Capecitabine as Salvage Therapy for a Pancreatic

Hamid Saadati, Muhammad Wasif Saif
Yale University School of Medicine. New Haven, CT, USA
Dear Sir:
There have been constant debates regarding
the issues of chemotherapy use and dosing in
setting of liver insufficiency in patients with
solid malignancies. Many chemotherapeutic
agents are metabolized by the liver, and it is
also relatively common for advanced cancer
patients to have liver dysfunction secondary
to metastatic disease. Some literature reviews
the use of specific cytotoxic drugs in such
patients [1, 2] but data are still lacking for
most agents. Hence, there are no formal
dosing recommendations. Furthermore, most
patients with hepatic insufficiency are
excluded from clinical trials and case review
series, perpetuating the lack of such
information. This situation is further
complexed when dealing with a patient with
pancreatic cancer, where options are
extremely limited and liver dysfunction is
very common.
Capecitabine is an oral, tumor-selective
fluoropyrimidine carbamate that is preferentially
converted to active 5-fluorouracil (5-FU)
within the tumor by a three-step enzymatic
conversion [3, 4, 5]. Due to ease of
administration and better safety profile,
capecitabine is being used with increasing
frequency as an alternative to infusional 5-FU
therapy for metastatic gastrointestinal
malignancies [6]. We recently reported a
series of three patients suffering from
gastrointestinal malignancies and associated
mild-moderate liver insufficiency who
received capecitabine for their metastatic
disease [7].
In this letter, we report another case of a
patient with pancreatic cancer and liver
insufficiency who received capecitabine as a
palliative chemotherapy.
Our patient is a 48-year-old male who
presented with progressively worsening of
abdominal pain prompting an evaluation by
his gastroenterologist. His abdominal CT scan
showed pancreatic mass involving the neck
and body of the pancreas with encasement of
the celiac axis. Extensive retroperitoneal
lymph node metastases and multiple
pulmonary nodules consistent with metastasis
were also noted. Fine needle aspiration of the
pancreas confirmed poorly differentiated
adenocarcinoma. Patient was initially treated
with gemcitabine-based chemotherapy.
However, this regimen was discontinued after
a staging CT scan confirmed progression of
disease. He then began treatment with
gemcitabine plus oxaliplatin but he developed
severe transaminitis with cycle one (AST 145
IU/L, reference range: 0-35 IU/L; ALT 242
IU/L, reference range: 0-35 IU/L) and normal
total bilirubin (0.42 mg/dL; reference range:
0-1.20 mg/dL). He received oxaliplatin alone
during cycle 2. Therapy was then changed to
single agent gemcitabine due to further
elevation in ALT (328 IU/L). In addition to
abnormal liver function tests, his chemo-
therapy was also complicated by grade 4

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JOP. J Pancreas (Online) 2008; 9(3):354-356.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 9, No. 3 - May 2008. [ISSN 1590-8577]
355
neutropenia (absolute neutrophil count
477/mm
3
, reference range: 1,500-8,000/mm
3
).
CT scan indicated progression of pulmonary
metastases. Due to persistent elevation of
AST and ALT, treatment options were very
limited due to concern about safety. After a
detailed discussion with the patient,
capecitabine 1,500 mg po twice a day with
one week on and one week off (7/7 schedule)
was administered. He tolerated capecitabine
well with significant improvement in
transaminases (Figure 1) with minimal
toxicity. Unfortunately, his restaging CT scan
after three cycles showed disease progression
with growing of peritoneal and liver
metastases as well as new liver metastases.
In addition to our two earlier reports of
pancreatic cancer patients with liver
dysfunction [7], this case further suggests that
capecitabine may be safely used to treat an
advanced pancreatic cancer with associated
hepatic insufficiency (Table 1). Generally, the
pharmacokinetics of capecitabine are not
affected in patients with mild to moderate
hepatic dysfunction, but there are no data
available for patients with severe hyper-
bilirubinemia. Our clinical experience also
corresponds to the findings of Twelves et al.
[8] who reported that impaired hepatic
function had no clinically significant
influence on the pharmacokinetics of
capecitabine and its metabolites. It is
important to remember that the liver
dysfunction in this patient was secondary to
his malignancy. Akin to other two cases of
pancreatic cancer, our patient also showed
clinical response even at a reduced dose of
capecitabine [9]. This finding is particularly
interesting, as it shows that the efficacy of
capecitabine
was
not
necessarily
compromised at the reduced doses chosen for
this patient. Clinical trials of low-dose
capecitabine in such patients are therefore
warranted. In addition, we used a novel
schedule of capecitabine [10]. Preclinical
studies in human tumor xenografts indicate
that inhibition of tumor growth depends on
the total dose of capecitabine but not
necessarily on its administration schedule.
This was tested in a randomized phase II
study suggesting that short intermittent
schedules have equal efficacy to more
protracted administration. This hypothesis
was tested further by Scheithauer et al., in a
single center, European phase I/II study in
advanced colorectal cancer. Patients received
oxaliplatin at a fixed dose of 85 mg/m
2
every
2 weeks combined with escalating doses of
capecitabine [11]. In this regimen, the dose
intensity of capecitabine was from 105% to
131% compared with the conventional
capecitabine administration schedule of days
1-14 every 3 weeks (21 days). Gastro-
intestinal toxicities, predominantly diarrhea,
were the principle toxicities seen in the study.
Figure 1. Response of liver function tests to
capecitabine (present case).
Table 1. Summary of three cases treated with capecitabine.
Case 1 (present case)
Case 2 [7]
Case 3 [7]
Chemotherapy
Chemotherapy
Chemotherapy
Pre
Post
(3 cycles)
Pre
Post
(2 cycles)
Pre
Post
(2 cycles)
AST (IU/L)
109
40
117
46
81
18
ALT (IU/L)
273
43
121
37
84
17
Alkaline phosphatases (IU/L)
492
451
317
288
229
176
Total bilirubin (mg/dL)
0.52
0.69
4.63
1.0
3.96
0.69

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JOP. J Pancreas (Online) 2008; 9(3):354-356.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 9, No. 3 - May 2008. [ISSN 1590-8577]
356
It is noteworthy that cohort expansion was
necessary in all but the first dose level where
no dose limiting toxicities were seen.
Additionally, the toxicity profile began to
shift beyond 1,500 mg/m
2
twice-daily from
nausea and vomiting to diarrhea at higher
doses. Despite the shift toward more severe
and clinically significant toxicities being seen
at the higher dose levels and the need for
cohort expansion, the dose recommended for
further testing was capecitabine 1,750 mg/m
2
orally twice-daily for 7 days followed by 7
days without capecitabine in repeated 2-week
cycles. Interestingly, efficacy results were
encouraging with a response rate of 50 % and
a median progression-free survival of almost
9 months. Our case also emphasize that
capecitabine can be used in a range of dosing
schedules and intensities and future studies
should focus on a dose intense weekly
schedule in patients with liver dysfunction.
Received January 30
th
, 2008 - Accepted
February 15
th
, 2008
Keywords Breast Neoplasms; capecitabine;
Colonic Neoplasms; Jaundice; Liver
Diseases; Liver Function Tests; Pancreatic
Neoplasms
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Muhammad Wasif Saif
Yale University School of Medicine
Section of Medical Oncology
333 Cedar Street; FMP 116
New Haven, CT 06520
USA
Phone: +1-203.737.1569
Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL: http://www.joplink.net/prev/200805/09.html
References
1. Eklund JW, Trifilio S, Mulcahy MF.
Chemotherapy dosing in the setting of liver
dysfunction. Oncology (Williston Park) 2005; 19:1057-
63. [PMID 16131047]
2. Chase JL, Ignoffo RJ, Stagg RL. Gastrointestinal
Cancers in Pharmacotherapy: A Pathophysiologic
Approach. In: DiPiro JT, Talbert RL, Hayes PE, et al,
editors. Elsevier, New York, 1988:1384-94.
3. Budman DR, Meropol NJ, Reigner B, Creaven PJ,
Lichtman SM, Berghorn E, et al. Preliminary studies of
a novel oral fluoropyrimidine carbamate: capecitabine.
J Clin Oncol 1998; 16:1795-802. [PMID 9586893]
4. Saif MW, Eloubeidi MA, Russo S, Steg A,
Thornton J, Fiveash J, Carpenter M, et al. Phase I study
of capecitabine with concomitant radiotherapy for
patients with locally advanced pancreatic cancer:
expression analysis of genes related to outcome. J Clin
Oncol 2005; 23:8679-87. [PMID 16314628]
5. Schüller J, Cassidy J, Dumont E, Roos B, Durston
S, Banken L, et al. Preferential activation of
capecitabine in tumor following oral administration to
colorectal cancer patients. Cancer Chemother
Phamacol 2000; 45:291-7. [PMID 10755317]
6. Mackean M, Planting A, Twelves C, Schellens J,
Allman D, Osterwalder B, et al. Phase I and
pharmacologic study of intermittent twice-daily oral
therapy with capecitabine in patients with advanced
and/or metastatic cancer. J Clin Oncol 1998; 16:2977-
85. [PMID 9738566]
7. Saif MW, Tejani MA. Safety of capecitabine use
in patients with liver dysfunction. Clin Adv Hematol
Oncol 2007; 5:730-2. [PMID 17982413]
8. Twelves C, Glynne-Jones R, Cassidy J, Schüller J,
Goggin T, Roos B, et al. Effect of hepatic dysfunction
due to liver metastases on the pharmacokinetics of
capecitabine and its metabolites. Clin Cancer Res
1999; 5:1696-702. [PMID 10430071]
9. El-Helw L, Coleman RE. Reduced dose
capecitabine is an effective and well-tolerated
treatment in patients with metastatic breast cancer.
Breast 2005; 14:368-74. [PMID 16216738]
10. Hoimes CJ, Lamb L, Elligers K, Mezes M, Grant
N, Ruta S, et al. A phase I/II study of PHY906 plus
capecitabine (CAP) in patients (pts) with advanced
pancreatic carcinoma (PC). 2008 Gastrointestinal
Cancers Symposium (abstract 260).
11. Scheithauer W, Kornek GV, Raderer M, Schüll B,
Schmid K, Kovats E, et al. Randomized multicenter
phase II trial of two different schedules of capecitabine
plus oxaliplatin as first-line treatment in advanced
colorectal cancer. Clin Oncol 2003; 21:1307-12.
[PMID 12663719]

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