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Annals of Oncology 22: 1500–1506, 2011
doi:10.1093/annonc/mdq545
Published online 3 January 2011
Pancreatic cancer treatment and research: an
international expert panel discussion
M. A. Tempero1*, J. Berlin2, M. Ducreux3, D. Haller4, P. Harper5, D. Khayat6, H.-J. Schmoll7,
A. Sobrero8 & E. Van Cutsem9
1
Division of Hematology/Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; 2Division of Hematology/
Oncology, Vanderbilt Ingram Cancer Center, Nashville, USA; 3Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; 4Department of Medicine,
University of Pennsylvania Cancer Center, Philadelphia, USA; 5Department of Medical Oncology, London Oncology Clinic, London, UK; 6Department of Medical
Oncology, Pitié-Salpêtrière Hospital, Paris, France; 7Department of Internal Medicine IV, Hematology & Oncology, Univesitätsklinikum, Halle, Germany; 8Department of
Medical Oncology, Ospedale S. Martino, Genova, Italy; 9Division of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium
Received 10 May 2010; revised 28 July 2010; accepted 5 August 2010
review
Background: Pancreatic cancer has proven extremely challenging to treat. A collaborative effort is needed to
advance research and improve treatment. An expert conference was conducted to elicit perspectives regarding the
current treatment and future research of pancreatic cancer.
Methods: The conference comprised an international panel of experts representing five European countries and the
United States.
Results: Adjuvant radiotherapy is used more frequently in the United States than in Europe. In locally advanced
disease, there is now more emphasis on early chemotherapy in both Europe and the United States. In metastatic
disease, combination chemotherapy is commonly used in Europe and the United States. This varies by country.
Advancing pancreatic research will require improving biorepositories and developing a roadmap to prioritize
therapeutic targets in different models. Small randomized phase II trials of both non-selected and enriched patient
populations will help identify activity of new agents. Phase III trials should only be initiated in appropriate patients based
on strong clinical and biological signals. Developing drugs in the adjuvant setting may be preferable to eliminate some
of the challenges of drug development in the advanced disease setting.
Conclusion: Progress in research combined with encouraging improvements from the past offer hope for the future
of pancreatic cancer patients.
Key words: ductal adenocarcinoma, pancreatic cancer, pancreatic neoplasm, research, therapeutic targets,
treatment
introduction
Despite notable declines in cancer-related mortality over recent
decades, progress in pancreatic cancer has remained
exceedingly slow [1]. With one of the highest mortality-toincidence rate ratios, pancreatic cancer is the eighth leading
cause of cancer-related death in men worldwide and the ninth
leading cause in women [2]. The majority of patients are
diagnosed with advanced disease and have a median survival
with treatment of 6 months [3, 4]. Even for those seemingly
fortunate enough to have early-stage local and resectable
disease, the 5-year survival is only 20% after resection.
Pancreatic cancer is well recognized as an extremely
challenging disease on multiple fronts. The disease is usually
detected at an advanced stage, carries a poor prognosis regardless
*Correspondence to: Dr M. A. Tempero, Division of Hematology/Oncology, University of
California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600
Divisadero Street # B726, San Francisco, CA 94115, USA. Tel: +1-415-885-3846; Fax:
+1-415-353-9636; E-mail: [email protected]
of stage and is associated with debilitating symptoms. Fueling this
paradigm is a set of underlying biological attributes uncommon
to other cancers. Three key attributes—multiple molecular
aberrations, intense desmoplastic stroma, and hypoxia—result
in a cancer that is biologically and clinically aggressive. This
aggressiveness leads to a host of negative consequences, including
exceedingly short overall survival (Figure 1).
Advances in treating pancreatic cancer have been few and
modest. In the advanced setting, the current standard of care
was established over a decade ago when gemcitabine improved
symptoms and prolonged survival in a phase III trial when
compared with 5-fluorouracil (5-FU) [3]. However, building
on gemcitabine as an anchor drug has been difficult. Recent
phase III trials adding oxaliplatin, bevacizumab, or cetuximab
to gemcitabine have been negative [5–7]. A modest
breakthrough occurred when the addition of erlotinib to
gemcitabine was shown to prolong survival compared with
gemcitabine monotherapy [4].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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Annals of Oncology
In the adjuvant setting, the Charité Onkologie (CONKO)001 trial demonstrated the benefit of gemcitabine over
observation [8, 9] and the European Study Group for
Pancreatic Cancer (ESPAC) group has demonstrated a similar
benefit for 5-FU plus leucovorin without a clear advantage for
either 5-FU and leucovorin or gemcitabine [10, 11].
An expert conference was conducted in order to elicit
perspectives regarding the current state of treatment, to discuss
the issues, and to identify optimal areas in which to focus
research. What are the problems? Are phase II data being overinterpreted? Have the wrong targets been pursued? Is
inadequate drug delivery to blame? Is the biology of pancreatic
cancer more complicated than previously thought? With this
multifaceted challenge, a collaborative effort is justified to
identify barriers hindering progress in improving outcomes in
this disease.
methods
The expert conference was conducted by an international consensus panel
that comprised oncologists with an expertise in treating pancreatic cancer
(MAT, JB, MD, DH, PH, DK, H-JS, AS, and EVC). Members of the panel,
chosen on the basis of their knowledge in the field and their international
recognition, represented six countries: five in Europe (France, Germany,
Italy, Netherlands, and UK) and the United States. Panelists reviewed and
discussed pertinent data from published trials and reports and from
abstracts presented at selected oncology association meetings [American
Society of Clinical Oncology (ASCO) and European Society of Medical
Oncology]. The final manuscript was reviewed by all panel members and
approved by each author.
current practice
review of available treatments
Chemotherapy plays an integral role in the management of all
stages of pancreatic cancer, with gemcitabine and
fluoropyrimidines being the leading agents employed. The
only targeted therapy proven effective to date, erlotinib, has
shown a statistically significant benefit in combination with
gemcitabine in patients with advanced disease [4]. The panel
provided perspectives regarding current management of
pancreatic cancer (Table 1).
adjuvant treatment
chemotherapy. The role of systemic therapy in the adjuvant
treatment of pancreatic cancer is undisputed, and
gemcitabine is the favored agent in both the United States and
the Europe. Gemcitabine and 5-FU each produced an
approximate doubling of 5-year survival rates in adjuvant trials
(CONKO-001: 21%, gemcitabine versus 9%, observation;
ESPAC-1: 29%, 5-FU and leucovorin versus 11%, observation)
[9, 10], raising the question of whether a choice should be
made between the two agents. However, because of a more
favorable toxicity profile, more enthusiasm exists for utilizing
gemcitabine.
Gemcitabine is a prodrug and requires a nucleoside
transporter to gain access to the intracellular compartment.
Emerging data link the absence of human equilibrative
nucleoside transporter 1 (hENT1) expression to lack of
a survival benefit with gemcitabine [12]. If a patient’s tumor
does not express hENT1, one might argue that an optimally
delivered fluoropyrimidine is a better option. However, this
assay is not available yet for clinical decision making. It is
agreed that using hENT1 as an enrichment tool must be further
studied and validated.
radiotherapy. The potential role of radiotherapy and its timing
in the postoperative regimen varies worldwide. In the United
States, chemotherapy alone and chemotherapy plus
chemoradiotherapy are accepted standards of care for
postoperative adjuvant therapy. An analysis of the National
Cancer Data Base showed that between the time periods of
1985–1994 and 1995–2003, use of adjuvant chemoradiation
increased from 26.8% (n = 2255/8400) to 38.7% (n = 8655/
Table 1. Summary of key perspectives from the expert panel on
pancreatic cancer: current practice
Perspectives on current practice in adjuvant therapy
Key Peculiarities of Pancreatic Cancer and
Resulting Consequences
• Early molecular complexity
• Intense desmoplastic reaction
• Hypovascular,hypoxic, but non-necrotic tumor
Biological and clinical aggressiveness
•
•
•
•
•
•
•
•
No early detection
No chemoprevention despite precursor lesions
Low resectability
Early relapse
Early metastases
Short overall survival
Severe symptoms and poor quality of life
Resistance
Figure 1. Three key peculiarities associated with pancreatic cancer result
in a cancer that is biologically and clinically aggressive, leading to multiple
negative consequences.
Volume 22 | No. 7 | July 2011
Adjuvant chemotherapy represents the standard of care.
Gemcitabine remains the agent of choice in the United States and Europe.
The potential use of human equilibrative nucleoside transporter 1 deserves
further analysis.
Adjuvant radiotherapy is more commonly employed in the United States
than in Europe.
Radiotherapy schedules vary among countries and centers.
Perspectives on current practice in metastatic disease.
Gemcitabine is the agent of choice in the United states and Europe with
concomitant erlotinib more commonly employed in the United States.
Reimbursement for erlotinib varies throughout Europe.
Developing criteria to prospectively select appropriate patients for erlotinib
is an important goal; K-ras may prove beneficial.
Combination chemotherapy is used more commonly in Europe than in the
United States with gemcitabine–platinum combinations utilized in
patients with good performance status.
No second-line therapy is standard, yet over half of patients receive secondline therapy.
doi:10.1093/annonc/mdq545 | 1501
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21679) (P < 0.0001) and was more common at academic
institutions [13]. However, some United States centers argue
that its role in the postoperative adjuvant setting is unproven.
The Radiation Therapy Oncology Group is planning an
intergroup trial that will test both the value of radiotherapy
and the value of erlotinib in resected patients, similar to the
design of the French LAP 07 trial in locally advanced patients.
Studies evaluating the role of radiotherapy in the locally
advanced setting have proven challenging in the United States;
the Eastern Cooperative Oncology Group (ECOG) 4201 trial
of gemcitabine with or without radiotherapy failed to accrue its
target sample size [14], possibly reflecting unwillingness of
physicians to change long-standing clinical practices.
European countries have also hesitated to adopt adjuvant
radiotherapy, although some agree that this should be further
evaluated. Several studies are underway in the UK. In Europe,
radiotherapy is generally considered only for patients with
R1 resections or with locally advanced disease. In the setting
of R1 resection, the specific treatment regimens vary in the
length of gemcitabine monotherapy before the initiation of
chemoradiotherapy. Some countries follow the European
Organisation for the Research and Treatment of Cancer study
regimen of administering gemcitabine alone for 2 months
followed by chemoradiotherapy with gemcitabine [15]. In other
countries, chemoradiotherapy is more commonly delayed for
6 months to allow occult metastases to reveal themselves before
subjecting the patient to radiotherapy. Regardless of the
number of cycles used, chemotherapy is most frequently
initiated prior to chemoradiotherapy rather than after. For
locally advanced disease, both prospective studies and a metaanalysis support the sequence of chemotherapy followed by
chemoradiation [16, 17].
metastatic disease
first-line therapy. Gemcitabine (difluorodeoxycytidine) is
a nucleoside analogue capable of inhibiting ribonucleotide
reductase to deplete nucleoside pools and its phosphorylated
metabolite is incorporated into DNA, causing chain
termination. Gemcitabine is recognized and accepted as the
current chemotherapeutic agent of choice in the treatment of
advanced pancreatic cancer, as supported by the landmark
phase III study of Burris et al. [3].
Erlotinib is an oral HER1/EGFR tyrosine kinase inhibitor.
This tyrosine kinase is over-expressed in many pancreatic
tumors and is associated with poor prognosis and disease
progression. Blocking HER1/EGFR tyrosine kinase signaling
decreases the growth and metastasis of human pancreatic
tumor xenografts and improves the anticancer effects of
gemcitabine. The PA.3 trial conducted by the National Cancer
Institute of Canada showed significantly improved overall
survival [hazard ratio (HR) = 0.82] in the patient group treated
with gemcitabine (1000 mg/m2 weekly · 3 out of 4)
plus erlotinib (100 mg/day) over the group treated with
gemcitabine plus placebo [4]. Both the US Food and Drug
Administration and the European Medicines Agency have
approved erlotinib for advanced disease. Usage varies across the
United States and Europe. Because the survival improvement
was small, gemcitabine plus erlotinib has not been deemed
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standard of care and single-agent gemcitabine is still
acceptable [18].
It would be optimal to enrich for patients more likely to
benefit from treatment with erlotinib. More benefit has been
demonstrated in those patients who developed skin rash
compared with those who did not (HR = 0.74, 95% confidence
interval 0.56–0.98, P = 0.037) and the median survival rates
for patients with grades 0, 1, and 2+ rash were 5.3, 5.8, and
10.5 months, respectively [4]. The AViTA trial [19], which
tested gemcitabine plus erlotinib, with or without bevacizumab,
has confirmed the correlation between rash and improved
survival. The association with rash and survival observed in
these retrospective analyses is now under prospective study and
may become a valuable tool in identifying which patients will
ultimately benefit from anti-EGFR therapy. Nonetheless, rash
is not a factor that can be used to preselect patients for
treatment.
K-ras mutation occurs in 70%–90% of pancreatic cancers
and RAS activation predicts for resistance to erlotinib in other
malignancies. This suggests that only a small number of
patients may benefit from erlotinib therapy. However, available
data do not yet define a relationship between K-ras status
and erlotinib efficacy in pancreatic cancer [20].
combination chemotherapy. Combination chemotherapy is
utilized in both the United States and the Europe, except for the
UK. Despite many negative phone III trials [21–23],
gemcitabine–platinum combinations are still used particularly
for those with good performance status. Gemcitabine plus
capecitabine has also been extensively studied. The most recent
phase III trial using a 3-week schedule of capecitabine
demonstrated a clear benefit for progression-free survival but
not overall survival [24]. These practices are supported by
meta-analyses that demonstrated significantly superior survival
for patients who received a gemcitabine–platinum combination
versus gemcitabine alone (HR = 0.85; P = 0.01) and for
patients with good performance status who received
gemcitabine-based combination therapy (regardless of agent)
versus gemcitabine monotherapy (HR = 0.76, P < 0.001)
[25, 26]. Combination regimens with 5-FU (without
gemcitabine) also appear promising [27].
second-line therapy. No standard second-line therapy exists for
pancreatic cancer, yet over half of patients are eligible for and
receive some form of second-line therapy. In the Fédération
Francophone de Carcinologie Digestive 0301 trial, which
compared gemcitabine followed by 5-FU–leucovorin plus
cisplatin or the reverse sequence, 55%–68% of patients received
second-line therapy [28]. In the United States, various regimens
are utilized in the second-line setting, including gemcitabine
plus erlotinib (in erlotinib-naive patients), gemcitabine plus
oxaliplatin, capecitabine, and infusional 5-FU–leucovorin plus
oxaliplatin. Evaluating the true benefit of second-line therapy
is difficult. The CONKO-003 study began by comparing
second-line 5-FU-leucovorin plus oxaliplatin versus best
supportive care; however, the protocol was amended after
46 patients to include 5-FU–leucovorin in the control arm
because of slow accrual and reluctance to accept best supportive
care [29, 30]. Nonetheless, results from those 46 patients
demonstrated a statistically significant survival advantage for
Volume 22 | No. 7 | July 2011
Annals of Oncology
5-FU–leucovorin plus oxaliplatin and the final results
demonstrated superiority of the regimen over 5-FU and
leucovorin. This signal for efficacy and the unmet need of
patients still able to receive second-line chemotherapy suggests
that second-line therapy warrants further investigation [29].
Since the benefit of therapy was most pronounced in
patients with good performance status (Karnofsky performance
status 90%–100%) or who responded poorly to first-line
gemcitabine, this approach may best be suited for a selected
group of patients.
perspectives on clinical trial design and
the future of treating pancreatic cancer
With the current state of pancreatic cancer treatment defined
in Europe and the United States, the panel turned toward
future research and management. Panelists discussed how to
advance the development of new treatments for pancreatic
cancer by responding to several currently pressing questions
(Table 2).
why have recent phase III trials failed?
Numerous phase III trials in recent years have tested either new
gemcitabine-based chemotherapy regimens or novel targeted
agents, and most have uniformly failed to produce improved
overall survival [5–7, 31–38]. These trials probably failed for
many reasons. One reason might have been inadequate
interpretation of phase II data and a lack of appreciation for
unintentional but biased patient selection. Phase II trials should
be interpreted carefully before proceeding to phase III. For
example, some argue that axitinib should not have been tested
in the phase III setting because the phase II study of
gemcitabine–axitinib did not meet its overall survival end point
[39]. The group conceded that at least a 50% improvement
in outcome over the standard regimen is needed in
Table 2. Summary of key perspectives from the expert panel on
pancreatic cancer: clinical trial design and future treatment
Clinical trial design and the future of pancreatic cancer treatment
Phase III trials may be more likely to succeed if larger differences are
secured at the phase II level and patient populations are appropriately
selected.
A phase II signal of 50% improvement over standard of care may warrant
continued drug development if patient selection factors are considered
or a biological signal is identified.
Randomized phase II design or replicate phase II trials will minimize the
chance of bias.
Predictive biomarkers should be explored in phase II trials in order to
target therapy to the appropriate patients.
Metastatic and locally advanced populations should be studied
separately.
The adjuvant setting is recognized as micrometastatic disease and should be
considered for new drug development.
Key targets of interest include K-ras, c-Met, and sonic hedgehog due to
their roles in cancer stem cells.
A virtual archive of annotated (molecular and clinical) tissue would
facilitate research aimed at early detection and treatment.
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a randomized phase II setting to predict for possible success
in phase III. Therefore, very large signals should be identified
at the phase II level before proceeding with phase III trials.
Small but statistically significant differences may secure
agency approval but may not have a major clinical benefit. A
rush to bring compounds into phase III testing without
extensive phase I/II modeling has been a major obstacle to
success.
Patient selection is another issue in clinical drug testing.
Investigators must be cognizant of the population evaluated in
phase II before translating results to phase III. For example,
encouraging 8.8 months median survival observed in the
phase II trial with bevacizumab did not translate to a successful
phase III trial [6, 40]. One possible reason for this discrepancy
is that the patient population enrolled in the phase II trial
was highly selected since the phase II trial excluded patients
with a history of thrombosis and a high proportion of patients
had an ECOG performance status of 0 or 1. Seemingly, minor
changes in eligibility criteria may lead to significant bias in
subsequent studies.
With respect to patient subgroups, patients with metastatic
disease should be investigated separately from those with locally
advanced disease. Obviously, survival is prolonged in patients
with locally advanced disease compared with those who have
distant metastases and a differential effect of treatment is
observed in clinical trials of both chemotherapy and targeted
therapy between the two populations [4, 26, 35].
Finally, we need a better understanding of factors that affect
prognosis and predict outcome in order to appropriately
stratify patients in studies and enrich for populations most
likely to benefit. A major investment must be made to identify
those new biomarkers.
what is the best clinical setting for new drug
development: metastatic or adjuvant?
The traditional paradigm has been to study new drugs in
combination with gemcitabine in the metastatic setting.
However, resectable pancreatic cancer is now recognized as
a condition in which most patients have micrometastatic
disease. Testing novel agents in the adjuvant setting may be
more useful than following the traditional paradigm.
Identifying drugs of interest should start in the preclinical
setting with appropriate characterization of targets. The targets
that might be explored include those within the malignant
epithelial compartment as well as the stromal compartment.
Examples of the former might include critical cellular signaling
pathways. Examples of the latter might include stromal
networks that promote invasion and metastases. Either
appropriate cell lines, or primary tumor xenografts, established
as either s.c. or orthotropic xenografts or selected transgenic
models, might be appropriate depending on the target of
interest. Once a target and drug of interest are established,
initial studies assessing safety and perhaps even efficacy might
be done in a metastatic setting. To minimize patient resources
required, validated surrogate end points for survival should be
developed. ‘Window of opportunity’ trials of new drugs are
difficult to do in the metastatic setting because these patients are
frail and may deteriorate quickly. Thus, in this setting, new drugs
should probably be tested within a chemotherapy backbone such
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as gemcitabine or a combination regimen such as fluorinated
pyrimidine and oxaliplatin. However, patients with locally
advanced disease have a somewhat more indolent course and
might be good candidates for ‘window of opportunity’ trials
including those in which posttreatment tissue might be desired.
From a safety perspective, this is best done through a endoscopic
ultrasound-directed fine needle aspiration.
It is reasonable to initiate testing of new drugs in end-stage
disease in the first- or second-line setting. If a strong signal is
identified, initiating a phase III trial in the adjuvant, rather than
metastatic, setting may be preferable for several reasons. It is
important to remember that the benefit of 5-fluoruracil and
gemcitabine in the adjuvant setting is considerably greater than
that observed in the setting of advanced disease [9, 3]. This
suggests differences in drug sensitivity or drug delivery or both.
Investigating new drug combinations in this setting affords
little additional risk to patients who are often managed variably
across centers and countries. Since the primary tumor is no
longer intact, the difficulty of penetrating the stroma is
minimized. The stroma may still be a significant barrier for
drug delivery in advanced pancreatic tumors but this may be
less of an issue in micrometastatic disease. Mounting
a comprehensive effort in the adjuvant setting would require
a global consortium. A large international rolling adjuvant
program using successive cohorts would be preferable to
independent small studies.
Opponents to this method counter that evaluating new drugs
in the adjuvant setting is unduly time consuming. However,
proponents point out that the new drug could advance directly
from a robust phase II trial to a randomized phase III adjuvant
trial with a smaller patient cohort if the benefit is predicted
to be substantial. This strategy was employed in CONKO-001,
where it was clearly shown that disease-free survival predicted
for overall survival. Also, the signal event—relapse—occurs
relatively quickly, so although accrual may take time, the
time-to-signal event does not.
can targets of interest be prioritized?
Interesting targets have been identified but prioritizing those
targets remains difficult. Twelve core-signaling pathways in
pancreatic cancer were recently elucidated (Table 3) [41]. Of
these, key targets of interest may include K-ras, c-Met, and
sonic hedgehog because of their role in cancer stem cells,
potentially an important avenue of research [42].
All potential targets require more thorough preclinical
investigation both alone as well as in combinations. Human
pancreatic cell lines and s.c. xenograft models may not be the
most optimal tools. Importantly, a clear plan for credentialing
interesting targets needs to be developed. Showing efficacy of
new targeted therapeutics in multiple models including
primary tumor explants will increase the level of confidence.
Targets within the microenvironment might best be explored
in transgenic mouse models.
what is the ideal biorepository?
Because so few patients undergo resection, access to clinically
annotated tumor tissue for research is a worldwide problem.
Creating an archive of well-annotated (clinical and molecular)
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Table 3. Core signaling pathways in pancreatic cancer [36]
Apoptosis
DNA damage control
Regulation of G1/S phase transition
Hedgehog signaling
Homophilic cell adhesion
Integrin signaling
c-Jun N-terminal kinase signaling
KRAS signaling
Regulation of invasion
Small guanosine triphosphatase-dependent signaling (other than KRAS)
Transforming growth factor-b signaling
Wnt/Notch signaling
tissue that can be viewed and explored virtually would be
a major step forward. Similarly, creating a related large DNA
(germ line) and serum and/or plasma bank could accelerate
research on interesting leads now emerging from genome-wide
association studies in the United States. Expansion of tissue as
primary tumor explants would also be useful for discovery
research and could potentially be exploited for therapeutic
target validation studies.
All of these efforts would need to rely on a network of centers
with appropriate infrastructure including informatics
capability, standardized procedures, and quality control
measures.
without early detection does hope for the future
exist?
Despite the seemingly grim outlook for pancreatic cancer
management, potentially valid targets and corresponding
agents exist. Furthermore, chemotherapy has shown efficacy in
this disease and is an avenue that, with continued exploration,
will yield additional benefits. A better understanding of
pancreatic cancer biology and an innovative approach to
clinical development will move this field forward. Breakthrough
treatments of chronic myelogenous leukemia and
gastrointestinal stromal tumors at one time appeared out of
reach. Exciting advances in these challenging tumors [43–45]
provide hope for the future of pancreatic cancer patients.
conclusions
Pancreatic cancer continues to pose a significant challenge to
physicians and investigators. Small but encouraging steps have
been made in improving outcomes with therapy.
Some variations occur between Europe and the United States
in the management of pancreatic cancer, particularly with the
application of adjuvant radiotherapy and the use of
combination chemotherapy or erlotinib in advanced disease.
However, targeting treatment to the individual patient remains
a goal worldwide and patient, tumor, and drug-related factors
are beginning to be identified to foster that goal.
Advancing the field of pancreatic cancer management will
require efforts on several fronts. Protocol-directed virtual
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Annals of Oncology
biorepositories with appropriately annotated samples will
improve access to tissue. Much more preclinical work is
required to select and prioritize appropriate targets. Small
randomized phase II trials of enriched patient populations will
help identify potentially useful new drugs. Only drugs that
produce a substantial survival benefit in phase II trials should
move into phase III development. Finally, developing drugs
in the adjuvant setting should be considered as an alternative
to the cohort paradigm. Progress on each of these fronts,
together with small but encouraging improvements from the
past, offers hope for the future of pancreatic cancer patients.
addendum
Subsequent to this consensus conference and prior to
publication, results of the ACCORD study [46] were made
public at the annual ASCO meeting in Chicago. This
randomized phase III study in patients with metastatic
pancreatic ductal adenocarcinoma having a good performance
status compared standard therapy with gemcitabine to
a combination of 5-FU, oxaliplatin, and irinotecan
(FOLFIRINOX). The FOLFIRINOX arm produced a significant
improvement in progression-free survival (6.4 versus 3.3
months, HR = 0.47) and overall survival (11.1 versus 6.8
months, HR = 0.57) but also produced significant
myelosuppression (42% of patients required growth factor
support) and grade 3 or 4 fatigue (23%). The panel has
reviewed these data and concurs that FOLFIRINOX is an
excellent option for selected patients but cannot be considered
standard of care for all. However, these data does support the
development of first-line regimens based on a fluorinated
pyrimidine (without gemcitabine) including regimens with
selected targeted drugs.
disclosure
JB has done advisory boards for Amgen, Clavis, Merck, Roche,
Bristol Myers Squibb Astrazeneca, Abbott, and Seattle Genetics.
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Volume 22 | No. 7 | July 2011