Pancreatic Cancer Surgery in the New Millennium

Transcription

ORIGINAL ARTICLE
Pancreatic Cancer Surgery in the New Millennium
Better Prediction of Outcome
Werner Hartwig, MD,∗ Thilo Hackert, MD,∗ Ulf Hinz, MSc,∗ Alexander Gluth,∗ Frank Bergmann, MD,†
Oliver Strobel, MD,∗ Markus W. Büchler, MD,∗ and Jens Werner, MD∗
Background: Surgery is the only therapy with potentially curative intention
in pancreatic cancer. This analysis aimed to determine prognostic parameters
in a patient cohort with resected pancreatic adenocarcinoma with a special
focus on the revised R1-definition.
Methods: Between October 2001 and August 2009, data from 1071 consecutively resected patients with pancreatic adenocarcinoma were prospectively
collected in an electronical database. Parameters tested for survival prediction
in univariate analysis included patient, tumor, and resection characteristics as
well as adjuvant therapy. The parameters with significant results were used for
multivariate survival analysis. Identified parameters with positive or negative
prognostic effect were used to define risk groups and to assess the effects on
patient survival.
Results: Age, ASA-score, CEA and CA19–9 levels, preoperative insulindependent diabetes mellitus, T-, N-, M-, R-, G-tumor classification, advanced
disease, and LNR were all significant in univariate analysis, whereas gender,
NYHA score, BMI, insurance status, type of surgical procedure, and adjuvant therapy were not. In multivariate analysis, age ≥70 years, preoperative
insulin-dependent diabetes, CA19–9 ≥400 U/mL, T4-, M1- or G3-status, and
LNR > 0.2 were independent negative predictors, whereas Tis/T1/T2-status,
G1-differentiation, and R0-status (revised definition) were independently associated with good prognosis. Using these risk factors, patients were stratified
into 4 risk-groups with significantly different prognosis; 5-year survival varied between 0% and 54.5%. Risk stratification resulted in improved survival
prognostication within the predominant AJCC IIA and AJCC IIB stages.
Conclusions: A newly defined prognostic profiling including the revised R1definition discriminates survival of patients with resectable pancreatic adenocarcinoma better than the AJCC staging system, and may be of particular
relevance for patient-adjusted therapy in the heterogeneous group of AJCC
stage II tumors.
(Ann Surg 2011;254:311–319)
T
o date, surgical resection is the only effective therapy that offers
the prospect of significant survival prolongation and the potential
of cure in patients with pancreatic cancer. Whereas overall survival of
patients with ductal adenocarcinoma is generally low, some patient
subgroups with good long-term prognosis have been identified.1,2
Cameron et al have described a 5-year survival rate of 41% in patients
with resected adenocarcinomas of the head of the pancreas in which
both lymph node and resection margin were negative.3 Likewise,
long-term survivors (>10 years) have been described in 5% of patients
with resected pancreatic adenocarcinoma.4 Adjuvant chemotherapy
From the *Department of General Surgery and †Department of Pathology, University of Heidelberg, Germany.
Reprints: Markus W. Büchler, MD, Department of General Surgery, University of
Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. E-mail:
[email protected].
Presented at the 2010 meeting of the American Pancreatic Association, Chicago,
IL, November 3–6.
C 2011 by Lippincott Williams & Wilkins
Copyright ISSN: 0003-4932/11/25402-0311
DOI: 10.1097/SLA.0b013e31821fd334
Annals of Surgery r Volume 254, Number 2, August 2011
or possibly also immunoradiochemotherapy may contribute to or even
improve these results.5–7
Prognosis of patients with pancreatic adenocarcinoma is defined by tumor stages according to the AJCC Cancer Staging
Manual.8 For pancreatic cancer, the last significant revision, published in 2002 (6th edition),9 newly classified T4 tumors as those,
which extend beyond the pancreas and involve the celiac axis or
superior mesenteric artery. These tumors generally are deemed irresectable. However, recent studies which assessed the survival of patients with resected pancreatic carcinomas mixed old and new staging
criteria, mostly due to prolonged acquisition periods of tumor registry databases,8,10 or are based on relatively small patient cohorts.11,12
Therefore, suggested nomograms, implemented additional prognostic
parameters, or risk models may be of only limited value for improved
prognosis estimation of patients with resected pancreatic adenocarcinoma which are classified according to the current TNM staging
system.
This analysis aims to determine prognostic parameters for patients with resected pancreatic adenocarcinoma. Patients have all been
treated by a highly standardized surgical strategy within a relatively
short period of time and have all been classified by the current AJCC
2010 cancer staging system. Including the revised R1-definition,13,14
which applied a standardized examination of resection specimens
with inking of the resection margins and defined R1 as a distance of the
tumor from the resection margin of ≤1 mm, we identified prognostic
parameters which provide additional information for improved prognosis estimation, in particular for the largely heterogeneous group of
patients with resectable locoregional pancreatic cancer.
PATIENTS AND METHODS
Patient Selection
A total of 1071 consecutive patients who underwent pancreatic resection for primary pancreatic adenocarcinoma were identified from a prospectively maintained database of 2633 pancreatic
resections that were undertaken between October 2001 and August
2009 at the Department of General Surgery, University of Heidelberg,
Germany. All tumors were classified according to the TNM criteria of
the AJCC 2010 cancer system.15 Those patients who were operated
before the AJCC revision in 2002,9 which newly defined T4 as tumors
that infiltrate the superior mesenteric artery or the celiac trunk, were
reclassified accordingly. Patients ± neoadjuvant chemoradiotherapy
where histopathologic evaluation demonstrated tumor-free hepatic or
mesenteric artery resection specimen were classified pT3. Patients
with ampullary carcinomas or carcinomas of the distal bile duct were
excluded from analysis.
Surgical Eligibility
Standard preoperative evaluation included physical examination, routine laboratory testing, serum levels of the tumor markers
CEA and CA19–9, chest radiography, contrast enhanced helical computed tomography, and/or state-of-the art magnetic resonance imaging. All patients in this series had primary adenocarcinomas of the
pancreas, all of which were confirmed by final pathology. In general,
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Hartwig et al
tumors were excluded from resection if the presence of metastatic disease was identified by presurgical imaging studies. Suspected ductal
adenocarcinomas with singular liver metastasis as identified by preoperative cross-sectional imaging or intraoperatively were resected
only in selected patients who were young or in otherwise extraordinary healthy condition. Patients with advanced locoregional disease
and tumor propagation to the large arterial vessels were generally
explored and eventually resected after neoadjuvant chemoradiation
when patients were in generally good condition and distant metastasis had been ruled out by imaging studies. Adjuvant therapy was
generally performed in all patients with histology-proven adenocarcinoma of the pancreas excluding those patients with a postoperatively
poor Karnofsky index whose condition did not permit adjuvant therapy. Furthermore, adjuvant chemotherapy was applied selectively to
patients with stage I IPMN- or MCN-associated carcinomas in the
first years of the investigated period due to their supposedly more
favorable tumor biology.16–18
Parameter Analysis
All parameters were prospectively collected in an electronic
database. Possible determinants of patient survival were tested for
patient, tumor, and resection characteristics. Patient characteristics
included age, gender, insurance status, ASA score, NYHA score,
presence of preoperative diabetes mellitus, body mass index (BMI),
and serum levels of CEA and CA 19–9. Tumor and resection characteristics include tumor location and histology, type of resection, T-,
N-, M-, R-, G-status, lymph node ratio (LNR), the number of lymph
nodes evaluated, and the time of surgery in relation to the revised
pathological specimen evaluation and R1-definition. The margin resection status (R-status) was defined according to general recommendations before June 2005 when R1 was defined as tumor formations
invading the resection margin. Starting June 2005, pathologic reporting included a standardized examination of resection specimens with
inking of the resection margins, and R1 was defined as a distance of
the tumor from the resection margin of ≤1 mm.13,14
Follow-up
To assess long-term survival, data from our pancreatic outpatient clinic was used. For those patients whom were not included
in our follow-up program, patients, general practitioners, relatives,
and insurance companies were contacted by telephone and asked for
patient survival, or the documented day of death. Follow-up was incomplete for 53 patients (5%). Of those, 36 patients were resected in
2009 and had a follow-up time of less than 6 months.
Statistical Analysis
SAS software (Release 9.1, SAS Institute, Inc, Cary, NC) was
used for statistical analysis. The quantitative variables age, BMI,
serum levels of CEA and CA 19–9, LNR, the number of lymph
nodes evaluated, and follow-up time were expressed as median with
interquartile range (IQR). Overall survival was defined as the time
from the date of pancreatic resection to either death from any cause or
last follow-up. Patients alive at the last follow-up were censored. Survival curves were constructed by using the Kaplan–Meier estimate.
The 5-year survival rates and the median survival time are presented.
Survival differences between subgroups of patients were analyzed by
the log-rank test. Univariate associations between patient characteristics, tumor and resection characteristics and overall survival were
assessed by Cox proportional hazards regression analysis. To confirm
predictors of survival, all significant parameters were further examined by a multivariate Cox proportional hazards regression analysis
among patients with complete data sets. Patients who died in the
hospital or were lost to follow-up were excluded from analysis of
312 | www.annalsofsurgery.com
prognostic factors. Two-sided P values were always computed and a
difference was considered statistically significant at P < 0.05.
RESULTS
In an 8-year period, pancreatic resection was performed in
1071 patients with a primary pancreatic adenocarcinoma. Median
age of patients was 65.4 years, and the male to female distribution
was 56% to 44%. Patient characteristics including insurance status,
comorbidity, BMI, and tumor markers are presented in Table 1. Pancreatic head resections were performed in 712 patients (66.5%), distal
pancreatectomies in 199 patients (18.6%), and total pancreatectomies
in 160 patients (14.9%). The 30-day mortality rate was 2.2%.
The majority of patients had the tumor located in the head of the
pancreas (73.2%), whereas multifocal lesions or tumors in the body
or tail of the pancreas were almost equally distributed throughout the
remaining patients (Table 2). Histopathologic evaluation identified
predominantly ductal adenocarcinomas (in 90.3% of patients) and
IPMN-based adenocarcinomas (in 5.8% of patients). Data on TNM
and AJCC stage including information about the resection status and
grading of the tumor is presented in Table 2. Likewise, data on LNR
in lymph node positive patients is shown in Table 2. Overall, a median
of 22 lymph nodes (interquartile range 15–29) has been resected and
evaluated by pathology. Before the revision of the R1-definition in
June 2005, more that 80% of resections where histopathologically
margin negative, whereas this rate decreased to 36% in the second
period (Table 2).
Median follow-up of patients alive at last contact was
17 months (range 1–92 months, interquartile range 10–31 months).
Parameters tested for survival prediction in univariate analysis included all presented patient, tumor, and resection characteristics as
well as adjuvant therapy. In univariate analysis, age ≥70 years, ASA
3/4 score, insulin-dependent diabetes mellitus, serum CEA level ≥5
μg/L, serum CA19–9 level ≥ 400 U/mL, advanced disease (T4, R2,
or M1), T4-, N1-, M1-, R1/2-, G3/4-status, and a LNR > 0 were negative predictive factors for survival. IPMN-based adenocarcinomas
TABLE 1. Patient Characteristics
Parameter
N (%)
Sex
Male
Female
Age (yrs)
Health insurance
Private
Compulsory
ASA Score
ASA I
ASA II
ASA III
ASA IV
NYHA Score
NYHA 1
NYHA 2
NYHA 3
Diabetes mellitus
BMI
Underweight (BMI < 18)
Normal weight (BMI 18–<25)
Overweight (BMI 25–<30)
Obesity (BMI ≥ 30)
CA 19–9 [U/mL]
CEA [μg/L]
Median (IQR)
599 (55.9%)
472 (44.1%)
65.4 (57.9–71.1)
591 (57.3%)
441 (42.7%)
30 (3,26%)
524 (56,89%)
359 (38,98%)
2 (0,22%)
43 (3.9%)
27 (2.5%)
3 (0.3%)
151 (14.6%)
24.3 (22.1–26.9)
27 (2.6%)
577 (55.7%)
340 (32.8%)
92 (8.9%)
124.2 (31.4–435.1)
2.8 (1.7–5.6)
IQR indicates interquartile range.
C 2011 Lippincott Williams & Wilkins
TABLE 2. Tumor Characteristics
Parameter
N (%)
Tumor location
Head
Corpus
Tail
>1 Location
Histology
Pancreatic ductal adenocarcinoma
Undifferentiated pancreatic carcinoma
Adenosquamous carcinoma
Cystic adenocarcinoma
Malignant IPMN
T factor
Tis
T1
T2
T3
T4
Positive lymph nodes
Lymph node ratio (N pos.)*
No. lymph nodes evaluated*
Distant metastasis
Resection status
R 0 revised
R 0 old
R 1 revised
R 1 old
R2
Grading
G1
G2
G 3/4
AJCC stage
Stage 0
Stage IA
Stage IB
Stage IIA
Stage IIB
Stage III
Stage IV
784 (73.2%)
97 (9.1%)
91 (8.5%)
99 (9.2%)
967 (90.3%)
13 (1.2%)
26 (2.4%)
3 (0.3%)
62 (5.8%)
21 (2.0%)
23 (2.2%)
18 (1.7%)
946 (88.5%)
61 (5.7%)
814 (76.1%)
0.17 (0.09–0.31)
22 (15–29)
86 (8.0%)
255 (24.0%)
270 (25.4%)
431 (40.5%)
51 (4.8%)
56 (5.3%)
30 (3.0%)
676 (66.6%)
309 (30.4%)
21 (2.0%)
21 (2.0%)
8 (0.8%)
182 (17.0%)
698 (65.3%)
53 (5.0%)
86 (8.0%)
*For lymph node ratio and number of lymph nodes evaluated, the median and the
interquartile range (IQR) are presented.
(IPMCs), Tis/T1/T2- and revised R0- and G1-status were associated with good prognosis (Table 3). The parameters with no significant effects on survival were gender, health insurance status, BMI,
NYHA-status, type of pancreatic resection, the number of lymph
nodes resected and subsequently evaluated by pathology in the resection specimen, and adjuvant chemo- or radiochemotherapy. Importantly, the time of surgery, which is assessed in relation to the onset of
the revised R1-definition, showed no significant effects on survival.
The parameters with significant results in univariate analysis
were subsequently used for multivariate survival analysis in the Cox
proportional hazards model. In this multivariate approach among 809
patients with complete data sets, age ≥70 years (P = 0.0045), the presence of preoperative insulin-dependent diabetes (P = 0.0094), serum
CA19–9 levels of ≥ 400 U/mL (P < 0.0001), T4- (P < 0.0001), or
M1-status (P < 0.0001), LNR > 0.2 (P < 0.0001), and G3-tumor
differentiation (P < 0.0001) were independent negative predictors
of survival (Table 4, Figs. 1A–D). Parameters which were independent positive predictors were Tis/T1/T2- and revised R0-status and
G1-tumor differentiation (Table 4, Figs. 1B, Figs. 1E, and Figs. 1F).
Whereas no differences in survival were seen between R0- and
R1-resected patients in the period before June 2005 (median
Prognosis in Resected Pancreatic Cancer
survival of 21.9 months vs. 19.6 months, respectively), patients with
R0-resections according to the revised definition had a significantly
better survival (Fig. 1E).
Patients were stratified according to the AJCC staging system (Fig. 2A) and were grouped using the number of independent
positive predictors (Tis/T1/T2, R0 revised, and G1; each weighted
–1) and negative predictors (age > 70, preoperative IDDM, serum
CA19–9 level ≥400 U/mL, T4-, G3/4-, M1-status, and LNR > 0.2;
each weighted + 1) identified by multivariate analysis. Calculating
the overall sum of the risk factors, 4 risk groups were identified with
5-year survival rates between 0% in the highest-risk group, 6.6% and
17.4% in the intermediate risk groups, and 54.5% in the lowest-risk
group (Fig. 2B). For the large groups of both AJCC IIA (17%) and IIB
(65%) patients the prognosis was inhomogeneous. Additional information from identified prognostic markers allowed the stratification
of these patients with significant survival differences within the AJCC
stages. Whereas median survival and 5-year survival rate were 29.8
months and 23.6% for the AJCC IIA group, respectively, the risk stratification resulted in median survival between 16.5 and 36.8 months
(Fig. 3A). Likewise, in the AJCC IIB group which showed a median
survival of 21.4 months and a 5-year survival rate of 9.6%, median
survival varied in dependency of the number of prognostic factors
between 10.3 and >50 months and 5-year survival rates between 0%
and 59.8% (Fig. 3B).
DISCUSSION
The study analyzed the survival of patients with resected primary adenocarcinoma of the pancreas. All patients have been treated
at a high-volume single institution within a period of about 8 years.
One thousand and seventy-one subsequent patients with major
pancreatic resections who had the diagnosis of primary pancreatic
adenocarcinoma in final histology were included in this analysis. A
relatively standardized surgical approach at our center within this period was accompanied by a uniform tumor classification according to
the AJCC staging system (6th edition, published in 20029 which is
identical to the 7th edition, published in 201015 for pancreatic carcinomas). Because the T4 and AJCC stage III definitions for pancreatic
cancer were newly defined in the AJCC 2002 system, all of our initially classified pT4 tumors (according to the AJCC criteria from
1997) were reclassified and remained pT4 only when the celiac axis
or the superior mesenteric artery were infiltrated by tumor. Furthermore, due to our pancreatic center status and a progressive surgical
attitude, patients with advanced locoregional disease who underwent
multivisceral resections19 and patients with resected limited metastasized disease20 also were included in this analysis. Therefore, all
stages of pancreatic cancer, which are resectable in potentially curative intention were included in this study.
The results of this study validate the 7th edition of the AJCC
staging system for pancreatic carcinomas and demonstrate sufficient survival discrimination between the tumor stages. As published
previously,8 we confirmed that tumor size, nodal status, and distant
metastasis were independent predictors of survival in patients who
underwent pancreatic resection. Importantly, additional independent
prognostic parameters were identified in our patient cohort: age older
than 70 years, the preoperative presence of insulin-dependent diabetes
mellitus, serum CA-19–9 levels above 400 U/mL, G3/4 tumor grading, and a LNR > 0.2 were negative predictors, and G1 tumor grading
was a positive predictor. Importantly, the resection margin status was
independently predictive in the multivariate Cox proportional hazards model only when the revised R-classification was applied.13,14
Therein, pathologic reporting included a standardized 3-dimentional
examination of resection specimens with inking of the resection margins, and R1 was defined as a distance of the tumor from the resection
margin of ≤1 mm.
Hartwig et al
TABLE 3. Univariate Analyses of Prognostic Factors for Overall Survival in 968 Patients with
Resection for Pancreatic Adenocarcinoma
Variables
Age
Sex
Health insurance
ASA
NYHA
Diabetes mellitus
Body mass index
CEA [μg/L]
CA 19–9 [U/mL]
Type of surgery
Tumor histology
Tumor progression intent
T-status
N-status
No. nodes evaluated
Lymph node ratio
M-status
R-status
Time of surgery
Grading
Adjuvant therapy
Category
Deaths/N
HR
<70 years
≥70 years
Male
Female
Compulsory
Private
1/2
3/4 (ASA 4: n = 2)
None
NYHA 1
NYHA 2 / 3
None
NIDDM
IDDM
<25
≥25
<5
≥5
<37
37–399
≥400
Pancreaticoduodenectomy
Distal pancreatectomy
Total pancreatectomy
Other adenocarcinoma
IPMC
Locoregional
Progressed (T4,R2,M1)
Tis / T1 / T2
T3
T4
N0
N1
≤15
>15
LNR 0
LNR >0–0.2
LNR >0.2–0.4
LNR >0.4
M0
M1
R0 old
R0 revised
R1 old
R1 revised
R2
10/01–06/05
07/05–08/09
G1
G2
G3/4
No
CTX
RCTX
412/688
186/280
340/538
258/430
340/551
245/393
325/557
244/370
557/904
27/38
14/26
417/703
58/97
100/137
338/543
237/395
348/571
148/220
114/232
266/418
175/239
420/654
103/181
75/133
581/907
17/61
486/833
112/135
21/61
533/855
44/52
126/235
472/733
164/246
419/701
120/224
240/414
139/200
85/111
534/888
64/80
219/258
103/233
43/50
184/372
44/49
300/347
298/621
16/29
372/619
186/269
96/155
384/638
70/109
1
1.28
1
0.98
1
0.95
1
1.26
1
1.15
1.31
1
0.93
1.38
1
0.89
1
1.40
0.76
1
1.58
1
0.99
1.07
1
0.23
1
2.23
0.36
1
1.73
1
1.77
1
1.02
1
1.51
1.91
2.24
1
2.44
1
0.69
1.07
1.15
1.91
1
0.89
0.44
1
1.53
1
0.99
0.85
95% CI
P
0.0045
1.08–1.53
0.7750
0.83–1.15
0.5094
0.80–1.12
0.0064
1.07–1.49
0.4797
0.78–1.69
0.77–2.23
0.0094
0.71–1.22
1.11–1.72
0.1691
0.75–1.05
0.0006
1.15–1.69
0.61–0.95
<0.0001
1.31–1.92
0.8460
0.80–1.23
0.84–1.37
0.14–0.38
1.81–2.74
0.23–0.56
1.27–2.36
<0.0001
<0.0001
<0.0001
<0.0001
1.45–2.15
0.8299
0.85–1.22
1.21–1.88
1.49–2.44
1.69–2.96
1.88–3.18
<0.0001
<0.0001
<0.0001
0.54–0.87
0.77–1.48
0.82–1.61
1.38–2.65
0.1704
0.75–1.05
0.27–0.73
<0.0001
1.28–1.83
0.4507
0.79–1.23
0.66–1.10
Bold values in the table represent significant values (P < 0.05).
CI indicates confidence interval; HR, hazard ratio.
When a prognostic risk score was calculated using the overall sum of independent positive (risk weighted –1) and negative
(risk weighted + 1) predictors identified by multivariate analysis,
the survival discrimination between prognostic groups was superior
to that in the AJCC staging system. For the entire cohort of patients
with resected primary pancreatic adenocarcinomas, 4 risk groups
were identified with 5-year survival rates varying between 0%, 6.6%,
17.4%, and a very good 54.6% from the highest-risk to the lowest-risk
group, respectively. The identified prognostic parameters apart from
the TNM-scoring provided additional relevant information for the
predominant and largely heterogeneous group of AJCC stage II patients, which are classified according to the AJCC-classification into
TABLE 4. Multivariate Analysis of Prognostic Factors for Overall Survival in
809 Patients with Resection for Pancreatic Adenocarcinoma
Variable
Category
HR
95% CI
P
Risk
Age
IDDM
CA 19–9
T-status
≥70 vs. <70 years
Yes vs. no
≥400 vs. <400 U/mL
Tis/T1/T2 vs. T3
T4 vs. T3
>0.2 vs. 0/≤0.2
M1 vs. M0
R0 revised vs. R0 old/R1/R2
G1 vs. G2
G3/4 vs. G2
1.25
1.53
1.48
0.57
1.83
1.34
1.88
0.64
0.40
1.57
1.03–1.51
1.20–1.94
1.22–1.79
0.34–0.95
1.30–2.57
1.11–1.61
1.39–2.54
0.50–0.83
0.23–0.69
1.29–1.90
0.0224
0.0005
<0.0001
0.0292
0.0005
0.0021
<0.0001
0.0005
0.0012
<0.0001
+
+
+
–
+
+
+
–
–
+
Lymph node ratio
Distant metastasis
R-status
Grading
CI indicates confidence interval; HR, hazard ratio; only patients with complete data sets included.
For risk stratification, patients were grouped using the number of independent positive predictors
(Tis/T1/T2, R0 revised, and G1; risk weighted -1) and negative predictors (age > 70, preoperative IDDM,
serum CA19–9 level ≥ 400 U/mL, T4-, G3/4-, M1-status, and LNR >0.2; risk weighted + 1).
stage IIA if nodal negative or stage IIB if nodal positive. Grouped
according to the newly defined prognostic scoring system, median
survival in the AJCC IIA stage varied between 36.8 months in the
lowest risk group (<0 risk factors), 26.0 months for the intermediate
risk group (0 or 1 risk factor), and 16.5 months in the highest risk
group (2 or 3 risk factors). A similar good survival stratification was
seen in the AJCC IIB group, with 5-year survival rates varying between 59.8%, 17.6%, 6.5%, and 0% in the groups with <0, 0, 1/2, and
3–5 risk factors, respectively. This clearly demonstrates the need to
include additional patient and tumor parameters to predict more accurately patient survival in this group of resected locoregional pancreatic
adenocarcinomas. As compared with the conventional AJCC staging
system, this system may help to adjust adjuvant therapy to patient risk
and tumor aggressiveness more properly. Negative predictive factors
including high age, the preoperative onset of insulin-dependent diabetes mellitus, high serum CA-19–9 levels, and the presence of distant metastasis confirmed by intraoperative frozen section may also
provide additional information for intraoperative decision making regarding the presumable benefit of potentially high-risk multivisceral
pancreatic resections.
This analysis provides strong evidence that a previously suggested revision of the R1-definition, which includes a detailed
3-dimentional histopathologic evaluation of resection specimens,13,14
is mandatory to predict patient survival. Survival rates of R0- and R1
resections were almost identical applying the general R1-definition
before June 2005, suggesting that the margin status is irrelevant
because systemic failure determines outcome in the majority of
patients.21 Importantly, R0-resections according to the revised definition were associated with significantly better prognosis, but were
achieved in only 36% of patients. This low rate of true R0-resections
may possibly account for the generally high rate of local recurrences
after pancreatic cancer resections.22
Along with the TNM staging criteria, tumor grading was one of
the strongest independent predictors of survival in our patient cohort.
Whereas G1-differentiated tumors were characterized by significantly
better median survival (43.5 months vs. 23.4 months, respectively)
and 5-year survival rates (36.0% vs. 11.4%, respectively) as compared
with G2 tumors, survival of G3/4 tumors was poor (median survival
15.2 months, 5-year survival rate 6.3%). Previously, the Memorial
Sloan Kettering Cancer Institute group suggested a nomogram to
better predict the likelihood of disease-specific survival after resection
of pancreatic cancer, where the degree of tumor differentiation was
included as one of the additional factors.23 Likewise several other
multivariate studies have shown that tumor grading is an important
independent prognostic factor after pancreatic carcinoma resection.
Analyzing 8082 patients with resected pancreatic cancer from the
Surveillance, Epidemiology, and End Results (SEER) database, Wasif
et al demonstrated that for each AJCC stage, survival was significantly
worse for high-grade versus low-grade tumors, and that a high tumor
grade was an independent predictor of survival for the entire cohort on
multivariate analysis.10 Summarizing the available evidence including
our study, it seems essential to include tumor grading in improved
prognostication models to reflect the aggressive biology of high-grade
pancreatic adenocarcinomas.
Extended lymphadenectomy during pancreaticoduodenectomy
neither had an effect on survival time in several randomized controlled trials,24–26 nor did a metaanalysis demonstrate any survival
benefit.27 However, the presence of lymph node metastasis in pancreatic cancer is strongly associated with impaired survival. The 5-year
survival rate decreased to 7,7% in nodal positive patients as compared
with 26.6% in nodal negative patients in this analysis. In the heterogeneous group of nodal-positive patients, survival could further be
stratified when the LNR was assessed. Whereas the 5-year survival
rate was 12.2% in patients with a LNR <0.2, it decreased to 6.6% and
1.7% when the LNR was >0.2 to 0.4 or >0.4, respectively. Importantly, LNR was an independent predictor in multivariate analysis.
In agreement with our analysis, several previous studies identified
LNR as independent factor determining survival in resected pancreatic carcinomas.28–30 Importantly, LNR must always be assessed in
combination with the number of lymph nodes resected, because a
low lymph-node retrieval may result in false-negative N0 findings.
Reflecting the quality of lymphadenectomy at our center, a median of
22 resected and histophathologically evaluated lymph nodes was reported for the entire cohort, where also distal pancreatectomies with
generally lower lymph node retrieval rates were included. This number
seems favorable when compared with those reported in the extended
lymphadenectomy groups of some randomized controlled trials for
pancreaticodudenectomy25,26 or in the large SEER database.31
Multiple studies have investigated tumor markers as possible
predictors for survival in patients with pancreatic cancer, and the
richest data is available on serum CA 19–9 levels. Using varying
cut-off levels between 100 and 1,000 U/mL, a significant shorter
postoperative survival of patients with high serum CA 19–9 levels
was reported.32–35 In a study including 129 patients, Berger et al found
lowest 5-year survival rates and shortest median survival in patients
with serum CA 19–9 levels >200 U/mL as compared with those
Hartwig et al
FIGURE 1. A–F, Prognostic parameters with highly significant effects (P < 0.0001) on survival identified by multivariate analysis.
Median survival time and 5-year survival rates are provided.
FIGURE 2. A and B, Survival of patients which were grouped
according to the AJCC staging system (A, n = 968) and
the number of risk factors identified by multivariate analysis
(B, n = 809). Only patients with complete follow-up and data
sets were included.
with moderately elevated (38–200 U/mL) or normal (<37 U/mL) CA
19–9 levels.33 Including preoperative data from 887 patients, our data
strongly supports this finding. With a cut-off point at 400 U/mL, high
serum CA 19–9 levels were one of the strongest negative survival
predictors in univariate as well as in multivariate analysis, with a
hazard ratio of 1.5. Whether high serum CA 19–9 levels reflect tumor
burden, tumor aggressiveness, or both is yet uncertain.
Diabetes mellitus may either be a risk factor for the development of pancreatic cancer36 or the result of pancreatic cancer
growth.37,38 For breast, prostate, as well as colorectal cancer there
is good data that diabetes mellitus is a negative predictive marker
for survival,39,40 whereas only limited data is available from smaller
cohort studies for pancreatic cancer.41,42 Our analysis provides very
strong evidence from uni- and multivariate analysis that a preoperative
existing insulin-dependent diabetes mellitus is a negative predictor of
survival in resected pancreatic adenocarcinomas. Interestingly, the
prognosis of patients with a non insulin-dependent diabetes mellitus
FIGURE 3. A and B, Survival of patients with AJCC IIA (A, n =
117) and IIB (B, n = 558) tumors stratified according to the
number of risk factors. Only patients with complete follow-up
and data sets were included.
was comparable to those without any evidence of diabetes mellitus.
Unlike preoperative insulin-dependent diabetes mellitus, an increased
BMI was not a negative predictive factor.
There is ongoing controversy about the prognosis of pancreatic
carcinomas which arise form intraductal papillary mucinocystic carcinomas (IPMCs) as compared with ductal adenocarcinomas. Some
reports suggested a better prognosis for IPMCs,16,17 but this benefit may just be based on earlier tumor diagnosis and subsequently
earlier tumor stages in IPMC resection specimens.43,44 In univariate
analysis, our data demonstrated significant better survival of IPMCs
compared with other adenocarcinomas of the pancreas, with a hazard
ratio of 0.23. This prognostic benefit was not sustained in multivariate
analysis. Therefore, this work clearly indicates that IPMCs and ductal
adenocarcinoms have comparable survival estimates when tumors are
corrected for TNM stage.
Several randomized controlled trials have produced strong evidence that have established adjuvant therapy as a cornerstone in
the multimodal treatment of pancreatic cancer.5,7 Accordingly, the
Hartwig et al
majority of patients in this series has received adjuvant chemotherapy
or chemoradiation, partially in the setting of randomized controlled
trials.16,17,45,46 Surprisingly, this analysis did not demonstrate a beneficial effect of either adjuvant chemotherapy or chemoradiation. This
finding may be explained by the heterogeneity of the “control” group,
which mixed severely impaired patients who had a low Karnofsky index and whose condition did not permit adjuvant treatment combined
with patients with favorable early stage mucinous carcinomas.16–18
Therefore this result does not contradict the beneficial role of adjuvant therapy.
In summary, this single-center analysis is one of the largest to
date, which investigated prognostic factors in patients with resected
pancreatic adenocarcinomas. With all tumors being staged according
to the current AJCC staging system, the study confirmed that tumor
size, nodal status, and distant metastasis were independent predictors
of patient survival. Additional independent prognostic parameters, including age older than 70 years, the preoperative presence of insulindependent diabetes mellitus, CA-19–9 serum levels above 400 U/mL,
R0 resection status as classified by the revised definition, G1 tumor
differentiation, and a LNR larger than 0.2 have been identified. Applying these independent predictors in a prognostic scoring model,
risk groups were identified with improved prognostication compared
with the AJCC system. This may have critical relevance for patientadjusted intraoperative decision making and adjuvant therapy which
incorporates individual predicted survival.
ACKNOWLEDGMENTS
The authors acknowledge Anne and Tom Queisser for their
help in manuscript preparation.
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Pancreatic Cancer Surgery in the New Millennium

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