Therapeutic Tools in Pancreatic Cancer

Christopher J Hoimes
1
, Alexios S Strimpakos
2
, Muhammad Wasif Saif
1
1
Yale Cancer Center, Yale University School of Medicine. New Haven, CT, USA.
2
Department of Medicine, Royal Marsden Hospital. Surrey, United Kingdom
Summary
Pancreatic cancer is the fourth leading cause of cancer death in the United States and has a lower survival rate than other digestive
tract tumors. It remains a therapeutic challenge with limited active agents. Honing our current understanding of markers of toxicity
and response, and individualizing treatment with the prognostic and therapeutic tools available are important to make a worthy
impact on a patient’s course. The authors summarize selected abstracts from the ASCO Gastrointestinal Cancers Symposium, San
Francisco, CA, USA, January 15-17, 2009. The Symposium featured pancreatic cancer in 84 research abstracts, of which, seven are
reviewed that focus on markers of toxicity: cytidine deaminase (Abstract #151) and haptogloin (Abstract #167) as markers of
gemcitabine toxicity; markers of response: use of PET scan for prognosis (Abstract #157), and correlations with CA 19-9 to post-
chemo-radiation resectability (Abstract #215) and time to progression (Abstract #160); and individualized applications:
characterizing the phenotypic similarities between a patient tumor and the direct xenograft (Abstract #154) and a report about the
poor outcome of patients with ascites (Abstract #220). Validated clinical tools that can assist in managing patients through the
narrow therapeutic window are needed.
Introduction
Pancreatic cancer is the fourth leading cause of cancer
death in the United States [1] and remains a diagnostic
and therapeutic challenge. The chances for achieving
five-year survival are best with early diagnosis and
treatment, though odds are still slim. Effective early
detection and screening for average-risk populations
are currently not available. Anatomically, the pancreas
is different from other tubular parts of the
gastrointestinal tract in that the retroperitoneal space is
more difficult to access, sample, and image. Thus, most
patients present with advanced disease at diagnosis
with a median expected survival with best supportive
care of 3-4 months. Symptom control is the focus of
treatment and decision to recommend cytotoxic therapy
is largely based on performance status. Existing
clinical markers of pancreatic cancer lack specificity,
as they are also found in inflammatory diseases of the
pancreas and biliary tract. Better clinical tools that can
assist in managing patients through the narrow
therapeutic window are needed. The “2009 ASCO GI
Cancers Symposium” featured pancreatic cancer in 84
research abstracts, of which we review seven that focus
on markers of toxicity, response, and individualized
therapy (Table 1).
I. Markers of Toxicity (Table 2)
Gemcitabine is a pyrimidine antimetabolite prodrug
that requires cellular uptake. It is either inactivated by
cytidine deaminase (CDA) to difluorodeoxyuridine
(dFdU), otherwise it is activated by deoxycitidine
kinase (dCK) where the nucleotide metabolite
difluorodeoxycytidine 5’-triphosphate (dFdCTP) is
incorporated into DNA resulting in chain termination.
dCK is the rate-limiting enzyme for the activation
pathway, and a patient’s phenotypic expression may
play an important role in response to gemcitabine
therapy [2, 3]. Similarly, CDA expression is
instrumental for inactivation and may play an
important role in gemcitabine toxicity.
The hypothesis that there is an association between
tumor dCK expression and outcome has been evaluated
in clinical trials of pancreatic cancer patients.
Sebastiani and colleagues showed dCK protein
expression from human pancreatic adenocarcinomas
varied in immunohistochemistry labeling intensity [4].
Keywords Ascites; CA-19-9 Antigen; gemcitabine; Cytidine
Deaminase; Haptoglobins; Pancreatic Neoplasms; Positron-
Emission Tomography; Xenograft Model Antitumor Assays
Abbreviations CDA: cytidine deaminase; dCK: deoxycitidine
kinase; FDG: fluorodeoxyglucose; mSUV: maximum standard
uptake value; MTB: metabolic tumor burden
Correspondence Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine, 333
Cedar Street, FMP 116, New Haven, CT, USA
Phone: +1-203.737.1569; Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL http://www.joplink.net/prev/200903/23.html

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They found that low intensity staining of dCK
correlated significantly with both overall survival and
progression-free survival when these patients were
treated with gemcitabine based therapy.
Similarly, CDA mutations and phenotype have been
implicated in anticipating gemcitabine toxicity.
Sugiyama et al reported on polymorphisms that could
be associated with gemcitabine toxicity in their patients
[5]. Others have suggested that rather than mutations,
CDA phenotype is perhaps a better predictor of
toxicity, and mutations can lead to false negatives [6,
7].
Dahan et al. in Abstract #151 [8] report on a
phenotypic test of CDA activity towards anticipating
those at risk for gemcitabine toxicity. They evaluated
baseline CDA phenotypes of 130 patients receiving
gemcitabine in retrospective fashion and found large
variability in CDA levels with a mean of 3.6±2.8
U/mg. Contrary to Sugiyama et al. [5] and other reports
on genotypic correlations with toxicity, Dahan et al.
found a trend of lower CDA levels with increased
toxicity (P values were not reported). They did not find
mutations of the CDA gene to be prognostically
relevant for toxicity.
Matsubara et al. (Abstract #167) [9] focused on finding
a test that would predict hematologic toxicity in
patients with pancreatic cancer receiving gemcitabine.
They used a case-control approach to evaluate the
plasma proteomes of 47 patients divided into two
cohorts of those without hematologic toxicity (grade
0), and those with grade 3-4 neutropenia and/or grade
2-4 thrombocytopenia. Using quantitative mass
spectrometry, they found 757, 1.2%out of 60,888
peptide peaks sampled, that were significant (P<0.001).
Out of these, haptoglobin was the marker found to have
the lowest P value, and they argue, most statistically
significant. They used haptoglobin in addition to
neutrophil and platelet counts, body surface area, in a
forward stepwise goodness-of-fit model to develop a
nomogram which they prospectively studied in two
independent validation cohorts of patients with
pancreatic cancer. They found that baseline absolute
neutrophil count and serum haptoglobin levels were
statistically significant (P=0.0003 and P=0.031,
respectively) with odds ratios (OR) of 0.72 and 0.71, in
predicting grade 3-4 neutropenia or grade 2-4
thrombocytopenia, respectively. The authors do not
specifically include a range of haptoglobin or
neutrophil values that they determine to correlate, nor
do they comment on other scenarios or clinical findings
in their patients that would account for altered
haptoglobin levels (such as intravascular hemolysis, or
fucosylated haptoglobin[10]).
II. Markers of Response (Table 3)
Positron emission tomography (PET) scan is not a
routine part of staging for pancreatic cancer. There are
situations where it may be obtained, such as post-
resection rising CA 19-9 with soft-tissue changes in the
surgical bed seen on CT, or with equivocal or
indeterminate findings in the liver or lung. The caveat
is 18F-fluorodeoxyglucose (FDG) is often not detected
in disease that is less than 1 cm. Schellenberg et al.
(Abstract #157) [11] correlated baseline PET scan
Table 1. Selected abstracts for this highlights review of the 2009 ASCO GI Cancers Symposium that describe therapeutic tools or markers to help
better understand treatment categories, toxicity, or response and prognosis in patients with pancreatic cancer.
Abstract Author
Tool/marker
Utility
Title
#151 [8] Dahan, et al.
CDA phenotype
Marker of toxicity A simple test to anticipate severe toxicities upon gemcitabine intake
#154 [23] Vinjamaram, et al.
Patient tumor
xenograft
Advancing
individualized therapy
Direct patient tumor xenograft prototype for drug testing and
individualizing chemotherapy in pancreatic cancer
#157 [11] Schellenberg, et al.
18FDG-PET
Marker of response Using PET scan parameters to predict survival in locally advanced
pancreas cancer
#160 [16] Boeck, et al.
CA 19-9
Marker of time to
progression
Application of a time-varying covariate model to the analysis of CA 19-
9 as a biomarker for time to progression in patients with advanced
pancreatic cancer
#167 [9] Matsubara, et al.
Haptoglobin
Predict hematologic
toxicity
Identification of a predictive biomarker for hematological toxicities of
gemcitabine
#215 [18] Rault, et al.
CA 19-9
Marker of resectability Use of post radiochemotherapy levels of serum CA 19-9 to predict
resectability for patients with locally advanced pancreatic
adenocarcinoma
#220 [21] Shimizu, et al.
Malignant ascites Individualize treatment
recommendations
Treatment efficacy and prognostic factors of gemcitabine for advanced
pancreatic cancer with malignant ascites.
CA 19-9: carbohydrate antigen 19-9; CDA: cytidine deaminase; 18FDG: 18F-fluorodeoxyglucose; PET: positron emission tomography
Table 2. Markers of toxicity in patients with pancreatic cancer receiving gemcitabine based therapy.
Abstract
Tool/marker
Clinical utility
No.
Design
Comments
#151 [8]
CDA phenotype - screen Anticipate gemcitabine toxicity 130
Observational,
retrospective
Do not clearly define toxicity measurement
#167 [9]
Baseline haptoglobin
Anticipate gemcitabine
neutropenia or thrombocytopenia
47 Case control followed
by two validation
cohorts
Not clear if the authors control for
fucosylated haptoglobin or other scenarios
for intravascular hemolysis
CDA: cytidine deaminase

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parameters with overall survival in locally advanced
pancreatic cancer. They used open source software
(developed at their institution and available for
download at http://rtimage.sourceforge.net/index.html
[12]) for measuring maximum standard uptake value
(mSUV) and metabolic tumor burden (MTB) of
baseline PET scans in 56 patients with locally
advanced pancreatic cancer [13, 14]. Median survival
was 12.7 months for all patients. They divided patients
into two cohorts of high and low mSUV, and high and
low MTB, and found significant differences between
these groups (Table 4). When they further divided the
patients into 4 subgroups of high and low mSUV and
MTB, they found that the patients with both low MTB
and mSUV had median survival of 18.7 months
compared to the median survival of 9.3 months of the
group that had high MTB and mSUV (P=0.058).
CA 19-9 is not specific for pancreatic cancer and may
be elevated in other GI tumors, however it is the most
commonly elevated serum tumor marker in pancreatic
cancer [15]. The serum value corresponds to the CA
19-9 antibody response to the carbohydrate moiety of
mucin 1 (MUC1). Decision for its use is based on
mostly retrospective data, and it is still unclear if or
how it should be used for prognosis, staging or pre-
operatively as an independent predictor of resectability.
Boeck et al. (Abstract #160) [16] sought to analyze
time to progression based on baseline versus trend of
CA 19-9 in their multicenter retrospective analysis of
non-resectable pancreatic cancer patients. They
included 115 patients with confirmed pancreatic cancer
and a pre-treatment CA 19-9 of at least 5.2 U/mL.
Nearly 90% had metastatic disease, and most were
treated on a clinical trial. Median time to progression
was 4.4 months and univariate and multivariate
analysis showed a significant (all P values <0.001)
correlation of time to progression and pre-treatment
CA 19-9 and CA 19-9 trend on treatment.
In 2003, Wolff et al. retrospectively examined pre-
gemcitabine/radiation levels of CA 19-9 in 79
resectable patients and found that patients with a CA
19-9 level of greater than 668 U/mL predicted
radiographic presence of metastasis or early relapse
[17]. Rault et al. (Abstract #215) [18] examined
neoadjuvantly treated CA 19-9 values to predict
resectability. Retrospectively, 33 patients with
histologically confirmed pancreatic cancer were
evaluated post-chemoradiation and 27 were surgically
explored. Of this surgical cohort, there was a 2:1 ratio
of patients with CA 19-9 less than 200 U/mL. Fifteen
were able to have a pancreatic resection, for a more
favorable resectability rate in patients with CA 19-9
less than 200 U/mL by a nearly 3:1 margin.
III. Individualized Therapy (Table 5)
Ascites in pancreatic cancer occurs in approximately
20% of patients and can be attributed to increased
production of tumor exudates, osmotically active
peptides that perturb vascular permeability, or
obstruction of diaphragmatic lymphatics [19]. When it
occurs ascites is usually the final manifestation, and it
need not be proven to be malignant cytologically [20].
However, it is not clear if the amount of ascites
matters. Shimizu et al. in Abstract #220 [21] performed
a retrospective review of 80 patients with malignant
ascites treated with gemcitabine, and looked for
efficacy in cohorts of patients noted as having minimal,
moderate, or massive ascites. Median survival was 4.2
months. Quality of life measures were not reported,
Table 3. CA 19-9 and PET scan as potential markers of response in patients with pancreatic cancer.
Abstract
Tool/marker
Clinical utility
No.
Design
Comments
#157 [11]
18FDG-PET Baseline PET to assess prognosis
in locally advanced disease treated
with chemo-radiotherapy
56
Retrospective Single radiation oncologist determined treatment
volumes. Institution developed software for
calculation of mSUV and MTB
#160 [16]
CA 19-9
Time to progression in advanced
pancreatic cancer
115
Retrospective Baseline CA 19-9 and trend during therapy may
have an impact in predicting time to progression
#215 [18]
CA 19-9
Decision for resectability in post
chemo-radiotherapy patients with
locally advanced disease
27 evaluable Retrospective
12 of 27 patients that were surgically explored
had a complete resection with clear margins
18FDG: 18F-fluorodeoxyglucose; CA 19-9: carbohydrate antigen 19-9; mSUV: maximum standard uptake value; MTB: metabolic tumor burden; PET:
positron emission tomography
Table 5. Validation for preserved phenotypic markers in patient tumor xenografts is an important step toward applying theragnostics in pancreatic
cancer. More options for patients with ascites are needed.
Abstract
Tool/marker
Clinical utility
No.
Design
Comments
#154 [23] Patient tumor - xenograft Toward theranostics - choose the
optimal drug for the patient’s tumor
15
Retrospective
Histology, E-cadherin, and c-kit are
preserved in their xenograft models.
#220 [21]
Malignant ascites
Choice of therapy
80
Retrospective
Ascites carries a poor prognosis in
pancreatic cancer and should be
considered in therapy decisions
Table 4. Abstract #157 found baseline PET scan values of mSUV
and MTB to independently predict length of survival in patients with
locally advanced pancreatic disease [11].
Cohort
Median survival
(months)
P
Maximum standard uptake value (mSUV:
Hi vs. Lo)
10.5 vs. 16.8
0.02
Metabolic tumor burden (MTB: Hi vs. Lo) 10.5 vs. 18.7 <0.01

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though improvement in ascites was noted in 17.5%
with a median time to treatment failure of 1.6 months.
A multivariate analysis did show that amount of
ascites, as well as performance status, were
independent prognostic factors.
It is clear that more progress is needed in drug
development for pancreatic cancer. Direct tumor
xenografts can be used to test therapeutic approaches in
pancreatic cancer; in fact, the model was recently used
as a platform to advance targeting the pancreatic cancer
stem cell [22]. An advantage is that all cellular
fractions of the tumor can be evaluated; not just the
tumor. However, it is not clear how well represented
the patient’s tumor is in a mouse xenograft that has
undergone some necessary processing in the lab,
including passaging once or twice, for nude mouse
implantation. Vinjamaram et al. (Abstract #154) [23]
compared the histologic grade and immuno-
histochemistry staining of E-cadherin, c-kit, and other
markers in the patient’s surgical specimen with that of
first and second passages that were used as xenografts
in severe combined immunodeficiency (SCID) mice.
The specimens were formalin fixed and paraffin
embedded for processing. They found that histologic
grade was preserved between patient and the passaged
cells. Staining for E-cadherin and c-kit was preserved
through the passages, however, this was not true for
fibronectin and vimentin (Table 6).
Conclusion
Better clinical markers can be beneficial for selecting
patients for therapy, timing of therapy, and
understanding prognosis of individual patients. With
further study and validation, it is possible some of
these tools make their way into randomized clinical
trials and help advance therapy.
Conflict of interest: The authors have no potential
conflicts of interest
References
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ.
Cancer Statistics, 2008. CA Cancer J Clin 2008; 58:71-96. [PMID
18287387]
2. Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis I,
Boven E, et al. Pretreatment deoxycytidine kinase levels predict in
vivo gemcitabine sensitivity. Mol Cancer Ther 2002; 1:371-6. [PMID
12477049]
3. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular
pharmacology of gemcitabine. Ann Oncol 2006; 17 Suppl 5:v7-12.
[PMID 16807468]
4. Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ,
Hidalgo M, et al. Immunohistochemical and genetic evaluation of
deoxycytidine kinase in pancreatic cancer: relationship to molecular
mechanisms of gemcitabine resistance and survival. Clin Cancer Res
2006; 12:2492-7. [PMID 16638857]
5. Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa
R, Maekawa K, et al. Pharmacokinetics of gemcitabine in Japanese
cancer patients: the impact of a cytidine deaminase polymorphism. J
Clin Oncol 2007; 25:32-42. [PMID 17194903]
6. Kirch HC, Schröder J, Hoppe H, Esche H, Seeber S, Schütte J.
Recombinant gene products of two natural variants of the human
cytidine deaminase gene confer different deamination rates of
cytarabine in vitro. Exp Hematol 1998; 26:421-5. [PMID 9590659]
7. Mercier C, Evrard A, Ciccolini J. Genotype-based methods for
anticipating gemcitabine-related severe toxicities may lead to false-
negative results. J Clin Oncol 2007; 25:4855-6. [PMID 17947739]
8. Dahan L, Ciccolini J, Mercier C, Duluc M, Giacometti S, Evrard
A, Seitz J. A simple test to anticipate severe toxicities upon
gemcitabine intake. 2009 ASCO Gastrointestinal Cancers
Symposium (Abstract #151).
9. Matsubara J, Ono M, Ueno H, Okusaka T, Furuse J, Furuta K, et
al. Identification of a predictive biomarker for hematological
toxicities of gemcitabine. 2009 ASCO Gastrointestinal Cancers
Symposium (Abstract #167).
10. Okuyama N, Ide Y, Nakano M, Nakagawa T, Yamanaka K,
Moriwaki K, et al. Fucosylated haptoglobin is a novel marker for
pancreatic cancer: a detailed analysis of the oligosaccharide structure
and a possible mechanism for fucosylation. Int J Cancer 2006;
118:2803-8. [PMID 16385567]
11. Schellenberg D, Chang DT, Kim J, Lee F, Columbo L, Koong
AC. Using PET scan parameters to predict survival in locally
advanced pancreas cancer. 2009 ASCO Gastrointestinal Cancers
Symposium (Abstract #157).
12. Graves EE. RT_Image. Department of Radiation Oncology and
MIPS at Stanford University. Stanford University School of
Medicine. Stanford, CA, USA.
13. Lee P, Weerasuriya DK, Lavori PW, Quon A, Hara W, Maxim
PG, et al. Metabolic tumor burden predicts for disease progression
and death in lung cancer. Int J Radiat Oncol Biol Phys 2007; 69:328-
33. [PMID 17869659]
14. Graves EE, Quon A, Loo BW Jr. RT_Image: an open-source
tool for investigating PET in radiation oncology. Technol Cancer Res
Treat 2007; 6:111-21. [PMID 17375973]
15. Saif MW. Translational research in pancreatic cancer. Highlights
from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 -
June 3, 2008. JOP. J Pancreas (Online) 2008; 9:398-402. [PMID
18648129]
16. Boeck S, Haas M, Laubender RP, Klose C, Kullmann F,
Buchner H, et al. Application of a time-varying covariate model to
the analysis of CA 19-9 as a biomarker for time-to-progression in
patients with advanced pancreatic cancer. 2009 ASCO
Gastrointestinal Cancers Symposium (Abstract #160).
17. Wolff RA, Ayers GD, Crane CH, Abbruzzese JL, Janjan NA,
Delclos ME, et al. Serum CA 19-9 levels in patients receiving
preoperative gemcitabine based chemoradiation for resectable
pancreatic adenocarcinoma. ASCO Gastrointestinal Cancers
Symposium 2003; 22: Abstract 133

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