Combined-Modality Treatment for Operable Pancreatic Adenocarcinoma

Combined-Modality Treatment for Operable Pancreatic Adenocarcinoma

ABSTRACT: Although in centers where pancreatectomy is performed frequently, associated morbidity and mortality rates have improved, long-term outcomes in pancreatic adenocarcinoma patients remain poor when surgery is the sole therapeutic modality. The impact of adjuvant chemotherapy on survival in patients with localized pancreatic cancer remains incompletely defined. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial has suggested that overall survival rates are superior when chemotherapy is added to surgery, even when regimens believed to be relatively ineffective in the treatment of advanced disease are used. The role of radiotherapy given with chemotherapy is also unresolved, but chemoradiation continues to receive consideration in the multimodality approach to localized pancreatic cancer. Enhanced collaboration and increased involvement by pancreatic surgeons have helped in the recruitment of pancreatic cancer patients for large-scale randomized clinical trials in Europe and the United States. Many newer chemotherapeutic agents with efficacy in gastrointestinal cancers have yet to be investigated in the adjuvant and neoadjuvant settings.

Pancreatic adenocarcinoma
acccounts for approximately
32,000 deaths per year in the
United States and more than 210,000
deaths per year worldwide.[1,2] The
disease is characterized by early
spread to the regional lymph nodes
and the liver. The majority of patients
who appear to have localized, operable
pancreatic cancer have subclinical
liver metastases at the time of
diagnosis, even when modern staging
studies reveal no evidence of extrapancreatic
disease. Outcome is dictated
primarily by the extent of disease
and performance status at presentation.
Pretreatment classification of tumors
as localized, locally advanced,
or metastatic is essential for treatment
planning. The median survival durations
for these clinical stages of pancreatic
cancer are 11 to 18 months, 10
to 12 months, and 5 to 7 months,

This review examines the oncologic
issues related to pretreatment
staging, surgical management, and
pre- and postoperative adjuvant therapy,
with specific emphasis on the
interpretation of recent clinical trials.

Pretreatment StagingImaging Studies

  • Computed Tomography-Multidetector,
    multiphase helical computed
    tomography (CT) is the foundation
    for clinical staging of pancreatic cancer.
    Although helical CT is widely
    available, accurate interpretation and
    reporting of the tumor-related find-
    remain inconsistent. For optimal
    pretreatment staging and assessment
    of operability, a CT report for a patient
    with a suspected pancreatic or
    periampullary malignancy should include
    the following information:

    (1) Commentary on the presence
    or absence of a primary tumor in the
    pancreas or periampullary region;
    (2) Commentary on the presence
    or absence of peritoneal and hepatic
    (3) Description of the patency of
    the superior mesenteric vein (SMV)
    and portal vein (PV) and the relation-
    ship of these veins and their venous
    tributaries to the tumor
    (4) Description of the relationship
    of the tumor to the superior mesenteric
    artery (SMA), celiac axis, hepatic
    artery, and gastroduodenal artery
    (5) Commentary on the presence or
    absence of aberrant vascular anatomy

    If a CT study performed early in
    the diagnostic evaluation is of insufficient
    quality to assess these issues, a
    new CT study using a pancreatic tumor
    scanning protocol[4] should be

    Specific, objective radiographic
    criteria should be used to assess operability.
    These objective criteria include
    (1) no extrapancreatic disease, (2) a
    patent SMV and PV, and (3) a definable
    tissue plane between the tumor
    and regional arterial structures including
    the celiac axis and SMA.[5] Using
    helical CT staging and objective
    criteria for assessment of resectability,
    many centers have reported resectability
    rates of 75% to 80% at
    surgery.[6,7] Thus, a single imaging
    study with accurate interpretation and
    use of objective criteria can facilitate
    preoperative assessment of resectability
    in most patients.

  • Laparoscopy-The role of laparoscopy
    in staging remains undefined.
    Direct inspection of the peritoneal surface
    and liver with laparoscopy allows
    for the identification of metastatic disease,
    the volume of which is below the
    threshold for detection by helical CT.
    Laparoscopy detects helical-CT-occult
    disease in 4% to 15% of patients.[8]
    Given the relatively low incidence of
    positive findings at laparoscopy, most
    centers utilize this technique selectively
    in patients who have CT and laboratory
    findings suggestive but not
    diagnostic of more advanced disease.
    Such findings include small volume,
    low-density liver lesions, low-volume
    ascites, marked elevation in CA 19-9,
    or a relatively poor performance status
    suggestive of more advanced disease.
  • Positron-Emission Tomography-The role of positron-emission
    tomography (PET) in pretreatment
    staging also remains undefined. Following
    two reports suggesting that results
    of 18-fluorodeoxyglucose PET
    altered clinical management in as
    many as 43% of patients with pancreatic
    cancer,[9,10] other reports have
    failed to confirm this degree of clinical
    benefit, suggesting instead that
    PET does not significantly change the
    clinical approach in most patients
    staged by helical CT.[11,12] As a
    consequence, the utility of PET in
    staging patients with no extrapancreatic
    disease on helical CT and
    patients with suspicious but nondiagnostic
    extrapancreatic CT findings
    remains unclear. The routine use of
    PET is also limited by its relatively
    high cost (relative to other diagnostic
    tests) and its low specificity for distinguishing
    between neoplastic and
    inflammatory causes of distal bile
    duct obstruction.

CA 19-9
CA 19-9 is a tumor-associated antigen
that is frequently elevated in the
serum of patients with pancreatic adenocarcinoma.[
13,14] CA 19-9 may
also be mildly elevated in certain benign
conditions such as pancreatitis,
and thus modest serum CA 19-9 elevations
cannot be used for the diagnosis
of or screening for pancreatic
malignancy. In addition, patients lacking
the Lewis antigen glycosyltransferase
are unable to produce CA 19-9;
this deficiency is present in 7% to
10% of the general population.[13,15]
Furthermore, the production of CA
19-9 by normal biliary ductal cells is
increased in the settings of biliary obstruction
and inflammation; serum CA
19-9 levels are influenced by the presence
of jaundice. Since the initial serum
CA 19-9 level is obtained soon
after presentation with clinical jaundice
in many patients, CA 19-9 measurements
should be repeated after
the biliary obstruction and jaundice
have been relieved.

There is no consensus on what CA
19-9 level is sufficiently reliable for
the diagnosis of cancer in patients in
whom there is a clinical suspicion of
pancreatic adenocarcinoma. In an
analysis by Forsmark and colleagues,
serum CA 19-9 levels above 90 U/mL
and above 200 U/mL had estimated
accuracy rates of 85% and 95%, respectively,
in the diagnosis of malignancy
in the clinical setting of a
suspected pancreatic neoplasm.[16] In
one study, the combination of CT and
CA 19-9 measurement in nonicteric
patients yielded a positive predictive
value of 99% to 100% in the diagnosis
of pancreatic cancer when a CA 19-9
reference value of 100 to 120 U/mL
was used,[17] and a report by Tian et
al. suggested that an elevation in CA
19-9 above 750 U/mL was associated
with a high probability of locally advanced
or metastatic disease.[18] As
with most tumor markers, CA 19-9
may be optimally used as supporting
clinical evidence in the diagnosis and
staging of pancreatic cancer.

Pretreatment Biopsy

The role of pretreatment biopsy in
patients who present with localized
disease and in whom surgery is anticipated
depends on specific patient and
physician factors. One school of thought
maintains that for patients presenting
with a clinical and radiographic picture
consistent with a resectable
pancreatic neoplasm, the surgical resection
should be both diagnostic and
therapeutic.[19] This approach assumes
that positive intraoperative
biopsies are not required before proceeding
with pancreatic resection and
that diagnostic pancreatectomy can be
performed with low morbidity and
mortality rates.

A second school of thought espouses
reasonable efforts to achieve a
pretreatment tissue diagnosis. This
approach seeks to separate the diagnostic
and therapeutic phases of pancreatic
cancer management because
doing so may have specific advantages
for patients and physicians.[20] A
pretreatment biopsy diagnosis allows
the patient to consider referral to a
regional center specializing in pancreatic
cancer treatment. In contrast,
when surgery for both diagnosis and
treatment is offered, the patient is usu-
ally not able to investigate options for
further staging or for referral until
after surgical staging with or without
tumor resection. At this point, an important
therapeutic bridge has been

As outlined below, consideration
of referral to a regional center is well
founded given the significant differences
in operative mortality and longterm
survival observed between
higher volume regional centers and
smaller hospitals. Fine-needle aspiration
guided by CT or endoscopic
ultrasonography is a relatively safe
and accurate means of pretreatment
tissue diagnosis.[21]

Subtotal pancreatic resection can
consist of a left (distal) pancreatectomy
or right pancreatectomy, which is
usually anatomically described as a
pancreaticoduodenectomy or Whipple
procedure. For most malignant tumors
arising in the pancreatic head
and uncinate process, pancreaticoduodenectomy
is required to achieve microscopically negative pancreatic
parenchymal and retroperitoneal
surgical margins.

Standard pancreaticoduodenectomy
involves resection of the distal
stomach, distal bile duct (with cholecystectomy),
duodenum, pancreatic
head and uncinate process, proximal
jejunum, and regional lymph
nodes.[22] Gastrointestinal reconstruction
following pancreaticoduodenectomy
requires enteric, biliary,
and pancreatic anastomoses, usually
by gastrojejunostomy (or duodenojejunostomy
in the case of pylorus-preserving
choledochojejunostomy, and pancreaticojejunostomy
(or pancreaticogastrostomy).

Technical modifications that have
no clearly demonstrated advantage or
adverse oncologic impact include pylorus
preservation[23] and extended
lymphadenectomy.[24,25] Randomized
trials of pancreaticoduodenectomy
with extended vs standard
lymphadenectomy have demonstrated
increased morbidity with the extended
dissection but no improvement
in survival rates.[24,25] As a consequence,
most Western surgeons perform
either a standard or pyloruspreserving
with a standard lymphadenectomy (including
peripancreatic lymph nodes)
but not extended regional lymphadenectomy.

The most oncologically significant
and technically demanding step in
pancreaticoduodenectomy is the retroperitoneal
vascular dissection along
the proximal SMA. This step occurs
during the final phase of the tumor
resection, after division of the stomach,
jejunum, bile duct, and pancreas.
This step can be technically difficult
and associated with a risk of hemorrhage
from the pancreaticoduodenal
arteries arising from the right posterolateral
side of the SMA. In an effort
to minimize this risk and save time,
many surgeons do not fully mobilize
the SMV to adequately expose the
SMA and instead choose an easier
dissection plane several millimeters
to the right of the SMA. Unfortunately,
this compromises the radial retroperitoneal
margin, which is of critical
oncologic significance.

Pancreaticoduodenectomy with
segmental resection of the SMV or
PV is necessary when the tumor is
inseparable from the lateral wall of
the SMV or PV.[26] When intraoperative
findings suggest venous involvement,
approximately 80% of patients
undergoing pancreatectomy with
venous resection have histologic evidence
of tumor extension into the vein
wall.[26] However, venous resection
should be performed only in carefully
selected patients who have tumor adherence
to the SMV or PV but have
no evidence of tumor extension to the
SMA or celiac axis (Figure 1). Following
with venous resection, patients with
pathologic invasion of the SMV or
PV do not have an increased frequency
of surgical margin or lymph node
positivity compared to patients without
involvement of the SMV or PV,
and patient survival after pancreaticoduodenectomy
with venous resection
is comparable to that observed in
patients with similar tumors that do
not require venous resection.[27]

Hospital Pancreatectomy
Volume and Mortality Rates

Several reports from Europe[28,29]
and North America[30-32] have established
a clear relationship between
institutional pancreatectomy volume
and perioperative mortality rates. For
North American patients, the recent
analyses of national databases by
Birkmeyer et al[30] and Kotwall et
al[31] of 10,507 and 25,000 patients
who underwent pancreatectomy are
among the most compelling of these
reports. Birkmeyer and colleagues
demonstrated that patients undergoing
pancreatectomy at institutions
with very low (< 1 pancreatectomy
per year), low (1 or 2 per year), or
moderate (3-5 per year) volumes had
mortality rates of 16.2%, 14.4%, and
10.9%, respectively. In comparison,
patients undergoing pancreatectomy
at higher-volume (> 16 per year) institutions
had a mortality rate of only

Kotwall et al reported similar findings
in an analysis of surgical volume
and postoperative mortality rates
at hospitals categorized as rural, urban
nonteaching, and urban teaching.
In that report, the overall national
operative mortality rate for pancreaticoduodenectomy
was 14%, and there
was a clear relationship between perioperative
and postoperative mortality
rates and hospital surgical volume
and category.[31] Data from these
two reports demonstrate that the majority
of patients undergoing pancreatic
resection in the United States have
surgery in hospitals where the pancreatectomy
volume is low or moderate
and the mortality rate is in excess
of 10%.

Higher-volume hospitals also have
improved long-term cancer-related
outcomes. Birkmeyer et al performed
a retrospective cohort study of all
7,229 patients over age 65 years who
underwent pancreaticoduodenectomy
in the United States between 1992
and 1995.[33] The 3-year overall survival
rates were higher at high-volume
centers (37%) than at moderate-
(29%), low- (26%), and very lowvolume
hospitals (25%, P < .001).
After exclusion of perioperative deaths
and adjustment for case mix, patients
who underwent surgery at high-volume
centers remained less likely to
experience late deaths than did patients
at very low-volume hospitals
(adjusted hazard ratio [HR] = 0.69;
95% confidence interval [CI] = 0.62-
0.76). The reasons for this apparent
improvement in long-term outcome
are not evaluable from this type of
analysis of administrative databases
but are presumed to be related to improved
staging and possibly increased
use of adjuvant treatments in these

The data establishing a definite relationship
between institutional volume
and short- and long-term survival
rates suggest that a public health policy
promoting regionalization of care
for patients with operable pancreatic
cancer would immediately improve
survival rates.[34,35] Indeed, the survival
advantages associated with regionalization
of care may approach
or exceed those available with current
adjuvant treatments.[35]

Complications and
Postpancreatectomy Recovery

Although mortality rates for pancreaticoduodenectomy
have declined
to less than 3% in high-volume
centers,[36-38] the morbidity of pancreatectomy
remains high, with pancreatic
leak and infection among the
most common surgical complications.[
39] Postpancreatectomy recovery
can be prolonged owing to the
complex interplay between comorbid
factors and surgical morbidity. Unfortunately,
prolonged recovery following
pancreatectomy may delay and
in some cases prevent planned adjuvant
treatment. Reports from major
referral centers for pancreatic surgery
demonstrate that approximately 25%
of postpancreatectomy patients do not
recover satisfactorily (ie, achieve a
good enough performance status) to
consider postoperative chemoradiation.[
40,41] However, this figure
should be considered a minimum estimate
of the impact of delayed postoperative
recovery, as the majority of
patients in North America undergo
pancreatectomy at low- to intermediate-
volume institutions, where morbidity
(as inferred from mortality data)
and mortality rates are considerably
higher than at regional centers.[30,31]

Many medical and radiation oncologists
have little familiarity with
normal postpancreatectomy recovery
and the specific intermediate-term
complications that can affect a patient's
performance status at the time
of assessment for adjuvant treatment.
For patients under age 70 with minimal
comorbidity, at least 6 to 8 weeks
is generally required for recovery to a
performance and nutritional status that
is satisfactory for consideration of
postoperative treatment. Clinically
significant issues that are frequently
present in variable degrees of severity
at the time of consultation for adjuvant
treatment include low-grade
delayed gastric emptying, as manifested
by occasional nausea or vomiting,
and pancreatic exocrine insufficiency,
manifested by frequent bowel
movements with bulky or greasy
stools and difficulty maintaining or
gaining weight.

A trial of metoclopramide is often
considered for patients with clinical
evidence of delayed gastric emptying.
In addition, pancreatic enzyme
supplements should be used in almost
all patients. These enzyme supplements
should be titrated to reduce
bowel movement frequency to one or
two per day. H2-receptor blockers or
proton pump inhibitors should also
be used in all patients to minimize the
risk for marginal ulceration at the gastrojejunal
anastomosis, prevent treatment-
related gastritis if radiotherapy
is planned, and facilitate the action of
pancreatic exocrine supplements,
which require an alkaline environment
for activation.

Classification and Oncologic
Significance of Surgical Margins

For tumors arising in the pancreatic
head and uncinate process, the retroperitoneal
margin is defined anatomically
as the margin between the medial
edge of the tumor and the right lateral
border of the SMA (Figure 1). During
pancreaticoduodenectomy, dissection
must occur in the immediate periadventitial
plane of the SMA to maximize
the radial retroperitoneal margin.
As a consequence, the SMA dissection
is the most oncologically significant
step in pancreaticoduodenectomy.

Difficulties in maximizing and
pathologically evaluating the retroperitoneal
margin include the technical
challenge of safe dissection along
the proximal SMA and the fact that
identification and orientation of the
specimen for accurate margin assessment
is usually possible only at the
time of surgery by combined efforts
of the surgeon and surgical pathologist.
This margin should be inked in
the surgical suite, and the pathology
report should describe the distance in
millimeters between the tumor and
the inked retroperitoneal margin; retrospective
evaluation of this margin
is not possible. Details of the procedure
for margin assessment are outlined
in the sixth edition of the AJCC
Cancer Staging Manual.

Pancreatectomy margins (especially
the retroperitoneal margin) should
be classified by the surgeon after integration
of the operative findings and
the microscopic surgical margin findings
in the final pathology report. All
pancreatic resections should be class-
ified according to residual disease
status (termed "R" factor): R0, no
gross or microscopic residual disease;
R1, microscopic residual disease (microscopically
positive surgical margins
with no gross residual disease);
and R2, grossly evident residual disease.
The pathologist cannot usually
differentiate an R1 (microscopically
positive) from an R2 (grossly positive)
retroperitoneal margin in the absence
of information regarding the
retroperitoneal dissection, which
should be included in the operative
note. The R designation should appear
in the final pathology report and
should be consistent with the dictated
operative note. For example, if the
surgeon states that gross tumor was
encountered when completing the retroperitoneal
dissection, a positive histologic
margin should result in the R2
designation in the final pathology report.
In the absence of this information
being included in the operative
report, the proper R designation cannot
be determined. The difficulty in
differentiating R1 from R2 resections
has significant implications for clinical
trials examining the potential
survival advantage of adjuvant or neoadjuvant

The limited data available suggest
that the radial retroperitoneal margin
is positive in 15% to 25% of patients
after pancreaticoduodenectomy (single-
institution data).[43] The clinical
significance of a positive margin is
indicated in Table 1. Surgical resection
with a grossly positive surgical
margin is associated with a median
survival of 6 to 12 months. This median
survival in patients with ostensibly
localized pancreatic cancer is
comparable to that observed in
patients with locally advanced pancreatic
cancer treated nonsurgically.[
44,45] Thus, a positive-margin
(R2) pancreatic resection represents a
suboptimal therapeutic result. Because
of the lack of accurate historical recording
of R status, the impact of an
R1 resection-especially in the era of
contemporary adjuvant therapy-is

Oncologic Outcome After
Pancreatectomy Alone

Unfortunately, despite improvements
in the short-term outcomes of
patients undergoing pancreatic resection
for pancreatic cancer, there has
been no significant improvement in
oncologic outcome over the past decade
when pancreatectomy is used as
the sole therapeutic modality. Many
surgical series have relatively short
median follow-ups and/or do not report
sufficient information on the use
of nonsurgical treatment to draw firm,
accurate conclusions regarding
outcome in patients treated by pancreatectomy
alone. However, retrospective
reports of surgical outcome
stratified by additional treatments and
results from the pancreatectomy-alone
arm of prospective randomized trials
of pancreatectomy alone vs pancreatectomy
plus postoperative chemoradiation
suggest that the median survival
following pancreatectomy alone (without
chemoradiation) for localized pancreatic
adenocarcinoma ranges from 11
to 17 months (Table 2).[46-49]

That said, the use of contemporary
pretreatment imaging and improved
patient selection may increase the median
survival a few months over these
historical estimates. For purposes of
treatment comparisons and protocol
planning, median survival durations of
12 to 18 months and 5-year actuarial
overall survival rates of 10% to 15%
with pancreatectomy alone appear to
be accurate estimates. On this basis, it
is clear that for most patients, pancreatectomy
is necessary but not sufficient
for cure of pancreatic cancer.


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