Received: 22.02.2008 Accepted: 29.05.2008
J Gastrointestin Liver Dis
September 2008 Vol.17 No 3, 285-290
Address for correspondence:
Inaam A. Nakchbandi, MD
University of Heidelberg
Im Neuenheimer Feld 305
69120 Heidelberg, Germany
Prospective Study on Warfarin and Regional Chemotherapy
in Patients with Pancreatic Carcinoma
Wes Nakchbandi1, Herwart Müller1, Manfred V. Singer2, J. Matthias Löhr2, Inaam A. Nakchbandi3
1) Department of Oncologic Surgery, Carl von Hess Hospital, Hammelburg; 2) Department of Medicine II, University
of Heidelberg at Mannheim; 3) Max-Planck Institute for Biochemistry and University of Heidelberg, Heidelberg,
Aims: The aim is to prospectively examine the effect
of regional gemcitabine and mitomycin-C with systemic
gemcitabine together with warfarin in patients with
inoperable pancreatic carcinoma, and compare the effect to
systemic gemcitabine alone. Methods: Seventeen patients
received 1.25 mg of warfarin daily, gemcitabine 800 mg/m²
on day 1 and mitomycin-C 8 mg/m² on day 2 regionally and
gemcitabine 800 mg/m² on day 14 peripherally. The cycle
was repeated every 4 weeks. Results: Median survival since
presentation was 6.8 months, while median total survival
was 9.6 months. Excluding the 3 patients who died before
receiving any therapy, the median survival since presentation
resulted in 10.7 months and the median total survival, 12.7
months. One patient developed bleeding that required
transfusion and 2 patients developed anemia (Grades III/
IV). Comparing these data to historical controls of large
cohorts supports the notion that this regimen offers a viable
alternative to systemic gemcitabine alone. Conclusion: A
regimen consisting of regional gemcitabine and mitomycin-C
with systemic gemcitabine and low-dose warfarin compares
favorably to the gold standard of systemic gemcitabine.
These data suggest the feasibility of a large prospective study
on the use of warfarin and combined regional and systemic
chemotherapy in patients with pancreatic carcinoma.
Pancreatic carcinoma – warfarin – regional
Despite progress in the treatment of many cancers,
pancreatic carcinoma remains a disease with a dismal
prognosis . An improvement in survival of 1 month with
the use of systemic gemcitabine compared to 5-fluorouracil
led to the establishment of this agent as the gold standard for
therapy . Further benefitsusingthistherapyarehampered
by the myelosuppression associated with high doses of
systemic gemcitabine therapy.
Pancreatic carcinoma has a number of characteristics
that could be taken advantage of. First, one of the main
characteristics of pancreatic carcinoma is that it tends to grow
locally . This property suggests that destroying the tumor
locally can be enough to cause remission. The best strategy to
increase survival in this disease is thus an extensive operation
to remove the pancreas and surrounding tissue in an attempt
to remove any potential cancerous cells [4, 5]. Regional
chemotherapy offers a possible strategy to control pancreatic
cancer , because it allows the administration of relatively
large doses of chemotherapeutic agents that cannot be
tolerated if given systemically [7-9]. Through the selection
of agents that have a high rate of uptake and metabolism by
the tumor this modality combines the benefitsofmaximizing
the dose of chemotherapy seen by the tumor and minimizing
the systemic complications including myelosuppression
caused by these agents [10, 11]. Thus, by using the right
dose one can still achieve that the tumor is exposed to a
high concentration while the systemic concentration is in
the range usually tolerated by the patients .
A second property of pancreatic cancer is an increase
in clotting in the tumor itself. In situ studies of pancreatic
carcinoma suggest an increase in blood clotting locally
and therefore a decrease in the accessibility of this tumor
to systemic chemotherapy [13-18]. These clotting factors
include: tissue factor, a major activator of coagulation [13,
14], thrombin receptor , and prothrombin fragments 1+2
as markers of coagulation activation . A decrease in an
inhibitor of coagulation: tissue factor pathway inhibitor-2
(TFPI-2)  as well as decreased fibrinolysis caused by
an increase in plasminogen activator inhibitor (PAI-1) 
290 Nakchbandi et al
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