Distal Cholangiocarcinoma and Pancreas

Adenocarcinoma: Are They Really the Same

Disease? A 13-Institution Study from the US
Extrahepatic Biliary Malignancy Consortium and the
Central Pancreas Consortium
Cecilia G Ethun, MD, Alexandra G Lopez-Aguiar, MD, Timothy M Pawlik, MD, MPH, PhD, FACS,
George Poultsides, MD, FACS, Kamran Idrees, MD, FACS, Ryan C Fields, MD, FACS,
Sharon M Weber, MD, FACS, Clifford Cho, MD, FACS, Robert C Martin, MD, PhD, FACS,
Charles R Scoggins, MD, FACS, Perry Shen, MD, FACS, Carl Schmidt, MD, FACS,
Ioannis Hatzaras, MD, FACS, David Bentrem, MD, FACS, Syed Ahmad, MD, FACS,
Daniel Abbott, MD, FACS, Hong Jin Kim, MD, FACS, Nipun Merchant, MD, FACS,
Charles A Staley, MD, FACS, David A Kooby, MD, FACS, Shishir K Maithel, MD, FACS

BACKGROUND: Distal cholangiocarcinoma (DC) and pancreatic ductal adenocarcinoma (PDAC) are often
managed as 1 entity, yet direct comparisons are lacking. Our aim was to use 2 large multi-
institutional databases to assess treatment, pathologic, and survival differences between these diseases.
STUDY DESIGN: This study included patients with DC and PDAC who underwent curative-intent pan-
creaticoduodenectomy from 2000 to 2015 at 13 institutions comprising the US Extrahepatic Biliary
Malignancy and Central Pancreas Consortiums. Primary endpoint was disease-specific survival (DSS).
RESULTS: Of 1,463 patients, 224 (15%) had DC and 1,239 (85%) had PDAC. Compared with PDAC, DC
patients were less likely to be margin-positive (19% vs 25%; p ¼ 0.005), lymph node (LN)-positive
(55% vs 69%; p < 0.001), and receive adjuvant therapy (57% vs 71%; p < 0.001). Of DC patients
treated with adjuvant therapy, 62% got gemcitabine alone and 16% got gemcitabine/cisplatin.
Distal cholangiocarcinoma was associated with improved median DSS (40 months) compared with
PDAC (22 months; p < 0.001), which persisted on multivariable analysis (hazard ratio 0.65; 95%
CI 0.50 to 0.84; p ¼ 0.001). Lymph node involvement was the only factor independently asso-
ciated with decreased DSS for both DC and PDAC. The DC/LN-positive patients had similar DSS
as PDAC/LN-negative patients (p ¼ 0.74). Adjuvant therapy (chemotherapy  radiation) was
associated with improved median DSS for PDAC/LN-positive patients (21 vs 13 months; p ¼
0.001), but not for DC patients (38 vs 40 months; p ¼ 0.62), regardless of LN status.
CONCLUSIONS: Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are distinct entities. Distal
cholangiocarcinoma has a favorable prognosis compared with PDAC, yet current adjuvant therapy
regimens are only associated with improved survival in PDAC, not DC. Therefore, treatment par-
adigms used for PDAC should not be extrapolated to DC, despite similar operative approaches, and
novel therapies for DC should be explored. (J Am Coll Surg 2017;224:406e413.
2016 by the
American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Disclosure Information: Nothing to disclose.
Presented at the Southern Surgical Association 128th Annual Meeting,
Palm Beach, FL, December 2016.
Received December 11, 2016; Accepted December 12, 2016.
From the Divisions of Surgical Oncology, Departments of Surgery, Winship
Cancer Institute, Emory University, Atlanta, GA (Ethun, Lopez-Aguiar, Staley,
Kooby, Maithel), Johns Hopkins University, Baltimore, MD (Pawlik), Vander-
bilt University, Nashville, TN (Idrees, Merchant), University of Louisville, Louis-
ville, KY (Martin, Scoggins), The Ohio State University, Columbus, OH
(Pawlik, Schmidt), University of Cincinnati, Cincinnati, OH (Ahmad, Abbott),
University of North Carolina, Raleigh, NC (Kim), and the University of Miami,
Miami, FL (Merchant); and the Departments of Surgery, Stanford University,
Stanford, CA (Poultsides), Washington University, St Louis, MO (Fields), Uni-
versity of Wisconsin, Madison, WI (Weber, Cho, Abbott), Wake Forest Univer-
sity, Winston-Salem, NC (Shen), New York University, New York, NY
(Hatzaras), and Northwestern University, Chicago, IL (Bentrem).
Correspondence address: Shishir K Maithel, MD, FACS, 1365C Clifton Rd NE,
Building C, 2nd Floor, Atlanta, GA 30322. email: smaithe@emory.edu

ª 2016 by the American College of Surgeons. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jamcollsurg.2016.12.006

All rights reserved. 406 ISSN 1072-7515/16
Vol. 224, No. 4, April 2017 Ethun et al
Abbreviations and Acronyms
CPC ¼ Central Pancreas Consortium
DC ¼ distal cholangiocarcinoma
DSS ¼ disease-specific survival
HR ¼ hazard ratio
IQR ¼ interquartile range
LN ¼ lymph node
PDAC ¼ pancreatic ductal adenocarcinoma
USEBMC ¼ US Extrahepatic Biliary Malignancy
Consortium
Distal cholangiocarcinoma (DC) and pancreatic ductal
adenocarcinoma (PDAC) of the pancreatic head belong
to a group of malignancies in close anatomic proximity
to each other known as “periampullary tumors.” Distal
cholangiocarcinoma is a biliary tract malignancy that
arises from the epithelium of the distal third of the
common bile duct. Although rare overall, it still repre-
sents 30% to 40% of extrahepatic cholangiocarcinomas
and approximately 10% to 14% of all periampullary
tumors.1-4 Pancreatic ductal adenocarcinoma arises
from the epithelium of the pancreatic ducts, is the
fourth most common cause of cancer-related deaths
in the US, and accounts for approximately 70% of all
periampullary tumors.2-5 Surgical resection with pan-
creaticoduodenectomy is the only potentially curative
treatment option for both DC and PDAC.
Because of the similar surgical management strategies
and perioperative outcomes, treatment algorithms for
PDAC are often extrapolated and applied to DC,
yet the role of adjuvant therapy in these tumors is
largely unclear.4 For patients with PDAC, adjuvant
therapy, either with chemotherapy alone or chemo-
therapy plus radiation, is generally considered standard
practice, although the exact modality and agent are
controversial.6 Few studies, however, have examined
the impact of adjuvant therapy in DC, and those that
do are limited by small numbers, combine DC patients
with those with other periampullary tumors, such as
ampullary and duodenal cancers, and have shown
mixed results.7-9
Even when adjuvant therapy is not considered,
data on long-term oncologic outcomes have also shown
mixed results, with some studies showing no difference
in survival between DC and PDAC, and others
showing improved survival in DC patients, albeit
modest.2,3,10-12 Again, due to the rarity of the disease,
many of the data are limited by small numbers
of DC patients, report single-institution experiences,
and focus primarily on the broader group of periampul-
lary tumors, rather than comparing DC and PDAC
Distal Cholangiocarcinoma and Pancreas Cancer 407
directly. The purpose of this study was to use 2 large,
multi-institutional databases to examine the pathologic,
treatment, and survival differences between patients un-
dergoing curative-intent pancreaticoduodenectomy for
DC and PDAC.
METHODS
The US Extrahepatic Biliary Malignancy Consortium
(USEBMC) is a collaboration among 10 high-volume
academic institutions: Emory University, Johns Hopkins
University, New York University, The Ohio State Univer-
sity, Stanford University, University of Louisville, Univer-
sity of Wisconsin, Vanderbilt University, Wake Forest
University, and Washington University in St Louis.
All patients from the USEBMC database with DC,
who underwent curative-intent pancreaticoduodenectomy
from January 2000 to December 2014, were evaluated.
The Central Pancreas Consortium (CPC) represents a
collaboration of 8 academic institutions: Emory Univer-
sity, Northwestern University, University of Cincinnati,
University of Louisville, University of North Carolina,
University of Wisconsin, Vanderbilt University, and
Washington University in St Louis. All patients from
the CPC database with PDAC of the pancreatic head,
who underwent curative-intent pancreaticoduodenectomy
from January 2000 to December 2012, were additionally
evaluated.
Pertinent baseline demographic, perioperative, and
pathologic data were collected retrospectively from patient
charts for both cohorts. Pathologic review was performed at
each institution by experienced gastrointestinal patholo-
gists, and pathologic staging was defined as per American
Joint Committee on Cancer 7th edition guidelines for
each disease site.13,14 The primary outcome was disease-
specific survival (DSS), which was determined from the
date of surgery until death from disease. Survival informa-
tion was verified with the Social Security Death Index,
when appropriate. Institutional review board approval
was obtained at each institution before data collection.
All statistical analysis was conducted using SPSS 22.0
software (IBM Inc). Chi-square analysis and Fisher’s exact
test were used to compare categorical variables, and Stu-
dent’s t-test was used for continuous variables, where
indicated. Univariable and multivariable Cox regression
analyses were performed to assess the association of
individual pathologic factors with DSS. Kaplan-Meier
survival plots for DSS were created and variables
compared using long-rank tests. Perioperative deaths
were defined as patients surviving less than 30 days post-
operatively, and were excluded from all survival analyses.
Statistical significance was predefined as p < 0.05.
408 Ethun et al Distal Cholangiocarcinoma and Pancreas Cancer J Am Coll Surg

Table 1. Comparisons of Baseline Demographics, Perioperative Data, and Pathologic Features of Distal Cholangiocarcinoma
and Pancreatic Ductal Adenocarcinoma
Distal Pancreatic ductal
cholangiocarcinoma adenocarcinoma
Variable (n ¼ 224, 15%) (n ¼ 1,239, 85%) p Value*
Age, y, mean  SD 66  11 65  10 0.17
Male sex, n (%) 140 (63) 629 (51) 0.001y
Race, n (%) <0.001y
White 176 (80) 1,048 (85)
African American 22 (10) 139 (11)
Other 23 (10) 47 (4)
Type of resection, n (%) <0.001y
Pylorus-preserving PD 104 (46) 408 (33)
Classic PD 117 (52) 831 (67)
PD þ hepatectomy 3 (2) 0 (0)
Portal vein resection, n (%) 8 (4) 166 (18) <0.001y
EBL, mL, mean  SD 619  878 600  722 0.77
Final margin status, n (%) 0.001y
R0 178 (80) 933 (75)
R1 45 (20) 306 (25)
Tumor size, cm, mean  SD 2.2  1.2 3.1  1.2 <0.001y
AJCC T-Stage, n (%) 0.39
T1/T2 49 (23) 224 (20)
T3/T4 168 (77) 989 (80)
Grade, n (%) 0.53
Well/moderate 154 (71) 833 (68)
Poor/undifferentiated 64 (29)
Lymphovascular invasion, n (%) 104 (52) 591 (55) 0.46
Perineural invasion, n (%) 168 (80) 972 (84) 0.14
LN positive, n (%) 120 (55) 855 (69) <0.001y
Positive LN, n, mean  SD 22 33 <0.001y
Total LN retrieved, n, mean  SD 17  9 17  10 0.71
Hospital LOS, d, mean  SD 13  11 13  43 0.99
Neoadjuvant therapy, n (%)z 3 (1) 110 (10) <0.001y
Adjuvant therapy, n (%)z 128 (57) 853 (71) <0.001y
*p Value from Pearson chi-square, Fisher’s exact, or t-test, where appropriate.
y
Significant.
z
Includes chemotherapy and/or radiation therapy.
AJCC, American Joint Committee on Cancer; EBL, estimated blood loss; LN, lymph node; LOS, length of stay; PD, pancreaticoduodenectomy.

RESULTS shown in Table 1. Compared with PDAC, patients

Of the 1,092 patients in the USEBMC database, 314
(29%) underwent resection for DC, 224 of whom
(71%) underwent curative-intent pancreaticoduodenec-
tomy. Of the 1,422 patients in the CPC database,
1,278 (90%) underwent resection for PDAC of the
pancreatic head, 1,239 (97%) of whom underwent
curative-intent pancreaticoduodenectomy. Combined, a
total of 1,463 patients were included in analysis: 224
(15%) DC and 1,239 (85%) PDAC.
Comparisons between groups for baseline demo-
graphics, perioperative factors, and pathologic data are
with DC were more likely to undergo a pylorus-
preserving pancreaticoduodenectomy (46% vs 33%;
p < 0.001), but less likely to require a portal vein resec-
tion (4% vs 18%; p < 0.001). There were no differences
in mean estimated blood loss or hospital length of stay
between groups.
Patients with DC had smaller tumors on average
(22 mm vs 31 mm; p < 0.001) and were more likely
to have negative microscopic margins (80% vs 75%;
p ¼ 0.001), but less likely to have lymph node (LN)-
positive disease (55% vs 69%; p < 0.001), despite
Vol. 224, No. 4, April 2017 Ethun et al Distal Cholangiocarcinoma and Pancreas Cancer 409

Survival data
1.0 DC (n=203)
Median: 40 months Median follow-up was 14.7 months (interquartile rage
PDAC (n=1093) [IQR] 6.1 to 32.1 months). The median DSS for the
Median: 22 months
0.8
entire cohort was 24.7 months (95% CI 21.8 to 27.5
months). Distal cholangiocarcinoma was associated with
Proportion Surviving

improved DSS compared with PDAC (39.8 months vs

0.6
0.4
0.2
0.0 p<0.001
0 20 40 60 80
Time (months)
Figure 1. Disease-specific survival. Distal cholangiocarcinoma (DC)
is associated with improved disease-specific survival compared with
pancreas ductal adenocarcinoma (PDAC); log-rank p < 0.001.
similar LN yields. The rates of advanced T-stage (T3/
T4), high pathologic grade, lymphovascular invasion,
and perineural invasion were also similar between
groups. Although less frequent among patients with
DC than with PDAC, adjuvant therapy (chemotherapy
 radiation) was given to the majority of patients in
both groups (57% vs 71%; p < 0.001). Among DC pa-
tients who were treated with adjuvant therapy, 62%
received gemcitabine alone and 16% received gemcita-
bine plus cisplatin, while 22% received some other
regimen.
22.0 months; p < 0.001; Fig. 1). Five-year DSS was
42% for DC and 24% for PDAC. On univariable Cox
regression analysis for the combined cohort, DC (hazard
ratio [HR] 0.58; 95% CI 0.46 to 0.74; p < 0.001) and
receipt of adjuvant therapy were associated with improved
DSS; LN-positive disease, margin positivity, lymphovas-
cular invasion, high pathologic grade, perineural invasion,
and advanced T-stage (T3/T4) were associated with worse
DSS (Table 2). Only DC (HR 0.65; 95% CI 0.5 to 0.84;
p ¼ 0.001), receipt of adjuvant therapy, LN-positive
100 120 disease, margin positivity, lymphovascular invasion, and
high pathologic grade maintained significance on multi-
variable analysis (Table 2).
Stratum-specific survival data by disease site
On stratum-specific analysis by disease site, LN status was
the only factor associated with DSS on multivariable Cox
regression among both DC and PDAC cohorts (Table 3).
Isolating out DC patients, LN-positive disease and
margin positivity were both associated with worse DSS
on univariable Cox regression analysis, but only LN-
positive disease maintained significance on multivariable
analysis (HR 1.63; 95% CI 1.02 to 2.62; p ¼ 0.04).
Among PDAC patients, adjuvant therapy was associated
with improved DSS, and LN-positive disease, margin
positivity, lymphovascular invasion, and high pathologic
grade were associated with worse DSS on multivariable
Cox regression analysis (Table 3).

Table 2. Univariable and Multivariable Cox Regression Analysis for Disease-Specific Survival among All Patients
Univariable analysis Multivariable analysis
Variable HR (95% CI) p Value HR (95% CI) p Value
Distal cholangiocarcinoma 0.58 (0.46e0.74) <0.001 0.69 (0.52e0.90) 0.007
Lymph node positive 1.82 (1.53e2.17) <0.001 1.60 (1.28e1.99) <0.001
Margin positive 1.79 (1.51e2.13) <0.001 1.68 (1.38e2.05) <0.001
LVI positive 1.69 (1.42e2.01) <0.001 1.37 (1.13e1.67) 0.001
High grade* 1.33 (1.13e1.56) 0.001 1.29 (1.07e1.56) 0.007
Tumor size >2cm 1.36 (1.13e1.64) 0.001 1.12 (0.89e1.41) 0.32
PNI positive 1.29 (1.02e1.62) 0.03 1.11 (0.85e1.44) 0.46
Advanced T-stagey 1.22 (1.01e1.48) 0.04 1.01 (0.80e1.28) 0.93
Adjuvant therapyz 0.82 (0.69e0.97) 0.02 0.65 (0.53e0.79) <0.001
Excludes 30-day mortalities, neoadjuvant therapy.
*Poor/undifferentiated vs well/moderate.
y
T3/T4 vs T1/T2.
z
Includes chemotherapy and/or radiation.
HR, hazard ratio; LVI, lymphovascular invasion; PNI, perineural invasion.
410 Ethun et al Distal Cholangiocarcinoma and Pancreas Cancer J Am Coll Surg

Table 3. Multivariable Cox Regression Analysis for Disease-Specific Survival Stratified by Tumor Site
Distal cholangiocarcinoma Pancreatic ductal adenocarcinoma
Variable HR (95% CI) p Value HR (95% CI) p Value
Lymph node positive 1.63 (1.02e2.62) 0.04 1.60 (1.25e2.03) <0.001
Margin positive 1.62 (0.94e2.77) 0.08 1.68 (1.38e2.08) <0.001
LVI positive d* 1.36 (1.10e1.67) 0.004
High gradey d* 1.26 (1.03e1.55) 0.02
Tumor size > 2 cm d* 1.19 (0.92e1.54) 0.20
PNI positive d* 1.17 (0.87e1.59) 0.30
Advanced T-stagez d* 1.01 (0.80e1.28) 0.63
Adjuvant therapyx d* 0.61 (0.49e0.76) <0.001
Excludes 30-d mortalities, neoadjuvant therapy.
*p > 0.1 on univariable analysis, therefore not included in multivariable analysis.
y
Poor/undifferentiated vs well/moderate.
z
T3/T4 vs T1/T2.
x
Includes chemotherapy and/or radiation.
HR, hazard ratio; LVI, lymphovascular invasion; PNI, perineural invasion.

When stratified by both disease site (DC vs PDAC) and
LN status, median DSS was the highest in DC/LN-
negative patients (60.5 months) compared with DC/
LN-positive (29.7 months), PDAC/LN-negative (37.0
months), and PDAC/LN-positive patients (19.0 months;
overall p < 0.001; Fig. 2). There was no difference in
DSS between DC/LN-positive and PDAC/LN-negative
patients (p ¼ 0.74). Adjuvant therapy was not associated
1.0
0.8
Proportion Surviving
with improved DSS in DC patients overall (HR 1.13;
95% CI 0.70 to 1.81; p ¼ 0.62), or in DC patients
when stratified by LN status (LN positive: HR 0.71;
95% CI 0.37 to 1.36; p ¼ 0.30; LN negative: HR
1.30; 95% CI 0.63 to 2.71; p ¼ 0.48). Although receipt
of adjuvant therapy was associated with improved DSS
among PDAC patients overall, when stratified by LN sta-
tus, this was true only in LN-positive disease (HR 0.61;
95% CI 0.49 to 0.77; p < 0.001), and not LN-negative
disease (HR 0.74; 95% CI 0.53 to 1.03; p ¼ 0.07).
DC / LN(-) DC / LN(+)
61 months 30 months
PDAC / LN(-) PDAC / LN(+)
DISCUSSION
37 months 19 months Due to their close anatomic proximity and similar man-
agement with pancreaticoduodenectomy, DC and

PDAC of the pancreatic head are often treated as 1 entity.

0.6
Detailed understanding of the differences in biologic
behavior and the value of adjuvant therapy between these
2 diseases, however, is lacking. In this study, we used
0.4 2 large, multi-institutional surgical databases to examine
the pathologic factors, treatment strategies, and long-
term survival in patients with DC and PDAC who under-
0.2
went curative-intent pancreaticoduodenectomy. Patients
with DC had improved DSS compared with those with
PDAC. Lymph node-positive disease was a poor prog-
0.0 p<0.001 nostic factor in both disease types, and adjuvant therapy
0 20 40 60 80 100 120 was associated only with improved DSS in LN-positive
Time (months) PDAC, but not in DC, regardless of LN status.
Figure 2. Disease-specific survival. Lymph node-negative disease In our cohort of 1,463 patients, 224 (15%) had DC
(LN) was associated with improved disease-specific survival (DSS) and 1,239 (85%) had PDAC. Baseline demographics
among both distal cholangiocarcinoma (DC) and pancreatic ductal for the 2 groups were similar to those in previous studies
adenocarcinoma (PDAC) patients. DC/LN() disease was associ-
that included DC and PDAC patients.3,10,11,15 Patients
ated with the best DSS, while PDAC/LN(þ) disease was associated
with the worse DSS; overall log-rank p < 0.001. There was no dif- with PDAC had a higher rate of portal vein resection
ference in median DSS between DC/LN(þ) and PDAC/LN() dis- (18%) compared with DC patients (4%), and had larger
ease; log-rank p ¼ 0.74. tumors (3.1 cm vs 2.2 cm). Rather than reflecting worse
Vol. 224, No. 4, April 2017 Ethun et al
biology, however, this may represent anatomic differences
between the 2 diseases, with pancreatic tumors potentially
being in closer proximity to the portal vein. In addition,
because of its location within the bile duct lumen, DC
tends to cause symptomatic biliary obstruction more
readily, which leads to earlier diagnosis even with small,
although not necessarily less aggressive, tumors. This is
further supported by the fact that there were no differ-
ences in the frequency of advanced T-stage, high grade
lymphovascular invasion, or perineural invasion between
groups in our study. Patients with PDAC were, however,
slightly more likely to have positive margins (25% vs
20%), and they more frequently had LN-positive disease
(69% vs 55%).
Distal cholangiocarcinoma was associated with
improved DSS compared with PDAC (40 months vs 22
months); this persisted in a multivariable model when
accounting for other adverse pathologic factors, including
LN-positive disease, positive margins, lymphovascular in-
vasion, high pathologic grade, tumor size, perineural inva-
sion, and advanced T-stage. Although LN-positive
disease, margin positivity, and high grade are widely
recognized as important poor prognostic factors for peri-
ampullary tumors in general, the favorable survival specif-
ically of DC histology compared with PDAC, as in our
study, has not always been recognized.2,3,10,12,15 In a study
of 890 patients who underwent pancreaticoduodenec-
tomy for periampullary tumors, including 144 DCs, Riall
and colleagues2 found that DC had a higher proportion of
actual 5-year survivors (23%) compared with PDAC
(17%), but there was no difference in survival between
the 2 groups on multivariable Cox regression analysis.
However, conclusions regarding the comparison of DC
and PDAC in this study are difficult to make because
ampullary and duodenal tumors were also included in
their analysis. In addition, their data spanned nearly 3 de-
cades, from 1970 to 1999, and may not reflect modern
management strategies and outcomes. Other more
contemporary studies have shown no difference in sur-
vival between DC and PDAC patients, yet some of these
are similarly limited by their inclusion of other periam-
pullary tumors with very few DC patients. Courtin-
Tanguy and associates11 found no difference in overall
or disease-free survival between propensity-matched DC
and PDAC, but they analyzed only 56 DC patients; Hat-
zaras and coworkers3 included only 18 patients with DC
in their study. Although Chen and coauthors12 did find
improved survival among DC patients compared with
PDAC by log-rank analysis, their study had only 52
DC patients, and these were grouped with other
nonpancreatic periampullary tumors for multivariable
analysis.
Distal Cholangiocarcinoma and Pancreas Cancer 411
After performing multivariable Cox regression anal-
ysis stratified by tumor site, we found that LN status
was the only factor associated with DSS among both
DC and PDAC patients. When stratifying by both tu-
mor site and LN status, DC/LN() patients had the
best survival and PDAC/LN(þ) patients had the worst.
Yet, interestingly, DC/LN(þ) patients had the same
survival as PDAC/LN() patients. Perhaps more
importantly, though, the significance of margin positiv-
ity, lymphovascular invasion, and high pathologic grade
previously seen in the entire cohort appears to have
been driven almost entirely by PDAC patients
(Table 3). This not only demonstrates the differences
in tumor biology between the 2 diseases, but it also
highlights the challenges of extrapolating data from
one disease and applying it to the other.
This is particularly important when it comes to
management strategies. In general, adjuvant therapy,
either with chemotherapy alone or in combination
with radiation, is advocated for most pancreas cancers,
particularly those with adverse pathologic features.6
Very few studies assess the role of adjuvant therapy in
DC, and those that do, do so in the context of other
malignancies and are limited by small numbers of DC
patients.7-9 Importantly, none of these have shown
convincing evidence that adjuvant therapy offers any
survival benefit in resectable DC. In addition, toxicities
from therapy can be significant. The European Organi-
zation for Research and Treatment of Cancer trial7
assessed the effect of a 5-FU-based regimen with
concomitant radiation therapy in patients with pancreas
and periampullary cancers, yet it included only 12 DC
patients as part of the periampullary group of the treat-
ment arm. Not only did the authors fail to show any
association between adjuvant therapy and survival,
they reported toxicities in 44% of patients in the treat-
ment arm. In another randomized controlled trial
on adjuvant therapy in nonpancreatic periampullary tu-
mors, Neoptolemos and colleagues9 compared survivals
among 3 study groups: 5-FU-based chemotherapy,
gemcitabine-based chemotherapy, and surgery alone.
The authors found no difference in survival among
the groups in their primary analysis, although a
marginal benefit was seen with gemcitabine on multi-
variable analysis for periampullary tumors as a whole.
Patients with DC, however, represented less than one-
quarter of those studied. Furthermore, 24% of patients
experienced grade 3 or 4 toxicities in each chemo-
therapy arm.
Despite this lack of evidence supporting the routine
use of adjuvant therapy in DC, many still apply the
data from pancreas cancer to the management of DC.
412 Ethun et al Distal Cholangiocarcinoma and Pancreas Cancer
Indeed, although more common in PDAC, still almost
60% of DC patients received adjuvant therapy in our
study. Of these, 78% received gemcitabine-based
chemotherapy, and 62% received gemcitabine alone,
the latter being one of the more frequently used regi-
mens for pancreas cancer. Although adjuvant therapy
was associated with improved DSS among all patients,
when stratified by tumor site, we found that this was
only true among PDAC and not DC patients. More
specifically, only among PDAC/LN(þ) patients was
the association between adjuvant therapy and improved
survival seen, and not among PDAC/LN() or DC pa-
tients, regardless of LN status.
There are several limitations to this study. First, data
for both the USEBMC and the CPC databases were
collected in a retrospective fashion. In addition,
although there was some overlap in the institutions
involved in the collaborative groups, 8 of the 13 institu-
tions were unique to one or the other, which introduces
a potential bias based on variable practice patterns
and how the data were collected. Finally, this study
lacks pathologic re-review to histologically confirm the
diagnosis of either DC or PDAC, so some patients
may be misclassified. However, this study incorporates
data from 13 geographically diverse, high-volume, aca-
demic institutions, which more closely represent the
disease characteristics and general practice patterns of
the US, and eliminates single-institution bias. In addi-
tion, centralized pathologic re-review may be ideal,
but it would be impractical to do given the large volume
of pathologic specimens required, as well as the associ-
ated geographic and financial limitations of such an
endeavor. All pathologic review was, however, per-
formed by experienced gastrointestinal pathologists
at each institution, and the pathologic characteristics
found in our study mirrored those found in the
literature.
CONCLUSIONS
In conclusion, this study is one of the largest series that
compares pathologic, treatment, and survival data
between patients who underwent curative-intent pan-
creaticoduodenectomy for DC and PDAC. To our
knowledge, this is also the largest series that investigates
the role of adjuvant therapy specifically in DC. Our
study demonstrates that DC and PDAC are distinct en-
tities that demand individual consideration and unique
management strategies. Distal cholangiocarcinoma has
a favorable prognosis compared with PDAC. Although
LN status is an important prognostic factor in both dis-
eases, other adverse pathologic features known to
J Am Coll Surg
pancreas cancer cannot be assumed in DC. Further-
more, current adjuvant therapy regimens are associated
only with improved survival in PDAC, but not in DC.
Therefore, despite similar operative approaches, treat-
ment paradigms used for pancreas cancer should not
be extrapolated to DC, and novel therapies for the latter
should be explored.
Author Contributions
Study conception and design: Ethun, Lopez-Aguiar,
Staley, Kooby, Maithel
Acquisition of data: Ethun, Lopez-Aguiar, Pawlik,
Poultsides, Idrees, Fields, Weber, Cho, Martin,
Scoggins, Shen, Schmidt, Hatzaras, Bentrem, Ahmad,
Abbott, Kim, Merchant, Staley, Kooby, Maithel
Analysis and interpretation of data: Ethun, Lopez-Aguiar,
Staley, Kooby, Maithel
Drafting of manuscript: Ethun, Lopez-Aguiar, Staley,
Kooby, Maithel
Critical revision: Ethun, Lopez-Aguiar, Pawlik, Poult-
sides, Idrees, Fields, Weber, Cho, Martin, Scoggins,
Shen, Schmidt, Hatzaras, Bentrem, Ahmad, Abbott,
Kim, Merchant, Staley, Kooby, Maithel
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Discussion
DR PETER J ALLEN (New York, NY): I congratulate Dr Ethun,
Dr Maithel, and the rest of their coauthors for a very well executed,
well presented, and well written multi-institutional study, which, as
Dr Maithel noted, compares the presentation, treatment, and out-
comes of patients with pancreatic ductal adenocarcinoma of the
head of the pancreas with patients with distal bile-duct carcinoma.
I think this study is a testament to the benefits of multi-institutional
collaboration, particularly when it comes to the study of a very un-
common disease such as distal cholangiocarcinoma. I also think, as
President Herndon mentioned in his address, that this is a real tes-
tament to the benefits of strong roots and a strong trunk; 11 of the
20 authors came out of Memorial Sloan Kettering, and it is nice to
see those branches continuing to intermingle and grow strong
research.
In my opinion, this study clarifies a couple of very important
differences between these 2 disease entities, and the greatest contri-
bution of this study to the oncology community will be in the
clarification and confirmation of 3 points. First, distal cholangiocar-
cinoma is a very uncommon malignancy. Only 15%, or 220
patients in this study, had this disease. If this disease was equally
spread between the 13 participating centers over the 15-year study
period, there would have been 1.2 cases seen per center per year. A
very rare disease indeed. Second, when compared with patients un-
dergoing resection for pancreatic carcinoma, patients who undergo
resection for distal bile-duct cancer are more likely to have earlier
stage disease, meaning smaller and node-negative tumors. The
teaching that bile-duct cancers present earlier than pancreatic can-
cer because of earlier biliary obstruction and subsequent jaundice
always made sense to me, and I am glad that the data support
this old teaching.
Third, patients with distal cholangiocarcinoma have improved
disease-specific outcomes when compared stage-for-stage with
patients with pancreatic cancer, and I think this study confirmed
that. I have recorded in my memory your survival curve in Figure 2
in the manuscript. I think that is a figure to remember, and it is
Ethun et al Discussion 413
certainly one that I will use with my patients, colleagues, and
trainees.
My questions focus on your conclusion regarding the use of
adjuvant therapy. Your conclusion states, “Distal cholangiocarci-
noma has a favorable prognosis compared to pancreatic cancer
yet current adjuvant therapy regimens are only associated with
improved survival in pancreatic cancer, not distal cholangiocarci-
noma. Thus, treatment paradigms utilized for pancreatic cancer
should not be extrapolated to cholangiocarcinoma.” I viewed this
as a treatment recommendation, a recommendation against the
use of adjuvant therapy in cholangiocarcinoma, and because you
dove into the muddy waters of making treatment recommendations
on retrospective data, I have the following 3 treatment-related
questions.
First, do you believe that this study and these data support,
refute, or should have no influence on the recommendation of adju-
vant therapy for patients with resected distal cholangiocarcinoma? I
ask this because many of our patients with this disease will receive
adjuvant therapy consisting of gemcitabine and cisplatin. You pre-
sented the confusing data with very small numbers of patients in
randomized trials; however, as you are aware, there are 2 random-
ized prospective trials showing gemcitabine and cisplatin to be su-
perior to gemcitabine alone in the use of patients with advanced
intrahepatic cholangiocarcinoma.
Second, in the discussion section of the manuscript, you noted
that adjuvant therapy is advocated for most patients with pancreatic
cancer, yet in this study, there was no difference in disease-specific
outcomes for patients with node-negative pancreatic cancer who
received adjuvant therapy. As you quite well described, there are
many prospective randomized trials that have shown a benefit to
this treatment. The CONKO-1 study demonstrated a survival
benefit, even in the node-negative subgroup. How do you rectify
the findings in this study with the prospective randomized trial
data, and do you believe that these data in your study should be
used as support to not give adjuvant therapy in resected node-
negative pancreatic cancer patients, as your data showed no
improvement in outcomes in this subgroup?
Finally, I would simply ask that proximal and distal cholangio-
carcinoma, as well as gallbladder cancer, have a similar genomic
profile and have some similarities in terms of their disease behavior.
Is your large group of 13 centers planning a prospective trial look-
ing at the treatment of these patients anytime in the near future?
DR JASON B FLEMING (Houston, TX): The authors continue to
teach us how to work together to gain information for unusual can-
cers or hepato-pancreato-biliary problems in general, from which
we can learn. I want to add a couple of comments to what Dr Allen
just outlined for you. It is important to remember 2 points about
interpreting data like this: this is retrospective knowledge and
data, so the question is whether it can help us prospectively; and
it is important to remember that the treatment strategy that was
used for these cases was essentially a surgery-first approach. Only
10% of patients received any preoperative therapy. So these patients
are coming to the clinic, they are being seen, they are having a
Whipple. After that, they are evaluated for adjuvant therapy. In
light of these comments, I have several questions for the authors.