The management of pancreatic cancer. Current expert opinion and recommendations derived from the 8th World Congress on Gastrointestinal Cancer, Barcelona, 2006.
ABSTRACT This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.
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ABSTRACT: Some comments about the role of ablation techniques in the management of advanced pancreatic cancer as palliative procedure.Cancers. 12/2010; 2(4):2055-2057.
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ABSTRACT: Radiofrequency ablation in the management of advanced pancreatic cancer should be no longer utilized in patients with locally advanced or metastatic pancreatic adenocarcinoma.Cancers. 12/2010; 2(4):2098-2099.
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ABSTRACT: Advanced ductal pancreatic carcinoma (PC) remains a challenge for current surgical and medical approaches. It has recently been claimed that radiofrequency ablation (RFA) may be beneficial for patients with locally advanced or metastatic PC. Using the MEDLINE database, we found seven studies involving 106 patients in which PC was treated using RFA. The PC was mainly located in the pancreatic head (66.9%) with a median size of 4.6 cm. RFA was carried out in 85 patients (80.1%) with locally advanced PC and in 21 (19.9%) with metastatic disease. Palliative surgical procedures were carried out in 41.5% of the patients. The average temperature used was 90 °C (with a temperature range of 30-105 °C) and the ratio between the number of passes of the probe and the size of the tumor in centimeters was 0.5 (range of 0.36-1). The median postoperative morbidity and mortality were 28.3% and 7.5%, respectively; the median survival was 6.5 months (range of 1-33 months). In conclusion, RFA is a feasible technique: however, its safety and long-term results are disappointing; Thus, the RFA procedure should not be recommended in clinical practice for a PC patient.Cancers. 09/2010; 2(3):1419-1431.
Annals of Oncology 18 (Supplement 7): vii1–vii10, 2007
The management of pancreatic cancer. Current
expert opinion and recommendations derived from
the 8th World Congress on Gastrointestinal Cancer,
C. Verslype1, E. Van Cutsem1*, M. Dicato2, S. Cascinu3, D. Cunningham4, E. Diaz-Rubio5,
B. Glimelius6, D. Haller7, K. Haustermans1, V. Heinemann8, P. Hoff9, P. G. Johnston10, D. Kerr11,
R. Labianca12, C. Louvet13, B. Minsky14, M. Moore15, B. Nordlinger16, S. Pedrazzoli17,
A. Roth18, M. Rothenberg19, P. Rougier16, H.-J. Schmoll20, J. Tabernero21, M. Tempero22,
C. van de Velde23, J.-L. Van Laethem24& J. Zalcberg25
1Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium;2Department of Haematology-Oncology, Luxembourg Medical Center, Luxembourg,
Luxembourg;3Medical Oncology, University of Marche, Umberto I Hospital, Ancona, Italy;4Department of Medical Oncology, The Royal Marsden Hospital, Surrey, UK;
5Department of Medical Oncology, San Carlos Hospital Clinic, Madrid, Spain;6Department of Oncology, Radiology and Clinical Immunology, University of Uppsala,
Uppsala and Karolinska Institutet, Stockholm, Sweden;7University of Pennsylvania Cancer Center, Philadelphia, PA, USA;8Medizinische Klinik and Poliklinik III,
University of Munich, Munich, Germany;9Department of Gastrointestinal Medical Oncology, Hospital Sirio-Libanes, Sao Paulo, Brazil;10Centre for Cancer Research &
Cell Biology, Queen’s University Belfast, Northern Ireland;11Department of Clinical Pharmacology, University of Oxford, Oxford, UK;12Medical Oncology Unit, Ospedale
Riuniti, Bergamo, Italy;13Department of Oncology, Ho ˆpital Saint-Antoine, Paris, France;14Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center,
New York, NY, USA;15Division of Applied Molecular Oncology, University of Toronto, Toronto, Ontario, Canada;16Departments of Surgery and Gastroenterology,
Ho ˆpital Ambroise Pare ´, Boulogne, France;17Department of Medical and Surgical Sciences, University of Padua, Padova, Italy;18Department of Surgery, Geneva
University Hospital, Geneva, Switzerland;19Division of Oncology, Vanderbilt University Medical Center, Nashville, TN, USA;20Department of Hematology and Oncology,
Martin Luther Universita ¨t, Halle, Germany;21Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, Spain;22Division of Medical Oncology, University
of California, San Francisco, CA, USA;23Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands;24Department of Gastroenterology,
Erasme University Hospital, Brussels, Belgium;25Peter MacCallum Cancer Centre and Department of Medicine, University of Melbourne, Melbourne, Australia
This article summarizes the expert discussion on the management of pancreatic cancer, which took place
during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary
approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery,
selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover,
optimal symptomatic management requires a dedicated team of health care professionals. Quality control of
surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now
solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined
with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in
advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced
disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with
pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the
evidence-based knowledge and to make further progress.
Key words: adjuvant treatment, chemotherapy, pancreatic cancer, radiotherapy
Pancreatic cancer represents just 2% of all cancers, but accounts
for 6% of all cancer deaths. Nearly 90% of pancreatic tumors
are ductal adenocarcinomas. The pancreatic cancer incidence of
10 cases per 100 000 individuals equals mortality, which
highlights the poor prognosis of this condition. Pancreatic
cancer is rare before the age of 45 years and the majority occur
>60 years. Aging of the population in the Western world will
lead to an increase in absolute numbers. Nowadays, it is still
more common in men than women [1, 2].
The cause of pancreatic cancer is unknown. Many authors
believe that once the genetic material of a pluripotent stem cell
in the adult pancreas is damaged and (epi)genetic changes
accumulate, preneoplastic lesions (pancreatic intraepthelial
neoplasia) may appear, which ultimately evolve into pancreatic
cancer. There are only a few established risk factors for the
*Correspondence to: Dr E. Van Cutsem, Digestive Oncology Unit, University Hospital
Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: 32-16-34-42-25;
Fax: 32-16-34-44-19; E-mail: firstname.lastname@example.org
ª 2007 European Society for Medical Oncology
at University of Portland on May 20, 2011
disease; age, cigarette smoking and body mass index stand out
as the most important . More recently, we are beginning to
appreciate the role of genetic factors in this devastating disease.
Of patients with pancreatic cancer up to 10% have a family
history of pancreatic cancer in >2 first-degree relatives. Some of
these cases are related to well-known genetic syndromes that
comprise familial atypical multiple mole melanoma syndrome,
familial adenomatous polyposis syndrome, Peutz–Jeghers
syndrome, breast cancer familial syndrome and hereditary
nonpolyposis colorectal cancer syndrome . The
identification of a family with pancreatic cancer may open the
perspective for genetic counseling and early detection.
Surgical resection remains the primary curative treatment
option in pancreatic cancer. Recurrences are frequent following
surgery, leading to 5-year overall survival (OS) rates of 10%–
25%, depending on disease stage . Interestingly, a Japanese
study demonstrated a postoperative 5-year survival rate of
100% for patients with pancreatic cancer <1 cm. In most
series though it is unusual to detect pancreatic cancer at such
an early stage . Seventy percent of these cancers are
located in the head of the pancreas. Those that arise in the
body or tail of the pancreas are almost always unresectable.
Most patients are not operable at the time of diagnosis, have
rapid ?tumor? progression and are in a poor general condition.
Several excellent clinical guidelines are available .
However, in this rapidly evolving field, new data are
available focusing on the extent of pancreatic resection and
on the additional treatment post- or preoperatively, which offer
hope for improved outcome for patients with pancreatic
This article summarizes the expert discussion on the
management of pancreatic cancer, which was organized
during the 8th World Congress on Gastrointestinal Cancer in
June 2006 in Barcelona, Spain. Opinion leaders and experts
from different nationalities, selected on scientific merit,
participated in the discussion. In preparation of this expert
discussion, a detailed survey and questionnaire was sent to all
participants and the questions, answers and conclusions were
rediscussed at the meeting.
Expert committee reports reflect clinical experience on top
of evidence-based medicine. As such, agreement or consensus
was not always reached. The main strength, however, of this
approach is that we hope to offer more than minimal
guidelines, in order to help clinicians in the difficult task of
making treatment choices in daily clinical practice.
diagnosis and staging algorithm
In order to offer patients a curative treatment option, it is of
paramount importance to detect the tumor at an early stage.
However, patients are usually asymptomatic until the tumor
has reached an incurable stage. Painless jaundice may be
present in 50% of resectable tumors in the pancreatic head, but
it may equally be caused by hilar or hepatic metastases.
Common symptoms and signs are weight loss, abdominal
discomfort (?dyspepsia?-like symptoms such as nausea or early
satiety), epigastric pain (back pain equals most often an
inoperable tumor), diabetes mellitus and venous thrombosis
. Acute pancreatitis may be a presenting feature of
pancreatic cancer. A careful clinical examination is essential
and supraclavicular palpable lymph nodes or umbilical
metastases should not be overlooked. Performance status
and a detailed family history should be recorded.
Diagnostic pancreatic imaging has evolved markedly in
recent years. Ultrasound, endoscopic ultrasound (EUS),
computed tomography (CT), magnetic resonance imaging
(MRI), endoscopic retrograde cholangiopancreaticography
(ERCP) and 2-[fluorine-18]fluoro-2-deoxy-D-glucose
postitron emission tomography (FDG–PET) may indicate
a diagnosis of pancreatic cancer. The question emerges which
tests are necessary and in what combination. The choice of
diagnostic imaging, supplemented by laboratory tests and
laparoscopy, should be based on the efficacy, availability and
cost–benefit of the test. Based on randomized comparisons,
spiral CT, MRI and EUS yield similar accuracy (>90%) in
diagnosing pancreatic cancer >15 mm [9, 10].
obtaining pathological proof
Not all tumors in the pancreas are ductal adenocarcinomas. The
differential diagnosis of a pancreatic mass include
a neuroendocrine tumor, a metastasis of other cancer (e.g.
breast, colon or renal cell carcinoma) or even an
inflammatory pseudotumor. It was therefore stressed by the
expert panel that pathological confirmation of the tumor should
be obtained at some time point in the course of the disease.
Obtaining a pathological proof of malignancy is necessary in
advanced cases or when neo-adjuvant therapy is planned. It is
not mandatory preoperatively inoperable tumors when resection
can be carried out with an acceptable morbidity. Preoperative
percutaneous sampling should be avoided. It may be challenging,
but often possible, to obtain a specimen by EUS-guided fine
needle aspiration of the primary tumor. The sensitivity and
specificity of this approach may reach 80%–95% and 100%,
respectively . Alternatively, a metastatic lesion can be
biopsied under ultrasound or CT guidance.
primary staging of pancreatic cancer
? A spiral contrast-enhanced CT is considered the cornerstone
of the diagnostic and staging algorithm of pancreatic cancer,
provided that contrast is administered in the arterial, portal
and venous phase. Pancreatic cancer appears as hypodense
mass during the pancreatic parenchymal phase; an important
desmoplastic reaction may artificially increase the size of the
tumor. There may be a dilated pancreatic duct (or bile duct)
and atrophy of the gland proximal to the mass. The CT
scan is the definitive test in the majority of cases due to the
additional yield of staging information (including the
detection of liver metastases and/or vascular invasion) .
? MRI is especially useful in the differential diagnosis of cystic
? EUS is largely dependent on availability and is used for
detection of small tumors if uncertainty exists with CT or
MRI. It may be especially useful to include EUS in family
screening protocols for pancreatic cancer, as these programs
Annals of Oncology
vii2 | Verslype et al.Volume 18| Supplement 7|June 2007
at University of Portland on May 20, 2011
are set up to detect very small tumors or preneoplastic
changes in the pancreas. EUS can help for determining blood
vessel invasion or to obtain cytology specimens by fine needle
aspiration in tumors.
? A chest X-ray (some experts advocate CT) is necessary to
exclude pulmonary metastases.
? Laparoscopy is very useful to detect small peritoneal and/or
small liver metastases, which may be missed by current
imaging modalities. According to several studies, laparoscopy
may change the therapeutic plan in up to 25% of patients.
Diagnostic laparoscopy can be recommended before resection
[especially in left sided large (>3 cm) pancreatic cancer] or if
a neo-adjuvant treatment is considered. The timing of the
procedure is dependent on the local organization .
? ERCP is not routinely done for diagnosis. The procedure has
a therapeutic purpose in case of obstructive jaundice for the
placement of a biliary endoprosthesis.
? The place of FDG–PET is considered very limited in the
staging algorithm of pancreatic cancer. FDG–PET certainly
allows earlier detection of recurrence than classical imaging
. It is not clear, however, to what extent this diagnostic
superiority translates into a clinical benefit for the patient.
? Tumor markers such as CA19.9 (and carcinoembryonic
antigen) are of limited diagnostic value, although they
are often taken as a baseline, in order to guide
treatment follow-up . It is well known that in case
of cholangitis or liver failure, very high values of CA19.9 may
be encountered in the absence of malignancy. In case of
suspicion of a neuroendocrine pancreatic tumor, serum
chromogranin A should be determined.
? Molecular markers are not yet available that may be of any
help in routine clinical practice.
different stages: decision on resectability
The decision on resectability requires a multidisciplinary
decision. A distinction should be made between tumors that
are resectable, borderline resectable, those that will never
become resectable (truly locally advanced) and metastatic.
The diameter of the tumor, as such, does not influence the
decision on resectability. However, it is unlikely that a tumor
>5 cm is resectable. Regional lymph nodes are not taken into
account for nonresectability; lymph nodes distant from the
tumor (such are celiac and para-aortic nodes) make surgery
a futile act. Patients should be classified in one of the following
groups, which are clearly correlated to survival (Tables 1 and 2)
? Potentially resectable disease is defined by (i) the absence of
extrapancreatic disease, (ii) a definable tissue plane between
the tumor and regional arteries [celiac axis (CA), superior
mesenteric artery (SMA), common hepatic artery], (iii)
a patent superior mesenteric vein (SMV), portal vein (PV)
and their confluence (taking into consideration the technical
ability to resect and reconstruct partially invaded venous
structures). This definition corresponds to stage I and II in
the tumor–node–metastasis (TNM) classification.
? Borderline resectable disease is not described as such in the
current TNM classification; it represents a stage between
potentially resectable and truly locally advanced disease .
It may be defined by (i) the absence of extrapancreatic disease
and (ii) the following tumor–vessel relationships, which can
still be considered for resection and reconstruction: a short
segment occlusion of the SMV–PV confluence with a suitable
venous structure above and below the area of occlusion;
a short segment encasement of the hepatic artery at the origin
of the gastroduodenal artery; encasement of the SMA or CA
£180? of the arterial circumference.
? Locally advanced disease which corresponds to stage III in the
TNM classification when there is invasion in the arterial
structures (encasement >180? of the circumference of the
Table 2. Clinical and radiological staging of pancreatic cancer (adapted
from ) and correlation with median survival
Stage Clinical/radiological criteria Long-term
I-IIResectable (T1–3, selected T4a,
No encasement of the celiac axis
Patent SMV-PV confluence
No extrapancreatic disease
Locally advanced (T4, Nx-N1, M0)
Tumor extension to involve celiac
axis or SMA, or venous occlusion
(SMV, SMPV confluence)
No extrapancreatic disease
Metastatic (any T, any N, M1)
III Nil 6–10 months
IV Nil3–6 months
aResectable T4 include those with partial involvement of the SMV or PV.
SMA, superior mesenteric artery; SMPV, superior mesenteric–portal vein;
SMV, superior mesenteric vein.
Table 1. Stage grouping of exocrine pancreatic carcinoma 
Tis (severe ductal dysplasia/carcinoma
T1 (£2 cm), limited to pancreas
T2 (>2 cm), limited to pancreas
T3 (beyond pancreas, no involvement
SMA or CA)
T4 (stomach, spleen, colon,
involvement of SMA or CA)
aN1 are regional lymph nodes which are located superior and inferior to
head and body of pancreas, anterior and posterior pancreaticoduodenal
and proximal mesenteric, pyloric (tumors of head only) and common
bile duct, hilum of spleen or tail of pancreas (tumors of body and tail
only) and celiac (tumors of head only).
SMA, superior mesenteric artery; CA, celiac axis.
Annals of Oncology
Volume 18|Supplement 7|June 2007 doi:10.1093/annonc/mdm210 | vii3
at University of Portland on May 20, 2011
SMA or CA) or definite occlusion of above-mentioned
venous structures (SMV, PV and their confluence).
? Metastastic disease (stage IV) is the presence of
extrapancreatic disease. As the specificity of current imaging
techniques is insufficient to diagnose enlarged lymph nodes
as malignant, pathological proof of suspicious distant lymph
nodes (on imaging) is considered mandatory before
witholding potentially effective surgical therapy.
At the time of diagnosis, 40% of patients have locally advanced
or unresectable disease, 40% have visceral metastases, mainly
liver and peritoneal implants, and 20% present with a possible
resectable lesion. Patients with locally advanced disease are
candidates for chemo(radio)therapy, whereas those with
visceral metastases are candidates for chemotherapy.
Resectional surgery is the only curative treatment, but is only
an option in 10%–20% of patients with pancreatic cancer.
Following resection, adjuvant treatment should be considered.
resectional and palliative surgery
Surgical resection of the primary tumors and regional lymph
nodes is the treatment of choice for a patient with
a potentially operable tumor. Surgery should be confined to an
expert team of surgeons in high volume centers, in order to
increase resection rates, minimize postoperative morbidity
and mortality . Any effort to achieve an R0 resection is
mandatory. For tumors of the pancreatic head, a pylorus
preserving pancreaticoduodenectomy is appropriate. In case
of proximal duodenal involvement or location of the tumor
close to the pylorus, a classical proximal
pancreaticoduodenectomy with antrectomy (Whipple’s
operation) is indicated. Pancreatic body and tail tumors
require a left (distal) pancreatectomy and involvement of the
splenic vessels do not preclude resection. More radical and
technically demanding procedures including PV or SMV
excision or total pancreatectomy are sometimes necessary in
order to obtain an R0 resection. Every procedure should
include a locoregional lymph node resection, but the benefit of
extensive lymphadenectomy has not been demonstrated. A
randomized trial of standard versus extended lymph node
resection failed to show a survival benefit . Biliary
drainage is mandatory in case of cholangitis; some experts
require biliary drainage before resection, if surgery is to be
delayed (>10 days).
In patients who are found irresectable during surgery (or
laparoscopy), surgical bypass (hepaticojejunostomy and/or
gastroenterostomy) is recommended and can also be carried
out laparoscopically with minimal morbidity. There are no
randomized comparisons of current expandable metal stents
for biliary or duodenal obstruction versus laparoscopic
Surgery is the only curative treatment for pancreatic cancer, but
long-term survival after surgical resection of pancreatic cancer
is <20% [20, 21]. Patterns of relapse are important when
considering adjuvant therapy. In a recent study, local
recurrence with or without distant metastasis occurred in
41% of patients who underwent surgery alone and distant
metastasis was diagnosed in 49% . This failure pattern
highlights the need for optimal surgery and evaluation of
adjuvant treatment strategies, which include chemoradiation
A well-designed trial of adjuvant therapy should include
only patients with pancreatic cancer who underwent a resection
with adequate locoregional lymph node resection (>10 nodes
retrieved). Patients should be stratified in trials according to
the resection status (R0 versus R1). Quality control of surgery
and pathology (evaluation of resection margins, including
inking of retroperitoneal margin) is mandatory. At the start
of the adjuvant treatment, metastases should be excluded by
CT scan of the thorax and abdomen. Many trials have been
carried out or are currently evaluating different treatment
options aiming at decreasing local relapse as well as distant
metastases. However, several of these studies lack the proper
design as delineated above. The first trial was initiated in the
United States by the Gastrointestinal Tumor Study Group
(GITSG) in 1974 , which was slow to accrue and was
terminated early following an analysis of the first 43 patients
that demonstrated a statistically significant median survival
advantage to adjuvant chemoradiation and 1 year maintenance
chemotherapy [bolus 5-fluorouracil (5-FU)] in patients with
resected pancreatic cancer. Patients who were treated with
a split-course radiotherapy schedule (40 Gy) and chemotherapy
(bolus 5-FU) during first and last week of radiation therapy,
and continued later on) had a median survival of 21 months,
a 2-year survival of 43% and a 5-year survival of 19%. This was
significantly better than those who did not receive adjuvant
therapy and who showed a median survival of 11 months, a 2-
year survival of 18 months and 5% 5-year survival (P = 0.03).
This suboptimal, low-powered trial represents the basis for the
adoption of adjuvant chemoradiotherapy (CRT) as standard of
care in the United States and Canada over the last 20 years.
However, the observed benefit may have been due to the
maintenance chemotherapy and not to the radiotherapy
Norwegian investigators randomized 61 patients between
combination chemotherapy (fluorouracil, doxorubicin,
mitomycin C) and no postoperative therapy. Median
survival was longer in treated patients (23 versus 11 months,
P = 0.02) .
An European Organization for Research and Treatment of
Cancer (EORTC) trial randomized 218 patients between
chemotherapy (5-FU) in combination with split-course
radiotherapy and no postoperative treatment in patients with
pancreatic carcinoma and ampulloma. In contrast with the
GITSG study, no chemotherapy was given following
completion of the CRT treatment. There was no benefit in
terms of survival . However, on reanalysis with more
appropriate statistical methods, there is a statistically
significant benefit to adjuvant chemoradiation for patients
with pancreatic head cancers .
Patients with resected pancreatic cancer did not benefit
from cisplatin and fluorouracil in a Japanese study .
Annals of Oncology
vii4 | Verslype et al. Volume 18| Supplement 7|June 2007
at University of Portland on May 20, 2011
The European Study Group for Pancreatic Cancer (ESPAC)-
1 trial was a large study carried out in 541 patients, which was,
however, heavily criticized because of randomization
methodology and the lack of quality control for surgery and
radiotherapy. Patients were treated with CRT, chemotherapy
(5-FU) or no treatment. There was no benefit for CRT whereas
an advantage for chemotherapy (5-FU) was indicated .
The results of the Charite ´ Onkologie (CONKO)-001
randomized trial of adjuvant chemotherapy in resected
pancreatic cancer patients were recently published . A total
of 368 patients with R0 or R1 resection of pancreatic cancer
were randomized to adjuvant chemotherapy with six cycles of
gemcitabine or observation. More than 80% of patients had
a R0 resection. Median disease-free survival (DFS) was
significantly better in the gemcitabine group (13.4 months)
than in the control group (6.9 months). Estimated DFS at 3 and
5 years was 23.5% and 16.5% in the gemcitabine group, and
7.5% and 5.5% in the control group, respectively. Subgroup
analyses showed that the effect of gemcitabine on DFS was
significant in patients with either R0 or R1 resection. There was
no difference in OS, but it is likely that the difference in OS
between groups will become statistically significant with
a longer follow-up and an increasing proportion of deceased
patients. However, major drawbacks of this study were the
lack of quality control of surgery, pathology and the
participation of a large number of low-volume centers.
Preliminary results are available from the Radiation Therapy
Oncology Group (RTOG) 9704 study , which included 442
patients, and was designed to determine whether the addition
of gemcitabine to adjuvant fluorouracil-based CRT improves
survival in patients with gross complete resection of pancreatic
cancer. Chemotherapy with either gemcitabine or fluorouracil
was given >3 weeks before and 12 weeks after chemoradiation
that consisted of radiation therapy with fluorouracil
(continuous infusion) as a radiosensitizer in both groups. In
the subgroup of 381 patients with pancreatic head tumors,
gemcitabine significantly improved OS [median 20.6 versus
16.9 months, 3-year survival 32% versus 21%, hazard ratio
(HR) 0.79, 95% confidence intervals (CIs) 0.63–0.99, P = 0.03],
but median DFS was not improved (11.4 versus 10.1 months).
The use of neo-adjuvant strategies in the preoperative setting
in potentially resectable tumors remains experimental. In
a promising phase II study, 86 patients were treated
preoperatively with gemcitabine plus radiotherapy 10 · 3 Gy
. Seventy-one patients underwent surgery and 74% of
them had a resectable tumor and 54% a pathological response.
Median survival in resected patients was 36 months versus 7
months in nonresected cases. However, randomized studies
are necessary to confirm these promising results.
Based on these studies and despite some shortcomings,
adjuvant treatment is strongly recommended following
pancreatic resection surgery. The agents used may be
gemcitabine for 6 months or 5-FU. Although there is a good
rationale for adjuvant CRT, the level of evidence that supports
its systematic use is lower. It may be considered in case of
positive margins or R1 resection, but there was no consensus
among the experts on this particular point.
Due to the ongoing controversy about postoperative CRT,
results are awaited from the current phase II/III EORTC 40013-
trial, in which patients are randomized following R0 resection
between gemcitabine therapy (for 4 months) and CRT (two
cycles of gemcitabine for a duration of 8 weeks, followed by
weekly (·5) gemcitabine in combination with 50.4 Gy
radiation therapy). The phase II part of the study is currently
The majority of patients with pancreatic cancer present with
either locally advanced, unresectable disease or with metastases.
Median survival of these patients is extremely short. Therefore,
all interventions in these patients should be carried out with
a low morbidity and mortality, aiming at improving or
maintaining quality of life (QoL). Endoscopic stenting, pain
relief and pancreatic enzyme supplementation represent the
mainstay of palliative care in advanced pancreatic cancer.
endosopic stenting of biliary and duodenal obstruction. Biliary
tract obstruction may lead to jaundice, pruritus, abdominal
discomfort, nausea, malabsorption and hepatic dysfunction.
As such, it seriously interferes with QoL . In addition, biliary
decompression is necessary before applying
chemo(radio)therapy. Endoscopic biliary stent placement is
the initial treatment of choice for patients with obstructive
jaundice due to pancreatic cancer. It is certainly less invasive, as
effective as surgical intervention in the treatment of cholestasis
and is characterized by the same median survival as surgically
treated patients [32–35]. However, endoscopic stenting requires
much more late interventions because of stent dysfunction, and
this may have a negative impact on QoL. The choice of therapy,
either surgical decompression or endoscopic stenting, should be
discussed with every individual patient, after a thorough
discussion with the patient of the pros and cons related to both
therapeutic procedures . The choice between the more
expensive metallic, self-expandable stent or the cheaper plastic,
polyethylene stent should be based on the prognosis and the
general condition of the patient and on his willingness to
undergo repeated procedures. Once deployed, metal stents have
a diameter of 30 French or 10 mm. They are characterized by
a longer median patency rate of ?10 months, as compared with
10 French plastic stents that have a median stent patency of ?4
months [37–39]. The mechanism of stent occlusion is tumor
ingrowth or overgrowth in metal stents and sludge formation in
plastic stents. Although both types of stents have similar
outcomes with regard to patient survival and early reduction of
jaundice, the insertion of a metal stent seems advisable if the
patient is likely to survive >4–6 months and who will never be
candidate for a surgical resection [39–41]. Information about life
expectancy can be derived from the general condition of
the patient, from the presence of distal metastases and from
the size of the primary tumor [42, 43]. Duodenal stents are
indicated for duodenal of gastric obstruction caused by
locally advanced or metastatic pancreatic cancer. Duodenal
stents are of the self-expanding metallic type with diameters
of 16–22 mm. The method is minimally invasive and has
a low morbidity rate .
intractable pain. The treatment of pancreatic cancer pain
includes pharmacotherapy, chemotherapy and/or radiotherapy,
Annals of Oncology
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at University of Portland on May 20, 2011
psychosocial support, celiac/splanchnic neurolytic blocks and
epidural or intrathecal infusion of medications. The
superiority of one method over the other, alone or in
combination, has not been established so far . Pain should be
treated initially with a nonsteroidal anti-inflammatory drug-
opioid sequence according to the World Health Organization
recommended method. If pain is intractable, a celiac/splanchnic
neurolytic block, either via EUS or percutaneous approach,
should be considered. Overall, success rate is ?75% [46, 47], and
the most prevalent complication being postural hypotension.
These procedures are, however, nowadays carried out less
frequently due to the venue of better medical relief with
morphine and its analogues. In addition to pain, depression is
a common problem in pancreatic cancer patients, which requires
the necessary attention .
pancreatic enzyme supplementation. Obstruction of the main
pancreatic duct may result in pancreatic exocrine failure and may
be responsible for significant fat malabsorption. Enteric-coated
pancreatic enzyme formulations may prevent weight loss and
improve QoL in patients with pancreatic cancer . However,
there are no large studies in this field. It is important to
administer sufficient dose of enzymatic activity, which should be
at least 10% of the normal postprandial output of lipolytic
activity (30 000 IU), to have some effect on steatorrhea.
chemotherapy for advanced pancreatic cancer
The majority of patients with pancreatic cancer will develop
metastases and are potential candidates for treatment with
systemic chemotherapy. The median survival of patients treated
with best supportive care (BSC) is ?3–4 months. However,
many patients have a poor performance status and succumb to
rapid tumor progression. Results obtained with chemotherapy
failed to have a large impact on the final outcome and have
been the reason for skepticism among clinicians and
oncologists for many years. Accurate tumor measurements are
often difficult to obtain (e.g. small peritoneal metastases),
which represents a major drawback for many clinical studies
carried out in pancreatic cancer. Moreover, the primary tumor
is composed of a large amount of reactive fibrous tissue, which
makes response evaluation in locally advanced tumors
troublesome. However, a totally fatalistic approach is not
justified because a significant proportion of patients do achieve
benefit from chemotherapy.
Many studies have been carried out with 5-FU in pancreatic
cancer. Early trials clearly overestimated the efficacy of 5-FU
because of inadequate response criteria. The actual response
rate is <10%. However, in these older studies, QoL was clearly
improved in those patients who received chemotherapy in
comparison with those who got only BSC . Biochemical
modulation of 5-FU with folinic acid and interferon did not
show significant better results. Combination chemotherapy
of 5-FU with mitomycin C, doxorubicin and streptozotocin
(FAM and SMF regimens) has failed, despite some initial
encouraging phase II studies . A few studies have
indicated that the activity of a protracted 5-FU infusion in
combination with cisplatin was superior in terms of
progression-free survival (PFS), but not OS [52, 53].
Gemcitabine is a nucleoside analogue with activity across
a broad range of solid tumors . The activity of gemcitabine
in pancreatic carcinoma was assessed in early phase II trials.
In a USA study of 44 patients, an objective response rate of
11% and a median survival of 5.6 months were found .
In a European study of 34 patients, a tumor response rate of
6.3% and a median survival of 6.3 months were found .
Both study groups reported symptomatic improvements in
their patients that were greater than indicated by the
objective tumor response rates. These improvements were seen
with reductions in both pain severity and analgesic
requirements as well as in performance status .
Therefore, ?clinical benefit response? was introduced as primary
end point to evaluate the efficacy of gemcitabine . In
a randomized trial, 126 patients with advanced pancreatic
cancer were treated with gemcitabine or with 5-FU.
Gemcitabine (1000 mg/m2) was administered as a 30-min
infusion weekly for seven consecutive weeks, followed by 1
week rest. Thereafter, the drug was given once weekly for three
out of every 4 weeks. 5-FU 600 mg/m2was administered once
weekly also as a 30-min infusion. Fifteen of 63 patients
randomized to gemcitabine, experienced clinical benefit
response (24%) with a median duration of 18 weeks versus
three of 63 (5%) in the 5-FU-treated patients with a median
duration of 13 weeks. In the gemcitabine group, 5.4% of the
patients (three of 56) with measurable disease had a radiologic
response versus none in the 5-FU group. Gemcitabine also
showed a modest survival advantage over 5-FU (1-year survival
18% versus 2%; median survival 5.65 months versus 4.41
months) , which has been confirmed in many other trials
where gemcitabine served as the control arm. As a result, the
drug has been widely accepted as the standard first-line
treatment of advanced pancreatic cancer. Some experts feel that
it is not definitely shown that gemcitabine is superior to an
optimal 5-FU or 5-FU/folinic acid schedule.
Although a pharmacokinetic rationale exists for
administering gemcitabine in a protracted infusion at
10 mg/m2/min (fixed dose rate, FDR) and a small clinical
trial was promising, a randomized phase III study comparing
the FDR regimen and the standard 30 min infusion failed to
show superiority for the FDR gemcitabine regimen [59, 60].
Combination of gemcitabine with a variety of cytotoxic agents
failed to show an increased survival in phase III studies [60–65].
Only one phase III study comparing the combination of
gemcitabine and capecitabine with gemcitabine monotherapy
has shown a significantly improved median (7.4 versus 6
months) and 1-year survival (26% versus 19%) in favor of the
combination arm (HR for survival 0.80; 95% CI 0.65–0.98,
P = 0.026) with a good safety profile . A previous Swiss
study was underpowered to show a survival difference .
Other studies with gemcitabine 6 5-FU failed to show
a difference between the two arms [68–70].
The individual studies combining gemcitabine plus
cisplatin or oxaliplatin demonstrated a significant advantage
in terms of response rates and PFS, but did not yield
a significant OS advantage for the combination of these
drugs, although there was a trend for an improved survival in
several studies [60, 64, 65]. The individual trials were
underpowered, which contributed to the negative outcome.
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at University of Portland on May 20, 2011
Two large meta-analyses of 3687 and 5561 patients,
respectively, indicated a survival benefit for the combination
of gemcitabine and the platinum analogue particularly for
patients with a good performance status [71, 72].
The interest in targeted therapies and novel biologic agents
has generated a wealth of clinical trials exploring combinations
with gemcitabine [73–75]. Only one trial of 569 patients has
shown a significant survival benefit of the combination of
gemcitabine plus the epidermal growth factor receptor (EGFR)
inhibitor erlotinib compared with gemcitabine alone .
Patients treated with the combination of gemcitabine and
erlotinib had an 18% reduction in the risk of death or an
overall 22% improvement in survival. The median survival and
the 1-year survival were better for the combination treatment:
6.24 versus 5.91 months and 24 versus 19% (HR for survival
0.82; 95% CI 0.69–0.99, P = 0.038). The excess toxicity of the
combination with erlotinib was relatively limited. These
numbers as well as the 1-year survival difference probably
reflect better the impact of the treatment with erlotinib for an
individual patient than the difference in median survival.
Combination of bevacizumab with gemcitabine did not result
in a survival benefit compared with gemcitabine monotherapy
in a large phase III study . The results of the randomized
phase III study of gemcitabine with or without the chimeric
anti-EGFR monoclonal antibody cetuximab are pending.
Based on all these clinical trial data, questions remain
regarding the actual standard treatment for patients with
advanced pancreatic cancer and the choice of the reference
treatment for clinical trials. The answer to these questions
remains controversial. From a clinical viewpoint, several
standard options can be proposed. Gemcitabine monotherapy
can certainly be defended, but the combination of gemcitabine
plus erlotinib, gemcitabine plus capecitabine and perhaps—in
patients with a good performance status—gemcitabine plus
a platinum analogue may result in a small benefit . The
choice of a reference arm in clinical trials is even more difficult.
In this setting, one is intended to use the most active
combination that is also widely used and accepted. Cooperative
groups and other investigators still have today the legitimate
option of gemcitabine monotherapy, although the choice of the
combination of gemcitabine with erlotinib or capecitabine
might be a preferable option as a control treatment to which
new treatment options and regimens should be compared .
Few studies have been conducted in patients who failed in
first line to gemcitabine. There is some evidence that a
combination of 5-FU and oxaliplatin may have some
efficacy in selected patients , but there is an unmet need
for studies in second line.
CRT for locally advanced pancreatic cancer
The optimal therapy for patients with locally advanced,
unresectable pancreatic cancer remains controversial. The
majority of chemotherapy trials also included patients with
locally advanced, unresectable disease. So, many of the
conclusions drawn previously are applicable to locally advanced
pancreatic cancer. The exact contribution of radiotherapy,
however, is unclear. Radiotherapy to the pancreatic bed is
limited by the proximity of radiosensitive structures. Several
small trials have shown a significantly longer survival following
CRT (10 months) as compared with chemo- or radiotherapy
alone (6–7 months) [79–81]. CRT should be reserved to those
patients who have a good performance status and peritoneal
metastases should be excluded by laparoscopy. Some patients
with locally advanced disease have rapid tumor progression and
develop metastases within a few weeks.
The phase III study from the Fe ´de ´ration Francophone de
Cance ´rologie Digestive randomly assigned 119 patients with
locally advanced pancreatic cancer between CRT (60 Gy in
6 weeks, 2 Gy per fraction, concomitant with 5-FU, 300 mg/m2
per 24 h as a continuous infusion, day 1–5 every week and
cisplatin, 20 mg/m2/d, day 1–5 at week 1 and 5) and
gemcitabine (1000 mg/m2weekly seven times every eight
weeks) as induction treatment. Maintenance treatment was
gemcitabine (1000 mg/m2weekly three times every four weeks)
in both arms until progression or limiting toxicity. Those
patients treated with first-line gemcitabine had a superior OS
(51.4% at 1 year versus 24%; stratified log-rank P = 0.014),
which led to a premature stop of the study . The reasons
why this exposure to immediate CRT failed are currently under
The French Groupe Coope ´rateur Multidisciplinaire en
Oncologie (GERCOR) proposes a different but attractive
strategy of initial chemotherapy for at least 3 months, followed
by CRT in patients whose disease had not progressed and
who have a good performance status . A retrospective
analysis of 181 patients with locally advanced pancreatic
cancer enrolled into prospective phase II and III GERCOR
studies was carried out to compare the survival of patients who
received CRT with that of patients who continued
chemotherapy alone . Fifty-three patients (29.3%) had
metastatic disease after 3 months of chemotherapy and were
not eligible for CRT. Among the 128 remaining patients
(70.3%) who had no disease progression and who were,
therefore, eligible for CRT, 72 (56%) received CRT (group A),
whereas 56 (44%) continued with chemotherapy (group B).
The two groups were balanced for initial characteristics
(performance status, gender, age, type and induction results
of chemotherapy). In groups A and B, the median PFS was
10.8 and 7.4 months, respectively (P = 0.005), and the
median OS was 15.0 and 11.7 months, respectively
(P = 0.0009). These results indicate that, following disease
control by initial chemotherapy, CRT could significantly
improve survival in selected patients with locally advanced
pancreatic cancer compared with chemotherapy alone. This
concept is explored in ongoing prospective phase III studies.
Outside clinical trials, it is therefore an interesting concept
to start with chemotherapy (gemcitabine or gemcitabine plus
erlotinib, capecitabine or cisplatin) and to consider the
addition of radiotherapy after 3 months of chemotherapy and
in the absence of disease progression, in patients with a good
performance status. Following CRT, it remains controversial
whether chemotherapy should be continued, as increased
hematological toxicity may be an issue .
treatment duration and monitoring
Following resection of pancreatic cancer and appropriate
adjuvant therapy, there is no clear evidence that systematic
follow-up is useful. An early detection of recurrence does not lead
Annals of Oncology
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at University of Portland on May 20, 2011
to curative therapeutic interventions. The experts recommend
limiting technical examinations to a minimum if the patient is
asymptomatic, with surveillance visits every 3–6 months.
In metastatic pancreatic cancer, the majority of the experts
continue chemotherapy until disease progression or toxicity.
Monitoring of treatment is done by (bi)weekly clinical
evaluation, serial measurements of serum CA19.9 and
imaging procedures (CT thorax and abdomen) every
2–4 months. There is no place for routine PET or PET-CT.
Following chemo(radio)therapy for locally advanced
pancreatic cancer and in case of a response (to be expected
in 10% of patients), surgical resection should be reconsidered
after the appropriate imaging examinations .
There are still many open questions for future research, which
include the evaluation of diagnostic modalities in order to
detect pancreatic cancer at an early stage. We need predictive
and prognostic tools to better select patients with pancreatic
cancer. This issue is becoming increasingly important in almost
all cancers since the increasing therapeutic options lead to an
increased economic burden to our health care system and also
lead to more complex drug regimens with higher toxicity.
Much is expected from the study of new targets beyond
EGFR and vascular endothelial growth factor, including
Mammalian target of rapamycin (mTOR), sarc (Src) or insulin-
like growth factor-1 receptor. The availability of intriguing
mouse models which recapitulate the pancreatic carcinogenic
process will undoubtedly lead to new insights in diagnosis and
The knowledge on the biology and on the management of
pancreatic cancer is progressing. A multidisciplinary approach
to a patient with pancreatic cancer is mandatory in order to
guarantee an optimal staging, surgery, selection of the
appropriate neo-adjuvant strategy and chemotherapeutic
choice management. Moreover, optimal symptomatic
management requires a dedicated team of health care
Quality control of surgery and pathology is especially
important in this disease with a high locoregional failure rate.
There is now solid evidence in favor of chemotherapy in both
the adjuvant and palliative setting, and gemcitabine combined
with erlotinib, capecitabine or platinum compounds seems to
be slightly more active than gemcitabine alone in advanced
pancreatic cancer. There is undoubtedly a place for CRT in
selected patients with locally advanced disease, while the role in
the adjuvant setting remains controversial and is subject to
Those involved in the care for patients with pancreatic cancer
should be encouraged to participate in well-designed clinical
trials in order to increase the evidence-based knowledge and to
make further progress.
The authors have not indicated any financial relationships with
companies whose products are mentioned in this article.
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at University of Portland on May 20, 2011