
0.002
1.55 (1.162.06)
Female
99
9.7
<0.001
1.15 (1.081.22)
62
6.6
[1,000 U/ml
61
3.5
123
log [LDH]
247
Not detectable*
20
8.9
B1,000 U/ml
128
10.5
0.002
2.00 (1.293.11)
[1,000 U/ml
140
8.0
<0.001
1.19 (1.081.31)
5.4
3.4
<0.001
1
2.04 (1.472.84)
0.004
1.65 (1.182.31)
CRP
59
6.1
[1.0 mg/dl
56
3.8
log [CRP]
110
0.062
1.52 (0.972.36)
0.026
1.24 (1.031.49)
Bilirubin
B1.0 mg/dl
224
4.9
[1.0 mg/dl
58
4.4
log [Bilirubin]
282
CEA
102
0.82 (0.581.17)
0.290
0.91 (0.771.08)
1
0.554
0.93 (0.721.20)
0.204
0.58 (0.261.34)
6.1
1
0.202
1.26 (0.881.79)
0.228
1.14 (0.921.41)
1
0.196
0.84 (0.641.01)
Pre-treatment CA 19-9
LDH
168
79
1
0.271
Gender
B1,000 U/ml
B250 U/l
[250 U/l
T stage
B1,000 U/ml
0.003
Tumor grading
Not detectable*
B4.5 ng/ml
B63 years
B1.0 mg/dl
Hazard
ratio
(95 % CI)
Stage of disease
Female
Median
TTP
(months)
T stage
Gender
Male
1
0.76 (0.451.27)
0.020
1.11 (0.661.84)
0.006
1.46 (1.111.90)
<0.001
1.13 (1.061.19)
0.048
1.49 (1.002.22)
0.002
1.15 (1.061.26)
<0.001
2.07 (1.552.78)
<0.001
1.93 (1.402.65)
Pre-treatment CA 19-9
B1,000 U/ml
128
10.5
[1,000 U/ml
140
8.0
62
10.3
[1,000
61
8.1
123
LDH
B250 U/l
168
9.9
[250 U/l
79
5.9
log [LDH]
CRP
B1.0 mg/dl
59
11.4
[1.0 mg/dl
56
6.8
1
0.009
1.69 (1.142.52)
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Table 2 continued
Variable
log [CRP]
Median
TTP
(months)
115
Hazard
ratio
(95 % CI)
0.001
1.40 (1.161.69)
Bilirubin
B1.0 mg/dl
224
9.7
[1.0 mg/dl
log [Bilirubin]
58
7.2
1
0.003
<0.001
1.62 (1.182.24)
1.43 (1.201.70)
CEA
B4.5 ng/ml
102
10.3
[4.5 ng/ml
101
9.0
log [CEA]
C12 g/dl
115
9.0
47
7.1
log [Hemoglobin]
1.35 (0.991.83)
0.053
1.07 (1.001.15)
0.463
1.15 (0.791.67)
0.547
0.64 (0.152.73)
123
1
0.054
Hemoglobin
\12 g/dl
Discussion
Within a pooled analysis based on data from two German
randomized phase II trials in conjunction with data from
one high-volume German Cancer Center, we were able to
investigate the prognostic role of 12 clinical and biochemical variables in patients with advanced PC. As
687
HR (95 % CI)
0.66 (0.440.98)
0.040
1.07 (0.691.65)
0.766
1.30 (0.871.95)
0.208
1.18 (1.091.28)
<0.001
log [LDH]
1.13 (0.642.00)
0.678
log [CEA]
log [CA 19-9] Elecsys (n = 84)
1.07 (0.981.18)
1.08 (0.941.24)
0.115
0.257
1.03 (0.821.30)
0.794
1.56 (1.032.35)
0.036
1.32 (0.941.85)
0.107
1.91 (1.372.67)
<0.001
1.02 (0.951.10)
0.581
log [LDH]
1.21 (0.831.75)
0.321
log [Bilirubin]
1.83 (1.432.36)
<0.001
1.04 (0.941.50)
0.429
1.32 (1.061.63)
0.011
expected, stage of disease and KPS were significant prognostic factors for TTP and OS also in our study population
(Heinemann et al. 2012). Interestingly, an age of C64 years
at study entry was associated with a prolonged TTP (5.8 vs.
4.2 months), without having an impact on OS (8.8 vs.
9.1 months), respectively. Thus, one might conclude that
age per se should be no contraindication for the use of
palliative chemotherapy in PC. We furthermore hypothesize that the prolongation of TTP in older patients might
argue for a slower tumor growth, which however was not
transferred into a survival benefit (possibly due to agedependent co-morbidities).
LDH is a known parameter indicating a high turnover of
cells with subsequent release of the intracellular enzyme.
The upper limit of normal (250 U/l) was chosen as a cutoff
for this study, and significant differences for TTP and OS
were observed in univariate (but not in multivariate)
analyses. The transformation into the natural logarithm,
potentially a more adequate method for the evaluation of a
continuous variable with a broad range, also revealed a
correlation with clinical outcome. Up to now, there are
only few reports describing a potential prognostic role of
LDH in patients with PC (Bramhall et al. 2001; Stocken
et al. 2008). Remarkably, baseline CRP levels also indicated a highly significant correlation with OS when using a
cutoff of 1.0 mg/dl in the univariate analysis (Falconer
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688
Table 4 Prognostic value of
CA 19-9 kinetics during the first
two treatment cycles (day
2064)
OS
(months)
Time-to-progression (TTP)
HR (95 % CI)
TTP
(months)
HR (95 % CI)
0.003
1.62 (1.172.25)
5.8
0.018
1.49 (1.012.09)
0.076
1.34 (0.971.87)
0.372
1.16 (0.841.61)
7.0
2.6
0.003
2.18 (1.283.72)
5.8
0.785
1.08 (0.631.83)
0.011
1.69 (1.122.55)
0.508
1.14 (0.781.66)
0.016
2.11 (1.133.95)
0.748
1.11 (0.602.04)
110
11.9
\25 %
76
8.2
C50 %
77
11.9
\50 %
109
8.8
4.4
5.5
5.4
46
37
13.4
8.6
0.004
2.03 (1.243.33)
C50 %
27
12.4
0.259
1.36 (0.792.34)
\50 %
56
9.5
6.1
C25 %
89
11.3
\25 %
49
6.2
C50 %
59
11.3
\50 %
79
6.8
<0.001
2.12 (1.443.14)
0.032
1.51 (1.032.22)
3.8
2.8
3.6
3.5
39
11.8
\25 %
25
7.5
C50 %
22
11.8
\50 %
42
7.6
0.001
2.52 (1.404.52)
5.9
2.8
0.146
1.57 (0.852.88)
4.7
4.7
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References
Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V
(2006) Prognostic and therapeutic significance of carbohydrate
antigen 199 as tumor marker in patients with pancreatic cancer.
Oncology 70(4):255264
Boeck S, Hoehler T, Seipelt G, Mahlberg R, Wein A, Hochhaus A
et al (2008) Capecitabine plus oxaliplatin (CapOx) versus
capecitabine plus gemcitabine (CapGem) versus gemcitabine
plus oxaliplatin (mGemOx): final results of a multicenter
randomized phase II trial in advanced pancreatic cancer. Ann
Oncol 19(2):340347
Boeck S, Haas M, Laubender RP, Kullmann F, Klose C, Bruns CJ
et al (2010) Application of a time-varying covariate model to the
analysis of CA 199 as serum biomarker in patients with
advanced pancreatic cancer. Clin Cancer Res 16(3):986994
Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA (2001)
Marimastat as first-line therapy for patients with unresectable
pancreatic cancer: a randomized trial. J Clin Oncol
19(15):34473455
Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW,
McKee RF et al (2005) The relationship between tumour
T-lymphocyte infiltration, the systemic inflammatory response
and survival in patients undergoing curative resection for
colorectal cancer. Br J Cancer 92(4):651654
689
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn
Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic
pancreatic cancer. N Engl J Med 364(19):18171825
Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor
R et al (2010) Tumor markers in pancreatic cancer: a European
Group on Tumor Markers (EGTM) status report. Ann Oncol
21(3):441447
Falconer JS, Fearon KC, Ross JA, Elton R, Wigmore SJ, Garden OJ
et al (1995) Acute-phase protein response and survival duration
of patients with pancreatic cancer. Cancer 75(8):20772082
Heinemann V, Haas M, Boeck S (2012) Systemic treatment of
advanced pancreatic cancer. Cancer Treat Rev 38(7):843853
Hess V, Glimelius B, Grawe P, Dietrich D, Bodoky G, Ruhstaller T
et al (2008) CA 199 tumour-marker response to chemotherapy
in patients with advanced pancreatic cancer enrolled in a
randomised controlled trial. Lancet Oncol 9(2):132138
Humphris JL, Chang DK, Johns AL, Scarlett CJ, Pajic M, Jones MD
et al (2012) The prognostic and predictive value of serum
CA19.9 in pancreatic cancer. Ann Oncol 23(7):17131722
Kullmann F, Hollerbach S, Dollinger MM, Harder J, Fuchs M,
Messmann H et al (2009) Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a
multicentre phase II study. Br J Cancer 100(7):10321036
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark
GM, Statistics Subcommittee of the NCI-EORTC Working
Group on Cancer Diagnostics (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J
Cancer 93(4):387391
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al
(2007) Erlotinib plus gemcitabine compared with gemcitabine
alone in patients with advanced pancreatic cancer. A phase III
trial of the National Cancer Institute of Canada Clinical trials
group. J Clin Oncol 25(15):19601966
Moses AG, Maingay J, Sangster K, Fearon KC, Ross JA (2009) Proinflammatory cytokine release by peripheral blood mononuclear
cells from patients with advanced pancreatic cancer: relationship
to acute phase response and survival. Oncol Rep 21(4):10911095
Pine JK, Fusai KG, Young R, Sharma D, Davidson BR, Menon KV
et al (2009) Serum C-reactive protein concentration and the
prognosis of ductal adenocarcinoma of the head of pancreas. Eur
J Surg Oncol 35(6):605610
Reni M, Cereda S, Balzano G, Passoni P, Rognone A, Fugazza C et al
(2009) Carbohydrate antigen 199 change during chemotherapy for
advanced pancreatic adenocarcinoma. Cancer 115(12):26302639
Stocken DD, Hassan AB, Altman DG, Billingham LJ, Bramhall SR,
Johnson PJ et al (2008) Modelling prognostic factors in
advanced pancreatic cancer. Br J Cancer 99(6):883893
Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van
Laethem JL et al (2009) Phase III trial of bevacizumab in
combination with gemcitabine and erlotinib in patients with
metastatic pancreatic cancer. J Clin Oncol 27(13):22312237
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011)
Pancreatic cancer. Lancet 378(9791):607620
123