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JOP. J Pancreas (Online) 2009 Jul 6; 10(4):361-365.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 4 - July 2009. [ISSN 1590-8577] 361
HIGHLIGHT ARTICLE
Any Progress in the Management of Advanced Pancreatic Cancer?
Highlights from the “45th ASCO Annual Meeting”. Orlando, FL, USA. May 29 - June 2, 2009
Jia Li, Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
Summary
Majority of the patients with pancreatic cancer present with advanced disease that is lethal and notoriously difficult to treat. Survival
has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel
therapeutic approaches. The treatment of advanced disease with gemcitabine has only a modest activity on survival with a favorable
impact on quality of life. So far, the current targeted agents that have been used in combination with gemcitabine have failed to
improve clinical outcomes. This failure may stem from the heterogeneous molecular pathogenesis of pancreatic cancers, which
involves several oncogenic pathways and defined genetic mutations. However, recent data support the evidence that the combination
of gemcitabine with erlotinib, capecitabine or platinum compounds could be more active than gemcitabine alone in advanced
pancreatic cancer. New therapeutic strategies, particularly using molecular target agents, are under evaluation. A number of
molecular mechanisms responsible of transformation and progression of pancreatic cancer have been identified, opening the
possibility to identify also possible pharmacological targets. Pancreatic cancer remains the 4th leading cause of cancer death in the
U.S.A.. How to treat a non-resectable pancreatic cancer has been a challenging topic for all medical oncologists. Historical 5-
fluorouracil has been replaced by single agent gemcitabine since 1997. Numerous combinations using gemcitabine as a backbone
have been tested in clinical trials; unfortunately, none of the combinations including the ones with biological agents was proved to be
significantly superior to gemcitabine alone. This year, more combinations were investigated and the results were presented on the
meeting. In first-line setting, two large phase III trials (Abstracts #4504 and #4601) failed to prove any additional benefit of a second
cytotoxic agent or a vaccine. Folinic acid plus 5-FU plus oxaliplatin (FOLFOX) and 5-fluorouracil plus leucovorin plus irinotecan
(FOLFIRI) could be considered in the second-line setting after failure of gemcitabine therapy (Abstract #4618). Novel agents
(Abstracts #4501, #4625, #4626, #4617) provide some hope; however, in general, all combinations are still significantly relying on
the backbone of gemcitabine. Thinking beyond the gemcitabine box and exploring novel agents are very crucial now.
Introduction
American Cancer Society has estimated in 2009, there
will be 21,050 new pancreatic cancer cases in men and
21,420 in women, while 35,240 (about 83%) will die of
pancreatic cancer in 2009 [1]. Pancreatic cancer
remains the 4th cause of death by cancer after lung,
prostate (breast in women), colorectal cancer since
1970s in the USA, although it represents only 2-3% of
all cancers. Endless effort has been put on this
aggressive disease; however, surgical resection remains
the only curative option. Locally advanced or
metastatic diseases are considered non-curable,
palliative chemotherapies are often administered for
alleviating symptoms. Fluorouracil (5-FU) had been
the only active drug in pancreatic cancer for over
decades until the emerging of gemcitabine in 1997 [2].
A significantly higher clinical benefit response
associated with gemcitabine treatment was observed
(23.8% vs. 4% in 5-FU arm) although the overall
objective response rate remained modest [2]. Based on
these results, FDA approved gemcitabine as the first
line therapy for advanced pancreatic cancer in 1997.
Since then, various combinations using gemcitabine as
a backbone were designed and tested in clinical trials.
Unfortunately, none of the combinations is proved to
be superior to gemcitabine monotherapy.
With the advances in molecular biology, newer
biologic agents such as erlotinib, cetuximab and
bevacizumab are adding some benefit to the
conventional cytotoxic agents. Unfortunately, these
agents all failed to show any significant superiority
over gemcitabine except the combination of erlotinib
plus gemcitabine [3]; however, the clinical impact of
this combination remains very controversial until now.
The disappointing results did not discourage
investigators but stimulated them to look for more
Key words Clinical Trials as Topic; Disease-Free Survival;
erlotinib; gemcitabine; Pancreatic Neoplasms; Survival
Abbreviations CONKO: Charité Onkologie; LMWH: low
molecular weight heparin
Correspondence Muhammad Wasif Saif
Section of Medical Oncology, Yale University School of
Medicine, 333 Cedar Street; FMP:116, New Haven, CT 06520,
USA
Phone: +1-203.737.1875; Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL http://www.joplink.net/prev/200907/24.html
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JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 4 - July 2009. [ISSN 1590-8577] 362
pharmaceutical agents or combinations. We have
gladly seen over 80 abstracts presented in the 2009
annual meeting of the American Society of Clinical
Oncology (ASCO) in the field of pancreatic cancer. In
this highlight article, we will focus on the management
of advanced (locally advanced and metastatic)
pancreatic cancer.
Since the approval of gemcitabine, true progress in the
management of pancreatic cancer has been very
minimal. There has been persistent effort in the field of
medical oncology regards to explore novel agents
based on better understanding of the diseases.
1. First-Line Therapies
Current standard first-line therapies for advanced
pancreatic cancer are gemcitabine or gemcitabine plus
erlotinib. A number of abstracts are exploring further
first-line options. Interestingly, gemcitabine remains
the core of the combinations.
1.1 Phase III Trials
Three large trials were presented (Table 1) [4, 5, 6];
unfortunately, two large trials (Abstracts #4504 and
#4601) failed to prove any additional benefit of a
second cytotoxic agent or a vaccine. The third trial
(Abstract #4604) comparing erlotinib plus capecitabine
with erlotinib plus gemcitabine only presented interim
toxicity data from 127 patients, efficacy data are
pending. To think beyond the gemcitabine box and
search for novel agents have become crucially urgent
in order to conquer this very aggressive disease.
1.1.1 Gemcitabine vs. Gemcitabine plus Cisplatin
The “Gruppo Oncologico dell’Italia Meridionale”
conducted a phase III trial to compare gemcitabine
with or without oxaliplatin, the benefit was only
observed in progression-free survival but not overall
survival, however later pooled- and meta-analysis
proved that the addition of platinum to gemcitabine did
offer survival benefit in selected patients [7, 8, 9]. The
“Gruppo Italiano Pancreas” (GIP) conducted another
superiority study to compare gemcitabine monotherapy
with gemcitabine plus cisplatin in advanced pancreatic
cancer patients [4]. The data were presented in this
annual meeting. A total of 400 patients were enrolled
from 46 Italian institutions. One-hundred and ninety-
nine patients received gemcitabine single agent (1,000
mg/m2 weekly x 7, then weekly x 3 every 4 weeks),
whereas the other 201 patients received combination
therapy of gemcitabine plus cisplatin (in addition to
gemcitabine administered as above, cisplatin was given
at 25 mg/m2 weekly). Surprisingly, this large trial did
not demonstrate any survival benefit by adding
cisplatin to gemcitabine. The results not only
confirmed a previously published negative phase III
trial, but also warned all clinicians to carefully interpret
pooled or meta-analyses.
1.1.2 Gemcitabine vs. GV1001 plus Gemcitabine
GV1001 is a telomerase peptide vaccine which showed
a median overall survival of 8.6 months in non-
resectable pancreatic cancer [10]. In order to compare
the efficacy of a combination therapy of GV1001 and
gemcitabine with gemcitabine monotherapy, a phase III
trial was designed [5]. A total of 520 patients were
planned. Patients were randomly assigned to either
gemcitabine monotherapy (1,000 mg/m2 over 30 min
weekly x 7, then weekly x 3 every 4 weeks) or a
sequential combination of GV1001 and gemcitabine
(GV1001 0.56 mg subcutaneous plus granulocyte-
macrophage colony-stimulating factor as immune
adjuvant on days 1, 3, 5, 8, 15, 22, 36, then every 4
weeks, gemcitabine was added when disease
progressed on GV1001). Unfortunately, after 365
patients were enrolled, a preliminary analysis indicated
no survival benefit by giving GV1001. Thus this trial
was prematurely terminated.
1.1.3 Erlotinib plus Capecitabine vs. Erlotinib plus
Gemcitabine
Erlotinib has been proved to have effect in combination
with gemcitabine for advanced pancreatic cancer.
Whether erlotinib can be combined with other
cytotoxic agents such as capecitabine in treating
advanced pancreatic cancer was investigated in a phase
III trial conducted by the “Arbeitsgemeinschaft
Internistische Onkologie” (AIO) group [6]. Two-
hundred and eighty-one patients randomly received
either capecitabine (200 mg/m2/day, days 1-14 every 3
weeks) plus erlotinib (150 mg/day) or gemcitabine
(1,000 mg/m2 over 30 min weekly x 7, then weekly x 3
every 4 weeks) plus erlotinib. The first interim analysis
was reported on the meeting. Sixty patients received
capecitabine plus erlotinib, 67 patients received
gemcitabine plus erlotinib. Toxicity data indicated that
erlotinib can be safely combined with capecitabine;
however, the efficacy data are not completed yet.
Whether this combination could achieve similar
efficacy in terms of progression free survival and/or
overall survival as the combination of erlotinib with
gemcitabine, we will have to wait for the final results.
Table 1. Randomized phase III trials of gemcitabine-based first-line therapies.
Abstract Study design PFS (months) OS (months) Comments
#4504 [4] Arm A: gemcitabine,
Arm B: gemcitabine + cisplatin 3.9 vs. 3.8
(P=0.8) 8.3 vs. 7.2
(P=0.38) Combination therapy did not provide any benefit in PFS, OS or
clinical benefit, but increased toxicities
#4601 [5] Arm A: gemcitabine,
Arm B: GV1001 + gemcitabine 3.7 vs. 1.9 7.3 vs. 5.9 GV1001 has no benefit in treating pancreatic cancer benfit when
administered in sequential combination with gemcitabine
#4604 [6] Arm A: capecitabine plus erlotinib,
Arm B: gemcitabine plus erlotinib Not presented Not presented The first interim analysis only presented toxicity data from the first
127 patients. The combination of erlotinib and capecitabine seems to
be tolerable; however, the efficacy data are not finalized yet
OS: overall survival; PFS: progression-free survival
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1.2 Phase I/II Trials
Several phase I/II trials studied more combinations,
including four novel agents which will be discussed in
more details in next section (Tables 2 and 3).
2. Second-Line Therapies
Lack of attention to second line treatment strategy in
advanced pancreatic cancer is due to the fact that we
still do not have first line option that renders true
survival benefit; therefore, development of novel
therapeutic agents should be an obvious area of our
focus in the future. However, there is growing evidence
supporting benefit of chemotherapy after gemcitabine
failure in selected patients with good performance
status [14].
Few clinical trials investigating second-line options in
patients with advanced pancreatic cancer after failure
of gemcitabine were presented at the meeting. One
study aimed at exploring folinic acid plus 5-FU plus
oxaliplatin (FOLFOX) and 5-fluorouracil plus
leucovorin plus irinotecan (FOLFIRI.3), two
commonly used regimens in colorectal cancer in this
setting (Aabstract #4618) [15]. Sixty patients were
randomly assigned to either FOLFOX (oxaliplatin 85
mg/m2 over 120 min on day 1, leucovorin 400 mg/m2
on day 1, 5-FU 2,000 mg/m2 over 46 hours every two
weeks) or FOLFIRI.3 (irinotecan 70 mg/m2 over 60
min on day 1, leucovorin 400 mg/m2 over 2 hours on
day 1, 5-FU 2,000 mg/m2 over 46 hours from day 1,
then irinotecan 70 mg/m2 over 60 min at the end of the
5-FU infusion every two weeks). Six-month overall
survival rate in both arms were 25% and 20%,
respectively. Based on patients’ overall performance
status, and prior chemotherapy toxicities, these two
regimens can certainly be considered as second-line
option; however, the clinical benefit needs to be
validated in larger trials.
Table 2. Phase I/II trials of gemcitabine-based first-line therapies.
Abstract Study design Phase
level Efficacy PFS
(months) OS
(months) Severe
toxicities Comments
#4607 [11] Triple combination of
gemcitabine + erlotinib +
capecitabine (n=43)
II PR: 32.6%
SD: 51.2% 6.5 12.0 Cytopenia,
GI toxicity, and
rash
EGFR expression is poor
prognostic factor
#4614 [12] Arm A: PDXG regimen (n=46)
Arm B: PEXG regimen (n=46) II PR:
61% vs. 37% 6-month PFS:
58% vs. 54% 1-year OS:
41% vs. 41% Cytopenia,
fatigue Capecitabine is equivalent to
5-FU, docetaxel seems to be
slightly superior to epirubicin in
terms of response rate
#4623 [13] GTX regimen (n=41) II PR: 21.9%
SD: 41.5% 6.9 14.5 Cytopenia,
infections, and
mucositis
Large trial is warranted to
validate this promising regimen
GTX: gemcitabine, docetaxel and capecitabine; OS: overall survival; PDXG: cisplatin, docetaxel, 5-FU, gemcitabine; PEXG: epirubicin replacing
docetaxel; PFS: progression-free survival; PR: partial response; SD: stable disease
Table 3. Novel agents in the treatment of advanced pancreatic cancer.
Novel agents;
Abstract# Rationale Administration/schedule Clinical
trials Results Future directions
AMG655
#4501 [18] AMG655 is an agonist monoclonal
antibody against human death receptor 5
(DR5), activates caspases, and
subsequently induces apoptosis in
sensitive tumor cells.
Preclinical studies showed synergistic
effect of AMG655 and gemcitabine.
AMG655 at 3 mg/kg or
10 mg/kg on day 1 and 15
plus gemcitabine at
1,000 mg/m2on days 1, 8
and 15 every 28 days
Phase I,
first-line
therapy
13 patients.
PR: 31%. PFS: 5.3 months.
6-month survival rate: 76.2%.
Severe toxicities: 9 (69%);
especially cytopenia.
Same group is
conducting a phase
II trial to compare
gemcitabine with
or without
AMG655.
Nab-paclitaxel
#4525 [19] Pancreatic cancer cells and surrounding
stroma overexpress SPARC.
A new formulated paclitaxel, nab-P, an
albumin-bound nanoparticle form of
paclitaxel increased tumor accumulation
of paclitaxel through binding of albumin
to SPARC
Nab-paclitaxel
at 100-150 mg/m2
plus gemcitabine
at 1,000 mg/m2
were given on days 1, 8,
and 15 every 28 days
Phase I/II,
first-line
therapy
63 patients.
CR: 2%, PR: 12%, SD: 41%.
PFS: 4.8 months for SPARC-.
PFS: 6.2 months for SPARC+.
mOS: 9 months.
Severe toxicities 12 patients;
especially cytopenia.
Nab-paclitaxel is
very promising.
SPARC could be a
predictive factor.
A phase III trial in
larger populations
is warranted.
EndoTAG-1
#4526 [20] EndoTAG-1 is a novel cationic
liposomal formulation of paclitaxel
which targets negatively charged
endothelial cells of tumor blood vessels
Weekly gemcitabine at
1,000 mg/m2,
with or without twice
weekly endoTAG-1 at
3 dose levels:
11, 22 and 44 mg/m2
Phase II,
first-line
therapy
200 patients.
Response rate and PFS were not
presented.
mOS: 11.5 months for gemcitabine
plus high dose endoTAG-1.
More infusion-reaction is associated
with endoTAG-1 treatment groups.
Needs large trial to
confirm the data.
Masitinib
#4617 [21] Masitinib is a tyrosine kinase inhibitor
targeting c-Kit, PDGFR, FGFR3 and
affecting the FAK pathway.
Masitinib was found to enhance the
antiproliferative effects of gemcitabine
in preclinical studies.
Masitinib at 9 mg/kg/day
plus weekly gemcitabine
at 1,000 mg/m2
Phase II,
first-line
therapy
22 patients.
Clinical benefit: 16%.
mPFS: 6.4 months.
mOS: 7.1 months.
18-month survival rate: 23%.
Severe toxicities were:
cytopenia, diarrhea and rash.
The same group is
conducting a phase
III trial to compare
gemcitabine with
or without
masitinib.
CR: complete response; FAK: focal adhesion kinase; FGFR3: fibroblast growth factor receptor 3; mOS: median overall survival; mPFS: median
progression-free survival; PDGFR: platelet-derived growth factor receptor; PFS: progression-free survival; PR: partial response; SD: stable disease;
SPARC: secreted protein acid rich in cysteine
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Current standard dose of erlotinib is 100 mg/day in
combination with gemcitabine [3]. Skin acne-like rash
has been proposed to be a “surrogate” marker for
response to biologic agents such as erlotinib and
cetuximab. In the 2007 ASCO Gastrointestinal Cancers
Symposium (Orlando, FL, U.S.A.; January 20th, 2007),
Van Cutsem et al. presented a dose-escalation study of
cetuximab in colorectal cancer (EVEREST). The
higher grade of skin rash correlating with increased
response rate was observed [17]. Whether this
“surrogate” marker can be used to maximize the
benefit from erlotinib was studied by Tang et al. in a
phase II trial [16]. Fifty patients with gemcitabine-
refractory pancreatic cancer were orally administered
erlotinib starting at 150 mg/day, dose-escalating by 50
mg every two weeks until rash more than grade 1 or
maximum dose of 300 mg/day (Figure 1). Twenty-five
percent of eligible patients achieved stable disease for
more than 8 weeks which met the primary end-point of
this trial. This trial certainly revolutionized our
understanding of erlotinib. It is worthwhile to perform
a large trial to validate these results and re-compare
gemcitabine with or without erlotinib in which the dose
of erlotinib should be based on skin rash.
3. Novel Agents
Development of novel therapeutic agents is an obvious
area of focus of research in pancreatic cancer. Several
novel agents either new biologic target agents
(AMG655 and masitinib) or newly formulated
conventional cytotoxic agents (endoTAG-1 and nab-
paclitaxel) are tested and results are promising (Table
3).
4. Supportive Therapy
Palliative care represents an important aspect of care in
patient with pancreatic malignancy. Identifying and
treating disease related symptomatology are priorities
[22].
The incidence of venous thromboembolism in
pancreatic cancer patients ranges from 17% to 57%.
Clinical data also suggest that the occurrence of venous
thromboembolism may be associated with poorer
prognosis in such patients. Recent data suggest that
anticoagulant treatments may improve cancer patient
survival by decreasing thromboembolic complications
as well as by anticancer effects [23]. Riess et al.
conducted the “Charité Onkologie” (CONKO-004)
trial to investigate whether the addition of enoxaparin,
a low molecular weight heparin (LMWH) improves
overall survival (Abstract #LBA4506) [24]. Safety and
feasibility of adding enoxaparin to chemotherapy have
been completed in their previously published pilot
study “Prospective, Randomized trial Of Simultaneous
Pancreatic cancer treatment with Enoxaparin”
(PROSPEC-CONKO-004) [25]. The primary endpoint
was to decrease the incidence of symptomatic venous
thromboembolic events. Three-hundred and twelve
patients were enrolled, 160 patients were treated with
chemotherapy plus enoxaparin. The occurrence of
venous thromboembolic events were 8/160 (5.0%)
compared with 14.5% in the non-LMWH arm (Table 4).
Clearly, enoxaparin is effective and safe for prevention
of symptomatic venous thromboembolic events;
however, whether the low incidence of venous
thromboembolic events is associated with some
survival benefit is still unclear. CONKO-004
preliminary data showed no difference in median
overall survival with or without exnoxaparin. We are
looking forward to their final results.
Future Directions
Options for pancreatic cancer in advanced/metastatic
setting are still very limited. Gemcitabine remains the
standard of care despite so many combinations were
examined. The two large phase III trials failed to show
any benefit beyond gemcitabine monotherapy by
adding a second cytotoxic agent such as cisplatin or a
vaccine GV1001. These combinations were promising
in early phase trials or pooled/meta-analysis. Again, we
should be careful when interpreting results from early
phase trials. Many promising results from phase II
trials were unable to be translated into phase III trials.
Over the last 12 years, we have extensively and
intensively explored all possible agents to combine
with gemcitabine, it is the time to think out of the
gemcitabine box and put more effort on novel agents.
Nab-paclitaxel, “an old drug in a new bottle”, seems to
be very promising when combined with gemcitabine.
Table 4. Results of CONKO-004 trial after a median follow-up of 30.4 weeks.
Primary/secondary end-points Chemotherapy arm
(n=152)
Chemotherapy plus
enoxaparin arm
(n=160)
Comments
Venous thromboembolic events 22 (14.5%) 8 (5.0%) P<0.05
Bleeding 15 (9.9%) 10 (6.3%) P=0.6
Median overall survival 29 weeks 31 weeks Preliminary results, not statistically calculated yet
Figure 1. Schema of phase II erlotinib single agent as second-line
therapy.
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We are looking forward to the phase III results. New
biologic target agent such as AMG655, a monoclonal
antibody against human death receptor-5, also achieved
encouraging results. However, the current designs of
clinical trials in advanced pancreatic cancer still rely on
gemcitabine, even for the aforementioned novel agents.
Nevertheless, gemcitabine is the only cytotoxic agent
providing significant clinical benefit for pancreatic
cancer. We encourage more novel agents should be
tested in second-line setting.
Conflict of interest The authors have no potential
conflicts of interest
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