Journal of Cancer Therapy, 2013, 4, 13-27
Published Online November 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.410A003
Open Access JCT
13
Recent Developments and Current Issues in the Treatment
of Pancreatic Cancer
Helmut Oettle
Charité-Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Berlin,
Germany.
Received July 18th, 2013; revised August 15th, 2013; accepted August 24th, 2013
Copyright © 2013 Helmut Oettle. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Presently, many questions exist about what the optimal regimen comprises for all stages and treatment settings for pan-
creatic cancer. Since the CONKO-001 trial, adjuvant therapy following resection has become standard of care; however,
outcomes are poor, with most patients experiencing disease recurrence, and new therapies have yet to be validated.
Furthermore, the value of adjuvant radiotherapy has still not been clearly defined. Targeted treatment in combination
with chemotherapy has been mostly disappointing so far in the adjuvant setting but immunotherapy holds potential for
improving survival outcomes. Neoadjuvant treatment does not appear to provide much benefit in resectable patients but
in the small subgroup of patients with borderline resectable/unresectable locally advanced disease it may increase the
possibility of an R0 resection and, consequently, a substantial increase in survival duration. Use of capecitabine-based
radiotherapy in patients with unresectable locally advanced disease appears to be more efficacious and better tolerated
than gemcitabine-based chemoradiotherapy, with respect to survival outcomes. However, as with adjuvant treatment,
the benefit of adding radiotherapy has not yet been definitively demonstrated. In patients with metastatic pancreatic
cancer, targeting the stroma with nab-paclitaxel has shown promising results in a phase III trial setting when adminis-
tered in combination with gemcitabine and, furthermore, this regimen is suitable for a broad range of patients due to its
generally good tolerability profile. Because of its high toxicity, FOLFIRINOX is more suitable for younger patients
with an excellent performance status who can withstand aggressive treatment and in patients with a worse performance
status, gemcitabine monotherapy is considered to be a more appropriate treatment. Alternatively, gemcitabine in com-
bination with erlotinib, the only targeted compound that has resulted in significant albeit small improvements in sur-
vival in patients with advanced disease, could be selected. However, the benefit-risk profile of this regimen is only fa-
vorable in a strictly defined, small patient subgroup who develop a treatment-related rash. Finally, with the elucidation
of prognostic and predictive markers, treatment is expected to become ever more individualized, leading to improved
efficacy outcomes and less unnecessary toxicity.
Keywords: Pancreatic Cancer; Chemotherapy; Adjuvant Therapy; Neoadjuvant Therapy
1. Introduction
With a median survival duration of approximately 6
months following diagnosis and a 5-year survival rate of
less than 5%, pancreatic cancer is considered to have the
poorest prognosis of any solid tumor [1]. Recent statistics
show that pancreatic cancer is the fourth most common
cause of death in the US and Europe and yet it accounts
for only 3% of total cancer cases [2]. As well as display-
ing a highly drug- and radio-therapy resistant phenotype,
pancreatic cancer has high potential for local invasion
and metastasis to distant sites compared with other solid
tumors [3]. Indeed, for the few patients who have seem-
ingly resectable disease at diagnosis, distant microme-
tastases have usually already been established [2]. More-
over, due to its initially highly asymptomatic nature,
more than 80% of patients only present once disease is
advanced [4]. However, although progress in the treat-
ment of pancreatic cancer in the past few decades has
been incremental, it is nevertheless steadily increasing.
2. Risk Factors
Recently, a number of factors have been identified as

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 14
having a possible causative role in the development of
pancreatic cancer, including non-O blood group, diabetes
mellitus, low vegetable intake and a high-fat diet; al-
though most of these have yet to be validated as defini-
tive risk factors [5]. However, a causative role for to-
bacco was determined several years ago, with smokers
being found to have an elevated pancreatic cancer risk of
2.5 to 3.6 times that of a non-smoker [6]. Another well
established risk factor is familial mutations, with ap-
proximately 5% - 10% of patients having a family history
of pancreatic cancer [7]. An individual from a family
with at least four affected members is approximately 57
times more likely to develop pancreatic cancer when
compared with an individual from a family containing no
affected members [4].
3. Genetics
Our understanding of pancreatic cancer genetics has in-
creased in the last decade with a number of germline and
aquired somatic mutations being identified and mapped.
The vast majority of patients with pancreatic cancer from
any cause carry at least one of four known mutations,
with 90% of tumors carrying a mutation in the KRAS
oncogene and 95% of tumors with inactivation of the
CDKN2A gene which codes for p16, a regulator of the
G1-S transition of the cell cycle [8]. In approximately
50% of tumors, the tumor suppressor gene DPC4 is lost
and in 50% - 75% of tumors, TP53, another tumor sup-
pressor gene, is abnormal. Recently, whole genome se-
quencing of 24 pancreatic cancers revealed on average
63 mutations per cancer, implying that pancreatic cancer
is a very complex and heterogeneous disease and conse-
quently that it might respond best to a multi-pronged
and/or individualized treatment approach [9].
4. Tumor Microenvironment
The importance of the microenvironment in tumor
propagation has begun to be realized in recent years and
is an area of great interest in the study of pancreatic can-
cer. A prominent feature of the tumour microenviron-
ment in pancreatic cancer is the formation of a dense
complex stroma, known as a desmoplastic reaction, around
the tumour which can comprise up to 90% of the tumor
volume [10]. This compact fibrous yet dynamic tissue
functions as more than just a mechanical barrier, playing
host to a complex interplay between normal host epithet-
lial cells, tumor cells, stromal fibroblasts, pancreatic stel-
late cells, endothelial cells and adipocytes, immune and
inflammatory cells as well as growth factors which acti-
vate oncogenic signaling pathways [11]. There is now
significant evidence that pancreatic stellate cells play a
key role in stromal formation and turnover. Following
activation by growth factors, pancreatic stellate cells se-
crete collagen as well as other extracellular matrix (ECM)
proteins [12,13]. Furthermore, pancreatic stellate cells
contribute to the hypoxia/fibrosis cycle in the peritu-
moural stroma via abnormal ECM protein secretion and
amplification of endostatin production by tumor cells
[14]. They also regulate stromal turnover and reabsorp-
tion, mostly through generation of matrix metallopro-
teinases. Proteins produced by stromal cells and associ-
ated with poor prognosis to treatment include stromal
cell-derived factor, chemokines, cyclooxygenase-2, PDGF
receptor, hedgehog pathway elements, vascular endothe-
lial growth factor, integrins, and SPARC (Secreted Pro-
tein Acidic And Rich in Cysteine) [4]. As a consequence
of our increased understanding of the tumour microenvi-
ronment, new therapeutic opportunities have arisen.
For example, the nanoparticle albumin-bound (nab)-
paclitaxel is able to bind with SPARC, which is found in
abundant levels in the stroma, resulting in increased de-
livery of paclitaxel to tumor cells [15]. Another emerging
area of research is of the small subset of cells within a
tumor termed stem cells. Pancreatic stem cells make up
approximately 0.5% - 1% of all tumour cells and express
the protein markers CD44, CD24 and epithelial-specific
antigen [16]. Responsible for tumor initiation and propa-
gation, they are also hypothesized to contribute to me-
tastasis although, thus far, solid evidence is lacking in
this area. However, stronger evidence has come to light
for a role of stem cells in the typically high resistance
displayed by pancreatic cancer towards chemotherapy
and radiotherapy. In an in-vitro study [17], exposure to
gemcitabine resulted in an enriched population of
CD133+ cells in the 13.6 p pancreatic cancer cell line
and in another in-vitro study [16], exposure to gemcit-
abine and ionising radiation resulted in an enriched
population of CD44, CD24, and ESA in xenografts of
human pancreatic cancer. However, although our under-
standing of the molecular processes that underpin the
development and propagation of pancreatic cancer has
deepened in recent years, translation of this knowledge
into effective therapies has yet to be realized.
5. Adjuvant Therapy
5.1. Chemotherapy/Chemoradiotherapy
Currently, surgical resection is the only curative treat-
ment for stage I/II pancreatic cancer (Figure 1). Never-
theless, following surgery, rates of locoregional and dis-
tant recurrence are high, occurring in 50% - 80% and
more than 70% of patients, respectively. As a result, 5-
year survival rates following surgery with a curative in-
tent are low, ranging from 10% - 15% [18] and, conse-
quently, adjuvant therapy is considered an important
facet of treatment for early-stage pancreatic cancer. Al-
though accepted now as standard of care, for a long time
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer
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Figure 1. Current issues in pancreatic cancer treatment.
the benefits of administering adjuvant chemotherapy
with or without radiotherapy following resection were
unclear. In trials conducted in the late 1960s and early
1970s, patients with advanced unresectable pancreatic
cancer received external beam radiotherapy with or
without systemic chemotherapy [19,20]. As a result of
the antitumour activity observed in these studies, the first
randomized trial of adjuvant therapy was initiated by the
Gastrointestinal Tumour Study Group (GITSG) in which
patients undergoing resection with curative intent re-
ceived 5-FU + folinic acid administered with radiother-
apy or underwent observation alone [21]. Significantly (p
= 0.03) longer median survival durations were observed
in patients who had received adjuvant therapy, compared
with those who had not (20 vs. 11 months) [21]. Unfor-
tunately, this trial was found to have multiple shortcom-
ings and reliable conclusions could not be drawn from it
[2]. In response to these criticisms, the GITSG conducted
a single-arm study (n = 30) comprising the same adjuvant
treatment protocol which demonstrated similar results
[22]. Adjuvant therapy therefore appeared to be benefi-
cial although it still remained unclear as to whether che-
motherapy alone or chemoradiotherapy was responsible
for these improvements in survival. Following the GITSG
trial, two pivotal trials, (EORTC-40891 and ESPAC-1)
were conducted which showed contradictory outcomes.
In the EORTC-40891 trial, 5-FU + folinic acid-based
chemoradiotherapy did not significantly improve overall
survival at 5 years when compared with observation
alone in the overall patient population which included
patients with periampullary tumors (median of 24.5 vs.
19.0 months) yet a trend (p = 0.099) towards a survival
benefit was observed in patients with pancreatic head
cancer (median survival duration of 17.1 vs. 12.6 months)
[23]. Moreover, a long-term survival analysis also
showed no significant benefit of adjuvant treatment in
the overall patient population, with median survival du-
rations of 1.8 and 1.6 years in the chemoradiotherapy and
observation alone arms, respectively [24]. However, due
to inadequate statistical power, one of the numerous
shortcomings of the EORTC-40891 trial, a possible sur-
vival advantage of adjuvant chemoradiation could not be
definitively ruled out. In the ESPAC-1 trial, which util-
ized a 2 × 2 factorial design, 5-FU + folinic acid-based
chemoradiotherapy actually had a deleterious effect on
survival, resulting in a significantly (p = 0.05) lower sur-
vival rate at 5 years, compared with no chemoradiother-
apy (10% vs. 20% of patients). However, adjuvant 5FU +
folinic acid was found to be significantly (p = 0.009)
more efficacious than no adjuvant 5-FU + folinic acid,
with respective survival rates at 5 years of 21% and 8%
[25].
Due to these conflicting outcomes, the benefit of ad-
juvant therapy remained debatable, especially with re-
spect to addition of radiotherapy to chemotherapy. How-
ever, subsequent publication of several larger and more
well-designed landmark clinical trials has shed more
light on this issue.
Due to its proven efficacy in the palliative setting,
gemcitabine was investigated as a possible adjuvant ther-

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 16
apy in several phase III studies. In the CONKO-001
study, we randomly assigned patients to receive adjuvant
gemcitabine or to undergo observation alone [26]. A sig-
nificant (p < 0.001) and clinically relevant benefit was
seen in the patients receiving adjuvant therapy, with a
median disease-free survival interval of 13.4 months be-
ing achieved, compared with 6.9 months in the treatment
group undergoing observation alone. Upon subgroup
analysis, significant benefit was seen across all sub-
groups, including in patients with an R1 resection (15.4
vs. 5.5 months; p < 0.001), who were node-negative
(22.4 vs. 10.4 months; p = 0.006) or with tumor stage
T1-2 (27.5 vs. 10.0 months; p < 0.05). Interestingly,
gemcitabine recipients with an R1 resection survived for
longer disease-free than gemcitabine recipients who had
achieved an R0 resection (median disease-free survival
interval of 15.4 vs. 13.1 months). As well as prolonging
disease-free survival, adjuvant gemcitabine also signifi-
cantly (p < 0.01), albeit to a lesser degree, improved the
hard endpoint of overall survival, with final results show-
ing gemcitabine recipients surviving for a median of 22.8
months, compared with 20.2 months in the observation
alone arm [26]. Again, significant benefit was observed
in gemcitabine recipients who had undergone an R1 re-
section, with overall survival in this group being almost
as long as gemcitabine recipients who had undergone an
R0 resection (median of 22.1 vs. 22.8 months). This re-
duction in the magnitude of benefit from gemcitabine
treatment in the overall patient population may have been
due to the majority of patients under observation alone
subsequently crossing over to the gemcitabine arm upon
progression. With respect to the resection margin, sig-
nificant (p < 0.05) benefit in overall survival remained in
patients who had undergone an R0 resection (median of
22.8 vs. 20.3 months) whereas only a trend towards im-
proved overall survival was observed in patients who had
undergone an R1 resection (median of 22.1 vs. 14.1
months) [26].
The large ESPAC-3 version 2 trial (n = 1088) [27] was
subsequently designed to compare the efficacy of adju-
vant 5-FU + folinic acid, already established as standard
of care for advanced pancreatic cancer, with gemcitabine
which had earlier been validated as adjuvant therapy in
the CONKO-001 trial. There had initially been an arm
undergoing observation alone but this was discontinued
prematurely due to the final results of ESPAC-1 demon-
strating a benefit for adjuvant therapy. The main aim was
to determine whether gemcitabine would result in an
improvement in overall survival. However, no significant
difference between the gemcitabine and 5-FU + folinic
arms was observed in median overall survival duration,
median progression-free survival duration or quality of
life. Gemcitabine appeared to be better tolerated than
5-FU + folinic acid which had resulted in significantly (p
< 0.001) increased rates of grade 3 or 4 stomatitis, grade
3 and 4 diarrhea and serious adverse events [27].
These results were in contrast to an earlier smaller
study [28] in which gemcitabine resulted in significantly
(p < 0.01) greater antitumour activity as well as a sig-
nificantly (p < 0.01) higher overall survival rate at 2
years when compared with fluorouracil. However, the
dose of 5-FU used in this earlier study was lower than the
fluorouracil dose used in ESPAC-3 version 2.
The benefit of using gemcitabine as part of adjuvant
chemoradiotherapy was again left unanswered in a trial
conducted by the Radiation Therapy Oncology Group
(RTOG-9704) [29]. In this trial, patients were randomly
assigned to receive either adjuvant gemcitabine or 5-FU
(control), both administered before and after 5-FU-based
chemoradiotherapy. No significant difference in the pri-
mary endpoint of overall survival was reported between
the treatment arms. However, in patients with cancer of
the pancreas head, gemcitabine resulted in a trend (p =
0.09) towards a longer overall survival duration (median
of 20.5 vs. 16.9 months), upon multivariate analysis.
Use of S-1 (gimeracil/oteracil/tegafur) as adjuvant
therapy was explored by the Japan Adjuvant Study
Group of Pancreatic Cancer in the JASPAC 01 trial [30].
In this noninferiority study, Japanese patients were ran-
domised to S-1 or gemcitabine with the aim of determin-
ing whether S-1 would be any less efficacious than gem-
citabine as adjuvant therapy. S-1 was found to be not
only significantly (p < 0.001) noninferior to gemcitabine,
but was also found to be significantly (p < 0.001) supe-
rior, with respect to overall survival at 2 years (70% vs.
53% in the full analysis set; HR 0.56; 95% CI 0.36 -
0.87).
Due to demonstrating efficacy in patients with ad-
vanced pancreatic cancer, capecitabine is being explored
as a possible option in adjuvant therapy. In the currently
recruiting ESPAC-4 trial (EudraCT2007-004299-38),
patients with resectable pancreatic cancer or periampul-
lary cancer are being randomised to gemcitabine + cape-
citabine or gemcitabine monotherapy. Completion is
scheduled for November 2014.
Addition of radiotherapy to adjuvant chemotherapy
remains controversial, with some studies reporting a
clinical benefit but others, such as the ESPAC-1 trial,
showing a deleterious effect [25]. Results from RTOG-
9704 and CONKO-001 seem to suggest that adjuvant
chemoradiotherapy is no more efficacious than adjuvant
chemotherapy [26,29]. However, this should be inter-
preted cautiously as the patient populations in these trials
differed, with CONKO-001 having fewer patients with
margin- or node-positive disease as well as an inclusion
criterion of patients with CA19-9 concentrations of 90
U/mL or less. In an exploratory subgroup analysis from a
meta-analysis conducted by Stocken et al., chemoradio-
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 17
therapy was found to be significantly more effective than
chemotherapy in patients with positive (R1) resection
margins [31]. For most oncology practices in Europe
adjuvant chemotherapy alone is considered standard of
care and adjuvant chemoradiotherapy is generally not
administered whereas in the US adjuvant chemoradio-
therapy and subsequent chemotherapy is the standard of
care [32].
5.2. Targeted Therapies
After showing a small but significant benefit in overall
survival in the phase III PA.3 trial [33] in advanced pan-
creatic cancer patients, erlotinib is being assessed as part
of gemcitabine-based adjuvant therapy in the CONKO-
005 trial (EudraCT2007-003813-15) in patients who
have undergone an R0 resection. In another study cur-
rently being conducted by the Charité Oncology Group
(CONKO-006; EudraCT2007-000718-35), the multi-
kinase inhibitor sorafenib is being explored as part of
combination adjuvant therapy with gemcitabine, com-
pared with gemcitabine alone, in patients with an R1
resection of pancreatic cancer. The benefit of adjuvant
gemcitabine in patients with an R1 resection had already
been demonstrated in subgroup analysis of CONKO-001,
in which gemcitabine recipients with an R1 resection
survived for almost 10 months longer than patients with
an R1 resection who were under observation alone.
Therefore, the aim of this study is to determine whether
addition of sorafenib could increase disease-free survival
(primary endpoint) and subsequently overall survival
(secondary endpoint) in this patient subgroup. Duration
of therapy will also be assessed, with patients being
treated for one year in the CONKO-006 study, compared
with only six months in the CONKO-001 and CONKO-
005 studies.
5.3. Immunotherapy
Immunotherapy is a therapeutic field that may hold great
potential in the adjuvant setting, with the main aims be-
ing to inhibit regulatory T-cells which suppress the im-
mune response to pancreatic cancer or to prime the im-
mune system to recognize cancer cells via immunosti-
mulatory pancreatic cancer antigens or use of geneti-
cally-modified irradiated pancreatic cancer cells [34].
Algenpantucel-L, which is the most clinically advanced
pancreatic cancer vaccine currently in development,
comprises an irradiated live combination of two human
pancreatic cancer cell lines which present a non-human
surface epitope (alpha-galactosyl), thus stimulating an
immune response. A multi-institutional single-arm phase
II trial assessed the efficacy of algenpantucel-L, when
added to standard of care (adjuvant chemotherapy or
chemoradiotherapy with gemcitabine or 5-FU) [35]. In
this trial, the one-year survival rate was higher than that
observed in the RTOG-9704 trial (86% vs. 69% of pa-
tients), even though lymph node involvement was higher
at baseline (81% vs. 68% positive nodes). Furthermore,
algenpantucel-L was well tolerated [35]. Based on these
encouraging data, the randomised IMPRESS trial by
Fisher et al. (NCT01072981) was initiated in April 2010
and is scheduled to be finished by January 2014. In this
study, 922 patients will receive standard of care with or
without algenpantucel-L [34]. In a phase II single-centre
trial, a granulocyte-macrophage colony stimulating fac-
tor-transduced allogeneic whole cell vaccine was admin-
istered following adjuvant fluorouracil-based chemora-
diotherapy. Disease-free survival and overall survival
rates at one year were 67% and 85%, respectively. Tol-
erability was good, with the most frequently reported
adverse events being transient injection-site reactions
[36]. Other vaccines containing ras-peptide, telomerase
peptide, mucin + carcinoembryonic antigen and survivin
are also in early-phase development as are vaccines
comprising antigen-pulsed dendritic cells presenting ei-
ther mucin 1 or carcinoembryonic antigen [34].
6. Neoadjuvant Therapy
As a result of waiting list times for surgery and the sub-
sequent time needed for postoperative recovery, the time
between diagnosis and receipt of chemotherapy can be 2
months or more. Due to micro-metastases in lymph
nodes, lung, peritoneum and liver being present at diag-
nosis in the majority of patients, a rationale exists for the
use of neoadjuvant therapy. Furthermore, as patients are
at an earlier disease stage and therefore have an im-
proved performance status, it is more likely that they will
be eligible for treatment, compared with patients waiting
to undergo adjuvant therapy. Neoadjuvant treatment may
also reduce the risk of peritoneal tumor cell implantation
during surgery due to decreasing intraoperative tumor
spillage and may also result in more definitive surgical
resections [37].
Unfortunately, clinical outcomes for neoadjuvant ther-
apy have mostly been disappointing although positive
results were shown in a small phase II study [38] in
which 28 patients with resectable adenocarcinoma of the
pancreatic head received 4 courses of neoadjuvant gem-
citabine + cisplatin. Resection rate was 93%, above that
of the predetermined primary endpoint of at least 70%
and improvements in nutritional status and quality of life
were observed. Another phase II study [39] compared
gemcitabine monotherapy with gemcitabine + cisplatin.
Resection rates were 38% and 70%, respectively, but
survival outcomes were poor, with patients only surviv-
ing a median of 9.9 and 15.6 months, respectively. Ad-
ministration of subsequent chemoradiotherapy following
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 18
initial neoadjuvant chemotherapy has also been assessed
in the phase II setting. One phase II trial [40] assessed
gemcitabine then gemcitabine-based radiotherapy in 20
patients and another phase II trial [41] assessed cisplatin
+ gemcitabine then gemcitabine + radiotherapy in 90
patients. Disappointingly, survival outcomes were gener-
ally no better than those observed with surgery alone.
Furthermore, in a meta-analysis [42] comprising 4394
patients, resection rates in patients with initially re-
sectable tumours were found to be the same, regardless
of whether or not patients received neoadjuvant treatment.
Therefore, although there is a hypothetical rationale for
use of neoadjuvant therapy in patients with resectable
pancreatic cancer, stronger clinical data are needed to
support its use in standard practice.
Currently, a neoadjuvant regimen comprising nab-pa-
clitaxel and gemcitabine is being explored in a phase II
pilot trial [43]. Preliminary results were presented at
ASCO 2013 in which this regimen was determined as
being feasible and warranting study in a larger trial.
7. Borderline Resectable/Unresectable
Pancreatic Cancer—A New Indication?
Patients with borderline resectable/unresectable locally
advanced pancreatic cancer constitute a unique patient
population. In patients who are borderline resectable,
neoadjuvant treatment offers an increased chance of an
R0 resection and in those patients who are borderline
unresectable, neoadjuvant treatment offers an increased
chance of resection, including the possibility of an R0
resection and, consequently, for both patient populations,
a much extended survival duration. In the previously
mentioned meta-analysis by Gillen et al. [42], although
benefit from neoadjuvant therapy was not demonstrated
in patients with resectable tumours, approximately one
third of patients who had initially unresectable tumours
at baseline were able to undergo resection following
neoadjuvant therapy, especially if combination chemo-
therapy was administered. Survival in this group was
similar to that observed in patients with initially resectable
tumours. A large retrospective series at a single institu-
tion subsequently confirmed these data [44]. Patients
with locally-advanced unresectable pancreatic cancer re-
ceived neoadjuvant gemcitabine-based chemoradiother-
apy. Of the 215 patients studied, 26% were able to un-
dergo secondary resection, with the median overall sur-
vival duration being substantially longer in the 36% of
resected patients who underwent an R0 resection, com-
pared with those patients who did not undergo any resec-
tion at all (22.1 vs. 11.9 months). Moreover, in an analy-
sis of patients undergoing curative pancreatoduodenec-
tomy or total pancreatectomy [45], patients requiring a
portal/superior mesenteric vein resection had a signifi-
cantly (p < 0.05) shorter mean survival time, compared
with patients who did not require this resection. However,
adjuvant gemcitabine improved the prognosis of these
patients such that the mean survival time was similar
between these 2 groups of patients.
8. Unresectable Locally Advanced
Pancreatic Cancer
8.1. Chemoradiotherapy
For patients with locally advanced unresectable disease,
treatment options, including whether or not to administer
radiotherapy, are not yet clearly defined. In a phase III
study [46], chemoradiotherapy comprising fluorouracil +
cisplatin and a total radiotherapy dose of 60Gy resulted
in a significantly (p = 0.03) shorter median overall sur-
vival duration, compared with gemcitabine alone (me-
dian of 8.6 vs. 13.0 months), as well as increased moder-
ate-to-severe toxicity. Yet in a subsequent phase III trial
conducted by the Eastern Cooperative Oncology Group
[47], chemoradiotherapy comprising gemcitabine (600
mg/ m2/week) and radiotherapy administered to a total
dose of 50.4 Gy was found to significantly (p = 0.017)
improve overall survival over gemcitabine alone (median
of 11.1 vs. 9.2 months). Unfortunately, due to limited
statistical power resulting from poor patient accrual, this
study was terminated prematurely and was not able to
provide definitive evidence that could impact standard of
care.
The SCALOP trial [48] was the first randomized mul-
ticenter trial to compare capecitabine-based chemoradio-
therapy with gemcitabine-based chemoradiotherapy, both
administered following induction treatment with gemcit-
abine + capecitabine, in patients with locally advanced
disease. Radiotherapy was 3D conformal or intensity-
modulated and was administered as 5.5 fractions per
week to a total dose of 50.4Gy, although only 68% - 69%
of patients received the full protocol dose. Progression-
free survival rates at 9 months (primary endpoint) were
63% and 51%, respectively, which met prespecified cri-
teria according to a Fleming’s design. However, capecit-
abine resulted in a non-significantly (p = 0.111) longer
median progression-free survival interval, compared with
gemcitabine (12.0 vs. 10.4 months; HR 0.60; 95% CI
0.32 - 1.12), including a longer median local progres-
sion-free survival interval (14.6 vs. 12.0 months) as well
as a longer distant progression-free survival interval
(14.3 vs. 11.9 months). More importantly, capecitabine
was found to significantly (p = 0.012) extend overall
survival, compared with gemcitabine (median of 15.2 vs.
13.4 months; HR 0.39; 95% CI 0.18 - 0.81). With respect
to secondary endpoints, 2 patients (6%) in the capecit-
abine arm alone experienced a complete response but, in
general, response rates were similar between treatment
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 19
arms. Of the 58% of patients with progression in each
treatment arm, 33% and 32%, respectively, experienced
local relapse, 52% and 46%, respectively, experienced
metastatic relapse and 14% and 23%, respectively, ex-
perienced both types of relapse. Following radiotherapy,
similar numbers of patients were eligible for resection
(6% vs. 8% of patients, respectively). Furthermore, cape-
citabine resulted in fewer grade 3 and 4 adverse events,
compared with gemcitabine (11% vs. 37% of patients),
including significantly (p = 0.007) fewer grade 3 and 4
hematological adverse events (0% vs. 18% of patients)
and a trend (p = 0.095) towards fewer grade 3 and 4
non-hematological adverse events (11% vs. 26% of pa-
tients) [48].
The 2 × 2 factorial LAP07 study [49] aimed to com-
pare switching to capecitabine-based chemoradiotherapy
with continuing either erlotinib + gemcitabine or gem-
citabine monotherapy. Patients who had received er-
lotinib during the initial induction treatment could con-
tinue to receive erlotinib as maintenance therapy, regard-
less of whether or not they were randomized to continue
treatment. Disappointingly, no significant difference in
the primary endpoint of overall survival was observed
between the chemoradiotherapy and the chemotherapy
arms (15.3 vs. 16.5 months; HR 1.03; 95% CI 0.79 - 1.03)
and nor was there any significant difference in progres-
sion-free survival (HR 0.9; 95% CI 0.7 - 1.1).
Comparison of chemoradiotherapy versus chemother-
apy alone following induction with either gemcitabine,
gemcitabine + nab-paclitaxel or 5-FU + folinic acid +
irinotecan + oxaliplatin (FOLFIRINOX) is being inves-
tigated in the CONKO-007 trial by Fietkau and Oettle
(NCT01827553). Following completion of radiotherapy,
patients will continue to receive the same chemotherapy
regimen as they received for induction therapy until dis-
ease progression. Overall survival is the primary end-
point and resectability status is being assessed as a sec-
ondary endpoint.
8.2. Investigational Agents in Locally Advanced
Pancreatic Cancer
Gene therapy was recently assessed in a phase III trial in
which golnerminogene pradenovec, a genetically-modi-
fied adenovirus 5 vector encoding tumour necrosis fac-
tor-alpha, was administered with 5-FU + radiotherapy
and compared with 5-FU + radiotherapy alone. Nonsig-
nificant improvement in the primary endpoint of overall
survival was observed in the investigational treatment
arm [50].
9. Metastatic Pancreatic Cancer
9.1. First-line Therapy
Gemcitabine has comprised the first-line standard of care
for metastatic pancreatic cancer since 1997 when a piv-
otal study by Burris et al. demonstrated superiority of
gemcitabine over 5-FU [28]. Subsequently many differ-
ent combinations using gemcitabine as a backbone have
been evaluated including 5-FU [51], capecitabine [52],
oxaliplatin [53], cisplatin [54], irinotecan [55] and pe-
metrexed [56]. Overall, these combination regimes failed
to demonstrate significant prolonged survival as com-
pared to gemcitabine alone although a significant but
modest benefit in survival of gemcitabine-based combi-
nation regimens in patients with good performance status
was demonstrated in 2 meta-analyses [57,58].
9.2. Targeted Therapies
Although our understanding of the molecular and genetic
changes associated with the development and propaga-
tion of pancreatic cancer has increased over recent years,
there is still a lack of suitably targeted drugs for this dis-
ease. Despite demonstrating efficacy in other solid tu-
mours, targeted therapies have so far resulted in disap-
pointing outcomes in advanced pancreatic cancer. The
only targeted compound which has demonstrated pro-
longed survival in a phase III clinical trial setting was
erlotinib when administered in combination with gem-
citabine [33]. In the phase III PA.3 trial, erlotinib in
combination with gemcitabine resulted in a small but
significantly (p < 0.05) greater extension in overall sur-
vival, compared with gemcitabine alone (HR 0.82; me-
dian of 6.24 vs. 5.91 months). However, as this increase
was not considered clinically relevant by most oncolo-
gists erlotinib has not been broadly adopted as part of
standard of care. Other targeted therapies in combination
with gemcitabine that have been investigated, including
monoclonal antibodies such as bevacizumab and cetuxi-
mab or antiangiogenic multikinase inhibitors such as
axitinib and sorafenib, have failed to show survival bene-
fit in advanced pancreatic cancer [59-63]. Development
of the once-promising hedgehog signaling pathway in-
hibitor vismodegib (GDC 0449) for the treatment of ad-
vanced pancreatic cancer was discontinued recently due
to unfavorable results.
Many other targeted therapies are currently being in-
vestigated in early-phase clinical trials, including the
hypoxia-targeted drug TH-302 [NCT01746979], the anti-
IGF-R1 antibody MK 0646 [NCT00769483], and the
PARP inhibitor ABT-888 [NCT01489865], although
phase III confirmatory studies will be needed to defini-
tively prove the clinical benefit of these and other agents.
9.3. Polychemotherapy with FOLFIRINOX
Substantial progress in the treatment of advanced pan-
creatic cancer has been made by the introduction of the
FOLFIRINOX regimen (oxaliplatin, irinotecan fluorouracil,
and leucovorin) [64]. In this phase III clinical trial, which
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 20
compared FOLFIRINOX with the current treatment
standard gemcitabine, patients receiving FOLFIRINOX
benefited significantly in median progression-free sur-
vival (6.4 months vs. 3.3 months, p < 0.001) and also in
the primary endpoint of overall survival (11.1 months vs.
6.8 months, p < 0.001). However, it should be noted that
FOLFIRINOX resulted in higher toxicity as compared to
gemcitabine. Specifically, patients presented with more
grade 3 or 4 neutropenia (45.7% vs. 21.0%, p < 0.001)
and febrile neutropenia (5.4% vs. 1.2%), which required
use of granulocyte-colony stimulating factor. The toler-
ability profile of FOLFIRINOX was also less favorable
in terms of grade 3 or 4 thrombocytopenia (9.1% vs.
3.6%, p = 0.04), grade 3 or 4 diarrhea (12.7% vs. 1.8%, p
< 0.001) and grade 3 or 4 sensory neuropathy (9.0% vs.
0%, p < 0.001). Interestingly, despite the increased toxic-
ity of FOLFIRINOX regimen, time to deterioration in
quality of life was similar to that observed with gemcit-
abine. However, since inclusion critera were strict (pa-
tients had to be younger than 76 years with a high per-
formance status [ECOG 0 or 1] with no cardiac ischemia
and good hepatobiliary function) this does not represent a
real life setting and subsequently the clinical impact of
this study is thought to be modest. Moreover, FOLFIR-
INOX has not been readily adopted by oncologists prac-
tice due to general safety concerns about the risk of
cholangitis in stented patients [65]. Currently, a modified
FOLFIRINOX regimen with expected reduced toxicity
due to omission of the 5-FU bolus (FOLFOXIRI) is be-
ing investigated [66].
9.4. Targeting the Stroma with Nab-Paclitaxel
A unique feature of pancreatic cancer is an abundant
stroma which impairs drug delivery by reducing drug
diffusion into the primary tumour. This is thought to be a
major factor in the notable resistance of pancreatic can-
cer to chemotherapy [67] and, consequently, many re-
searchers have tried to improve drug delivery by target-
ing the stroma of pancreatic cancer cells. A recent break-
through in this area is nanoparticle albumin-bound (nab)-
paclitaxel that was initially developed to reduce treat-
ment toxicity by allowing omission of the solvent needed
to dissolve oily drug formulations of paclitaxel. Pancre-
atic peritumoral fibroblasts cancers overexpress SPARC
[68], which serves, via mediation of the albumin-binding
protein gp60, as a strong binding protein for nab-pacli-
taxel [69] (Figure 2). Von Hoff et al. demonstrated con-
vincing evidence of this principle in a phase I/II trial,
with a response rate to nab-paclitaxel of 48%, a median
overall survival (OS) of 12.2 months and 1-year survival
rate of 48% [70]. They also reported interesting preclini-
cal data; most importantly stroma depletion resulted in a
2.8-fold higher intratumoral gemcitabine concentration in
mice receiving nab-paclitaxel plus gemcitabine when
compared to gemcitabine alone. At this years ASCO gas-
trointestinal cancers symposium, Von Hoff et al. pre-
sented the results of a phase III trial in 861 patients
(MPACT), which confirmed the phase II data [71]. Nab-
paclitaxel plus gemcitabine was superior to gemcitabine
for all efficacy endpoints with a median overall survival
of 8.5 vs. 6.7 months (HR 0.72; p = 0.000015), a median
progression free survival of 5.5 vs. 3.7 months (HR 0.69;
p = 0.000024), an investigator-assessed overall response
rate of 29% vs. 8% (p = 3.3 × 10−16), and an improved
one-year overall survival of 35% vs. 22% (p = 0.0002).
These improvements in efficacy for nab-paclitaxel plus
gemcitabine were accompanied by good tolerability data.
With comparable dose intensities being administered in
both treatment arms, grade 3 or higher adverse events
with nab-paclitaxel comprised neutropenia (38% vs.
27%), febrile neutropenia (3% vs. 1%), thrombocyto-
penia (13% vs. 9%), anemia (13% vs. 12%) fatigue (17%
vs. 7%), and diarrhea (6% vs. 1%). Grade 3 or higher pe-
ripheral neuropathy occurred more often with nab-pacli-
taxel plus gemcitabine (17% vs. 1%) but improved to no
more than grade 1 over a median period of 29 days [71].
9.5. Is Nab-Paclitaxel a New Treatment
Standard?
Despite the inherent limitations of inter-study compari-
son, the tabular overview (Tables 1-3) shows that in
comparison to FOLFIRINOX, the nab-paclitaxel regime
provides similar efficacy to FOLFIRINOX but with bet-
ter tolerability. In contrast to FOLFIRINOX, nab-pacli-
taxel + gemcitabine was better tolerated even though the
patient population included less fit patients. Notably,
nab-paclitaxel + gemcitabine resulted in a lower rate of
grade 3 and grade 4 neutropenia, compared with FOLFIR-
INOX (45.7% vs. 38%). Grade 3 and 4 neuropathy was
found to be higher with nab-paclitaxel (17% vs. 9%), but
improved quickly within 29 days to no more than grade 1
[64,71]. Looking at different subgroups patients of the
MPACT trial upon multivariate analyses it was revealed
that patients with a Karnofsky performance status of 70 -
80 (HR 0.61), one metastatic site (HR 0.41), more than 3
metastatic sites (HR 0.5) and increased (≥59 × ULN)
CA-19-9 (HR 0.61) particularly benefited from nab-pa-
clitaxel + gemcitabine [72]. In comparison with gemcit-
abine alone [28] and gemcitabine + erlotinib [33], nab-
paclitaxel + gemcitabine resulted in a substantial benefit
in overall survival (8.5 month vs. 6.24 month vs. 5.65
month), mitigating the increased toxicity of nab-pacli-
taxel. In conclusion, nab-paclitaxel + gemcitabine has a
favorable toxicity profile and is a potentially new stan-
dard therapy for the treatment of metastatic pancreatic
cancer in a broad range of patients. FOLFIRINOX
should be restricted to younger patients who have an ex-
cellent performance status and are willing to undergo
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer
Open Access JCT
21
Figure 2. Mechanism of nab-paclitaxel drug-delivery.
Table 1. Patient demographics in selected pivotal phase III trials in patients with advanced disease.
Study GEM [28] GEM/ERL [33] FOLFIRINOX [64] NABPAC [71]
Age (range) 62 (37 - 79) 63.7 (37 - 84) 61 (25 - 76) 62 (27 - 88)
Performance status 30% KPS 80 - 90
70% KPS 50 - 70
29.8% ECOG 0
50.9% ECOG 1
18.9% ECOG 2
37.4% ECOG 0
61.9% ECOG 1
0.6% ECOG 2
58% KPS 90 - 100
42% KPS 70 - 80
Liver metastases NR NR 87.6 % 85%
Head of pancreas NR NR 39.2 % 44%
CA19.9 ≥ 59 ULN NR NR 41.5 % 46%
GEM, gemcitabine; ERL, erlotinib; NABPAC, nab-paclitaxel; KPS, Karnofsky performance status; ECOG, Eastern Cooperative Oncology Group performance
status; ULN, upper limit of normal; NR, not reported.
validated the value of fluoropyrimidine-based regimes in
second-line treatment. Oxaliplatin plus capecitabine
(XELOX) showed comparable efficacy in a phase II trial
and offers the possibility of oral fluoropyrimidine treat-
ment [75]. A recently presented randomized phase II trial
[76] compared the most readily available fluoropyri-
midine (5-FU, UFT or S-1) with continuation of gemcit-
abine. Fluoropyrimidine-treated patients benefited from a
non-significantly prolonged progression-free survival of
113 days vs. 50 days (p = 0.1050) and a significantly
improved overall survival of 226 days vs. 161 days (p =
0.0384). The results of another randomized phase II trial
suggests that the combination of a fluoropyrimidine with
irinotecan could also be of value as second-line treatment
[77]. Summing up the currently available evidence, pa-
tients with a good performance status who have pro-
gressed on gemcitabine-based therapy are recommended
to receive second-line therapy consisting of oxaliplatin
and an (oral) fluoropyrimidine.
more aggressive treatment. In patients with a Karnofsky
performance status of <70%, gemcitabine monotherapy
can be administered, if applicable with erlotinib being
added but then subsequently discontinued if no rash has
developed within the first 10 - 15 days.
9.6. Second-Line Therapy
There is no generally accepted consensus with regard to
second-line therapy in pancreatic cancer. Nevertheless, a
growing number of studies suggest that patients can
benefit from second-line therapy. In the CONKO-003
trial [73,74], we randomly assigned patients to treatment
with oxaliplatin, folinic acid and 5-FU (OFF) or best sup-
portive care. Median survival in patients receiving sec-
ond-line treatment with OFF was 4.82 months versus
2.30 months with best supportive care alone (HR 0.45, p
= 0.008).
Meanwhile, subsequent phase II trials have further

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 22
Table 2. Efficacy data in selected pivotal phase III Trials in patients with advanced disease.
Study GEM [28] GEM/ERL [33] FOLFIRINOX [64] NABPAC [71]
ORR 5.4% 8.6% 31.6% 29%
OS 5.65 months 6.24 months 11.1 months 8.5 months
1-year OS 18% 23% 48.4% 35%
18-month OS NR NR 18.6% 16%
ORR, overall response rate; OS, overall survival; GEM, gemcitabine; ERL, erlotinib; NABPAC, nab-paclitaxel.
Table 3. Grade ≥ 3 adverse events in selected pivotal phase III trials in patients with advanced disease.
Study GEM [28] GEM/ERL [33] FOLFIRINOX [64] NABPAC [71]
Neutropenia 25.9% 24% 45.7% 38%
Febrile neutropenia NR NR 5.4% 3%
Thrombocytopenia 9.7% 10% 9.1% 13%
Fatigue NR 15% 23.6% 17%
Diarrhea 1.6% 6% 12.7% 6%
Peripheral neuropathy NR NR 9.0% 17%
ORR, overall response rate; OS, overall survival; GEM, gemcitabine; ERL, erlotinib; NABPAC, nab-paclitaxel.
10. Prognostic and Predictive Factors in
Pancreatic Cancer
Currently, a lot of research is being conducted to identify
and validate prognostic and predictive biomarkers in
pancreatic cancer to help guide therapy decisions. Prog-
nostic features predict prognosis independently from
treatment and are based on the clinical features of the
patient or the biological characteristics of pancreatic can-
cer such as tumor pathology whereas predictive factors
predict tumor response to therapy [78]. An elevated CA
19-9 level has been identified as an independent negative
prognostic biomarker in many trials. A recent compari-
son of the RTOG-9704 trial with the CONKO-001 trial
showed that CA 19-9 values ≥ 90 U/mL after surgery
were associated with a significantly shortened overall
survival [79]. In the previously mentioned trial by Von
Hoff et al. [71], CA19-9 decrease at 8 weeks predicted
overall survival [80].
Another predictive factor in erlotinib-containing treat-
ment regimens is the occurrence of a rash. In several
phase III trials comparing erlotinib in combination with
gemcitabine with gemcitabine alone in patients with un-
resectable advanced disease (AVITA, PA.3, AIO PK and
PANTAR), occurrence of a treatment-related rash was
indicative of response to erlotinib and resulted in signifi-
cantly (p < 0.001 for AVITA, PA.3 and AIO PK; p =
0.001 for PANTAR) improved survival, compared with
those patients who did not develop a rash [81-84].
hENT1, (human equilibrative nucleoside transporter-1)
has been identified as a potential predictor of overall sur-
vival in patients receiving gemcitabine [85]. Multivariate
analysis of the adjuvant ESPAC-1 and -3 randomized
trials confirmed increased intratumoural hENT1 expres-
sion as a predictive marker for response to gemcitabine
(Wald χ2 = 7.10, p = 0.008) but not fluorouracil (Wald χ2
= 0.34, p = 0.560) [86]. Similar results were seen in the
RTOG-9704 trial, in which higher hENT1 levels, upon
multivariate analysis, were also correlated with improved
overall survival in gemcitabine recipients (median of
24.2 vs. 14.8 months; p = 0.018), but not in 5-FU recipi-
ents [87].
In a trial currently being conducted by Evans et al.
(NCT01726582), feasibility of determining the most ap-
propriate neoadjuvant treatment is being assessed in pa-
tients with borderline resectable disease. Six biomarkers
have been selected based on their relevance to accepted
pancreatic cancer chemotherapy regimens: high expres-
sion of SPARC (nab-paclitaxel), low expression of RRM1
(gemcitabine), low expression of ERCC1 (platinum ana-
logs), high expression of TOPO1 (irinotecan), high ex-
pression of hENT1 (gemcitabine) and low expression of
TYMS (fluorouracil). The primary endpoint is the resec-
tion rate and completion is scheduled for August 2014.
11. Conclusion
Currently, resection offers the best chance of cure in
early-stage pancreatic cancer. Recent advances in adju-
vant treatment have resulted in meaningful improve-
ments in disease-free and overall survival, including in
patients with an R1 resection or with previously unre-
sectable disease, yet there is still no consensus on the
optimal line of treatment. With several large phase III
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Recent Developments and Current Issues in the Treatment of Pancreatic Cancer 23
trials scheduled to be completed in the next years, in-
cluding at least one investigating the emerging area of
immunotherapy, hopefully the way forward will become
better elucidated. Although progress has been made in
the treatment of metastatic pancreatic cancer in the last
few decades, it is clear that new strategies are needed if
patients’ lives are to be substantially extended and the
realization is starting to emerge that targeting the primary
tumor alone is not enough in the most resilient malignan-
cies. The relatively recent recognition of the tumor mi-
croenvironment as a key player in tumor development
and immune evasion and, moreover, that the stroma is a
major factor in the notable drug resistance of pancreatic
cancer, have marked the beginning of somewhat of a
paradigm shift in the way pancreatic cancer and its
treatments are viewed. New therapies, in which a multi-
pronged approach is employed, targeting not only the
primary tumor, but also the surrounding structures such
as the tumor stroma, are starting to be explored with the
hope of increasing response rates and subsequently im-
proving survival outcomes. Nab-paclitaxel heralds the
beginning of this new era, demonstrating significantly
greater efficacy in advanced disease when administered
with gemcitabine in the phase III setting than the current
standard of care, gemcitabine monotherapy, and with less
toxicity than FOLFIRINOX. It will be interesting to see
if this proven efficacy in the palliative setting can be ex-
trapolated to the adjuvant and neoadjuvant setting as well
as in patients with locally advanced unresectable disease.
Nab-paclitaxel should be considered as an eminent thera-
peutic option in combination with gemcitabine in the
treatment of patients with pancreatic cancer.
12. Acknowledgements
The authors wish to express their gratitude to all of the
participants who have taken part in clinical trials as well
as to the study investigators, study nurses and data col-
lectors and, finally, to the study groups and donors, all of
whom have helped contribute to developing more effec-
tive therapies for pancreatic cancer. Researchers continue
to search for new explanations, resulting in an increased
understanding of pancreatic cancer biology and, ulti-
mately, translation of this knowledge into novel ap-
proaches in the treatment of this challenging disease.
Medical writing assistance was provided by Dr. Marc
Esser and Melody Watson at co.faktor (Berlin, Ger-
many), funded by Celgene Corporation.
The author is fully responsible for all content and edi-
torial decisions for this manuscript.
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