Journal of Cancer Therapy, 2013, 4, 1068-1073
http://dx.doi.org/10.4236/jct.2013.46121 Published Online August 2013 (http://www.scirp.org/journal/jct)
Practical Use of Gemcitabine and Cisplatin Combination
Therapy as First-Line Treatment for Japanese Patients
with Advanced Biliary Tract Cancer*
Hisato Kawakami1, Isamu Okamoto1,2#, Wataru Okamoto1, Masayuki Takeda1, Shinya Ueda1,
Toshihiro Kudo1, Shin-ichi Nishina1, Ya su h i to Fuj i sa k a1, Masaki Miyazaki1, Junji Tsurutani1,
Takayasu Kurata1, Kazuhiko Nakagawa1
1Department of Medical Oncology, Faculty of Medicine, Kinki University, Osaka, Japan; 2Center for Clinical and Translational Re-
search, Kyushu University Hospital, Fukuoka, Japan.
Received May 14th, 2013; revised June 16th, 2013; accepted June 23rd, 2013
Copyright © 2013 Hisato Kawakami et al. 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
Gemcitabine and cisplatin combination therapy (GC) is accepted as a standard treatment for advanced biliary tract can-
cer (BTC). However, little information is available regarding such treatment in the clinical practice setting in Japan. We
retrospectively examined the clinical data of patients with unresectable or recurrent BTC who received GC as first-line
treatment. The regimen consisted of cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) administered intravenously on
days 1 and 8 of repeated 3-week cycles. Twenty patients were analyzed. A total of 148 cycles of GC was administered,
with a median of 8 and a range of 1 to 18 cycles. Treatment delay and dose reduction were noted in 35 (24%) and 41
(28%) of the 148 cycles, respectively. The major adverse events of grade 3 or 4 included neutropenia (50%), leukopenia
(45%), anemia (30%), and thrombocytopenia (15%). Nonhematologic toxicities included nausea (10%), appetite loss
(10%), and fatigue (10%). Median progression-free and overall survival times were 6.9 and 12.3 months, respectively.
Gallbladder cancer showed a significantly higher response rate than did other types of BTC (chi-squaretest, P = 0.002).
GC was thus effective and well tolerated as first-line chemotherapy for Japanese patients with advanced BTC in the
clinical practice setting.
Keywords: Gemcitabine; Cisplatin; Chemotherapy; Biliary Tract Cancer
1. Introduction
Biliary tract cancer (BTC) is a rare type of cancer world-
wide, but it is more common in East Asia and Latin
America than in other regions [1]. In Japan, BTC is the
sixth leading cause of death from cancer [2] and its
prevalence is increasing. Although the most effective
treatment for localized disease is surgery, most cases of
BTC are diagnosed as advanced and inoperable, despite
substantial progress in diagnostic imaging. Outcomes are
extremely poor in such patients, with a median survival
time of 2.5 months with best supportive care [3].
Gemcitabine has shown antitumor activity in patients
with BTC, as revealed by the results of predominantly
phase II studies [4-6], and this drug is generally used in
the palliative setting, yielding a median survival time of
6 to 9 months. Cisplatin is a key anticancer agent for
solid tumors and is widely administered in combination
chemotherapy. Gemcitabine and cisplatin combination
therapy (GC) has shown promising antitumor efficacy in
several phase II studies with BTC patients [7-12]. Given
these results, a phase III trial comparing GC with gem-
citabine alone was conductedfor locally advanced or me-
tastatic BTC in the United Kingdom (ABC-02 study). A
total of 410 patients were randomly assigned to receive
gemcitabine (1000 mg/m2 on days 1, 8, and 15 of a 4-
week cycle) or GC (1000 mg/m2and 25 mg/m2, respec-
tively, on days 1 and 8 of a 3-week cycle). The median
overall survival (OS)was significantly better forthe pa-
tients receiving GC than for those receiving gemcitabine
alone (11.7 versus 8.1 months; hazard ratio [HR] of 0.64,
with a 95% confidence interval [CI] of 0.52 to 0.80; P <
*Conflict of interest statement: None declared.
#Corresponding author.

Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line
Treatment for Japanese Patients with Advanced Biliary Tract Cancer
1069
0.001).The median progression-free survival (PFS) was
also significantly longer for the GC group than for the
gemcitabine group (8.0 versus 5.0 months; HR of 0.63,
with a 95% CI of 0.51 to 0.77; P < 0.001) [13]. On the
basis of the results of the ABC-02 study, GC was recog-
nized as the standard of care for the treatment of ad-
vanced BTC.A randomized phase II study comparing GC
with gemcitabine alone was also performed for locally
advanced or metastatic BTC in Japan (BT22 study), with
the same treatment dose and scheduleas adopted in the
ABC-02 study. Overall, 84 patients were randomized to
receive either GC or gemcitabine alone. The 1-year sur-
vival rate, which was the primary endpoint of the study,
was higher in the GC group than in the gemcitabine
group (39.0 versus 31.9%) [14]. The findings of the ABC-
02 and BT22 studies have thus resulted in GC becoming
accepted as a standard treatment for patients with BTC in
Japan. To date, however, information regarding the safety
and efficacy of GC in Japanese individuals with BTC has
been limited to that obtained from 42 patients in the BT
22 study. The safety and efficacy of GC in the clinical
practice setting have thus remained uncertain. We now
report our experience with GC for Japanese patients with
BTC in the clinical practice setting.
2. Methods
2.1. Eligibility Criteria
We reviewed the cases in our database and retrospec-
tively examined the clinical data of patients with unre-
sectable or recurrent BTC who received GC as the first-
line treatment. Patients were eligible if they had: 1)
pathologically or radiographically confirmed BTC; 2) an
Eastern Cooperative Oncology Group (ECOG) perform-
ance status of 0 to 2; and 3) adequate bone marrow func-
tion (white blood cell count of >3000/mm3, hemoglobin
content of >9.0 g/dl, and a platelet count of >100,000/
mm3), liver function (total serum bilirubin concentration
of less than three times the upper limit of normal [ULN],
and serum aspartate and alanine transaminase levels of
less than five times the ULN), and renal function (serum
creatinine concentration of <1.2 mg/dl and creatinine
clearance of >50 ml/min). In patients with obstructive
jaundice, the total serum bilirubin concentration was re-
quired to be less than three times the ULN after biliary
drainage. Written informed consent was obtained from
each patient prior to treatment administration.
2.2. Treatment Schedule
GC was administered mostly on an outpatient basis.
Gemcitabine was given intravenously (1000 mg/m2) over
30 min and cisplatin was administered intravenously (25
mg/ m2) over 120 min on days 1 and 8 of a 3-week cycle.
Treatment was continued until disease progression, the
occurrence of unacceptable toxicity, or patient refusal.
We adopted the following general administration criteria
for GC: a neutrophil count of ≥1500/mm3, a platelet
count of ≥75,000/mm3, a serum total bilirubin concentra-
tion of ≤2.5 mg/dl, a serum creatinine level of ≤1.5 mg/dl,
and other nonhematologic toxicity of grade 1 or less.
Administration of gemcitabine alone after discontinua-
tion of GC was allowed at the discretion of the physician,
whereas administration of cisplatin alone was not al-
lowed. Antiemetic prophylaxis with 5-HT3 serotonin
receptor antagonists plus dexamethasone was adminis-
tered in all cases. A neurokinin-1 receptor antagonist was
used at the physician’s discretion.
2.3. Toxicity Evaluation
All adverse events were reviewed based on medical re-
cords and evaluated according to the National Cancer
Institute Common Terminology Criteria for Adverse
Events, version 4.0. The highest toxicity grade for each
patient in all cycles of chemotherapy was used for toxic-
ity analysis.
2.4. Efficacy Measures
The efficacy end points were tumor response, PFS, and
OS. Tumor assessment by computed tomography of the
abdomen and chest was performed at baseline and after
two cycles of chemotherapy according to the Response
Evaluation Criteria in Solid Tumors (RECIST) version
1.1. PFS was defined as the time from enrollment to the
date of confirmation of progressive disease or of death
from any cause, whichever occurred first. OS was de-
fined as the time from registration until death from any
cause. Patients not known to have died or to have devel-
oped progressive disease were censored at the date of the
last progression-free assessment.
2.5. Statistical Analysis
Survival curves were constructed by the Kaplan-Meier
method and were compared with the log-rank test. Dif-
ferences in tumor response were evaluated with the chi-
square test. Statistical analysis was performed with the
use of IBM SPSS statistics software version 20. A P
value of <0.05 was considered statistically significant.
3. Results
3.1. Patient Characteristics
The characteristics of the 20 enrolled patients are listed
in Table 1. The median age of the patients was 64.5
years, with similar numbers of men and women. Six in-
dividuals were 70 years of age or older. Five patients

Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line
Treatment for Japanese Patients with Advanced Biliary Tract Cancer
1070
Table 1. Patient characteristics.
Characteristic No. of patients (%)
Sex
Male 11 (55%)
Female 9 (45%)
Age (years)
Median 64.5
Range 44 - 76
Performance Status
0/1/2 7/11/2 (35%/55%/10%)
Primary tumor site
Extrahepatic bile duct 6 (30%)
Intrahepatic bile duct 8 (40%)
Gallbladder 6 (30%)
Metastatic sites
Regional lymph nodes 17 (85%)
Distant lymph nodes 13 (65%)
Liver 15 (75%)
Peritoneum 2 (10%)
Lung 2 (10%)
Other 4 (20%)
Initial onset or recurrence
Initial onset 15 (75%)
Recurrence after surgery 5 (25%)
Histological type
Adenocarcinoma 14 (70%)
Adenosquamous carcinoma 1 (5%)
Cholangiocarcinoma 1 (5%)
Not obtainable 4 (20%)
Disease stage (extrahepatic bile duct cancer, gallbladder cancer)
IIA 0 (0%)
IIB 1a (5%)
III 1 (5%)
IV 6 (30%)
Reccurence after surgery 4 (20%)
Disease stage (intrahepatic bile duct cancer)
II 1a (5%)
III 0 (0%)
IVA 2 (10%)
IVB 4 (20%)
Reccurence after surgery 1 (5%)
Biliary drainage
Yes 2 (10%)
No 18 (90%)
aPatients were diagnosed as having unresectable disease with marked
regional node metastases involving the proper hepatic artery or main portal
vein.
(25%) had recurrent metastatic disease after surgical re-
section, and 15 (75%) had unresectable metastatic dis-
ease at the initial diagnosis. Tumor specimens were ob-
tained from 16 individuals, including 14 patients with
adenocarcinoma, one patient with adenosquamous carci-
noma, and one patient with cholangiocarcinoma. The
primary tumor sites included the gallbladder in six pa-
tients (30%), the intrahepatic bile duct in eight patients
(40%), and the extrahepatic bile duct in six patients
(30%). Regional lymph nodes were the most common
metastatic site, followed by the liver and distant lymph
nodes.
3.2. Treatment Delivery
The data for treatment delivery are summarized in Table
2. Seventeen patients (85%) required a treatment delay
and eight patients (40%) required dose reduction. A total
of 148 cycles of GC was administered, with a median of
8 and a range of 1 to 18 cycles per patient. Treatment
delays and dose reductions were noted in 35 (24%) and
41 (28%) of the 148 cycles, respectively. Most treatment
delays (24 out of 35 cycles) were due to hematologictox-
icity that persisted for up to 7 days;the remaining 11 cy-
cles were delayed for >2 weeks (15 to 70 days) be
Table 2. Summary of treatment delivery.
Total treatment cycles 148
Median no. of cycles (range) 8 (1 - 18)
Treatment delay
Cycles (%) 35 (24%)
Reasons (cycles) Neutropenia (19)
Fever (5)
Fatigue (3)
Anemia (2)
Patient's request (2)
Platelet count decreased (2)
Serum creatinine
level increased (1)
Febrile neutropenia (1)
Dose reduction
Cycles (%) 41 (28%)
Reasons (cycles) Neutropenia (25)
Platelet count decreased (8)
Fatigue (4)
Febrile neutropenia (4)

Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line
Treatment for Japanese Patients with Advanced Biliary Tract Cancer
1071
cause of the development of prolonged neutropenia (6
cycles), prolonged thrombocytopenia (2 cycles), pro-
longed anemia with refusal of blood transfusion (1 cycle),
febrile neutropenia of grade 3 (1 cycle), or fever of grade
1 (1 cycle). The reasons for dose reduction included the
development ofneutropenia (25 of 41 cycles), throm-
bocytopenia (8 cycles), fatigue (4 cycles), or febrile
neutropenia (4 cycles).Reasons for discontinuation of
treatment included radiologically determined progressive
disease (15 cases), treatment refusal (2 cases), and sur-
gery with curative intent (1 case).
3.3. Toxicity
Major adverse events during the entire period are pre-
sented in Table 3. No treatment-related deaths occurred.
The major adverse events of grade 3 or 4 included neu-
tropenia (50%), leukopenia (45%), anemia (30%), and
thrombocytopenia (15%). Although neutropenia was the
most common hematologic toxicity, febrile neutropenia
of grade 3 was observed in only one case (5%). With
regard to nonhematologic toxicity, no toxicities of grade
4 were observed and those of grade 3 included nausea
(10%), appetite loss (10%), and fatigue (10%), all of
which were manageable. Biliary tract infection of grade 3
was seen in one patient (5%), but it resolved within a
Table 3. Treatment-related toxicities (graded according to
National Cancer Institute Common Terminology Criteria
for Adverse Events) in the 20 study subjects.
No. of patients (n = 20)
Toxicity Grade 1 Grade 2 Grade 3 Grade 4
Leukopenia 1 1 8 1
Neutropenia 1 0 6 4
Febrile neutropenia - - 1 0
Thrombocytopenia 8 4 2 1
Anemia 5 6 6 0
Serum creatinine
increased 2 0 0 0
Constipation 12 4 0 0
Nausea 1 0 2 0
Appetite loss 8 4 2 0
Fatigue 7 4 2 -
Biliary tract infection - - 1 0
Vomiting 2 1 0 0
Fever 3 0 0 0
Stomatitis 3 0 0 0
Peripheral sensory
neuropathy 2 0 0 0
week of antibiotic therapy.
3.4. Response
The chemotherapeutic responses are summarized in Ta-
ble 4. All patients but one were assessable for tumor re-
sponse. Although no individual achieved a complete re-
sponse, six patients achieved a partial response, giving a
best overall response rate of 30% (95% CI, 15 to 52%).
Ten patients (50%) showed stable disease, and the re-
maining three patients (15%) had progressive disease.
Five of the six responders had gallbladder cancer (GBC).
Response differed significantly (chi-square test, P =
0.002) between patients with GBC (n = 6) and those with
other types of BTC (n = 14).
3.5. Survival
At the time of analysis, 18 patients had died of their dis-
ease. With a median potential follow-up time of 12.5
months, median OS and median PFS were 12.3 months
and 6.9 months, respectively (Figure 1). Neither median
OS nor median PFS differed significantly between pa-
tients with GBC and those with other forms of BTC.
Figure 1. Kaplan-Meier analysis of OS and PFS for all pa-
tients (n = 20) from the onset of chemotherapy.
Table 4. Chemotherapeutic response according to tumor
site.
No. of patients
Tumor site
CR PR SD PD NE
GBC 0 5* 1 0 0
Other BTCs0 1 9 3 1
All (%) 0 (0%)6 (30%) 10 (50%) 3 (15%)1 (5%)
Abbreviations: CR = complete response, PR = partial response, SD = stable
disease, PD = progressive disease, NE = not evaluable, GBC = gall bladder
cancer, BTC = biliary tract cancer. *P = 0.002 versus the corresponding
value for other BTCs (chi-square test).

Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line
Treatment for Japanese Patients with Advanced Biliary Tract Cancer
1072
Second-line chemotherapy was administered to 12 pa-
tients (60%), all of whomreceived S-1 monotherapy.
4. Discussion
GC is now accepted worldwide as a standard regimen for
first-line chemotherapy in patients with advanced BTC,
largely on the basis of the results of the first large phase
III study (ABC-02) showing the superiority of GC com-
pared with gemcitabine monotherapy for this condition
[13]. Although gemcitabine combined with oxaliplatin or
capecitabine has shown promising efficacy for patients
with BTC in single-arm phase II trials, yielding a re-
sponse rate of ~50% and OS of ~14.0 months [15], these
treatments have not been evaluated in randomized phase
III trials in comparison with gemcitabine alone. The
safety and efficacy of GC for Japanese patients with BTC
were also recently demonstrated in a randomized phase II
trial (BT22) [14].GC was thus approved in February
2012 for the treatment of advanced BTC in Japan. Given
the widespread adoption of GC for the treatment of ad-
vanced BTC, further information on its toxicity and
treatment delivery characteristics in the clinical practice
setting is of value.
Most toxicities observed in our study were hema-
tologic in nature. The incidence ofleukopenia (45%) or
neutropenia (50%) of grade 3 or 4 wassimilar to that ob-
served in theprevious Japanese BT22 study (29.3 and
56.1%, respectively) [14] but washigher than that appar-
ent among Caucasiansin the ABC-02 study (15.7 and
25.3%, respectively) [13], consistent with the notion of
anethnic difference in the hematologic toxicity of che-
motherapy between Japanese and Caucasian patients
with BTC [16]. We further investigated the effect of dose
reduction on efficacy. Overall, 40% (8/20) of patients
required a dose reduction, mostly as a result of hema-
tologic toxicity. Among the patients who underwent a
dose reduction, the median PFS and response rate were
5.8 months and 12.5% (1 out of 8 patients), respectively.
In contrast, a median PFS of 8.5 months and response
rate of 41.7% (5 out of 12 patients) were apparent for the
individuals who received the starting dose of GC through-
out the treatment period. Nonhematologic toxicity was
acceptable in the present study, with frequent adverse
events including fatigue and gastrointestinal manifesta-
tions, both of which were clinically reversible. The over-
all profile and frequency of nonhematologic toxicities in
our analysis are consistent with those observed in previ-
ous trials [13,14].
Cisplatin is one of the most effective chemotherapeutic
agents for the treatment of many types of solid tumors,
but its administration is limited over the long term be-
cause of its cumulative toxicity, including neurological
toxicity. Such problems occur even if cisplatin is admin-
istered at a low dose. In the ABC-02 study, GC was de-
livered for up to a maximum of eight cycles, corre-
sponding to a total cisplatin dose of 400 mg/m2 [13]. GC
was continued for up to a maximum of 16 cycles in the
BT22 study [14]. However, little has been known of the
safety or efficacy of GC in patients receiving a total cu-
mulative dose of cisplatin of >400 mg/m2. In the present
study, cisplatin was administered at a median total dose
of 347.5 mg/m2, with a range of 25 to 550 mg/m2. Four
of the 20 patients received cisplatin at >400 mg/m2, and
these individuals did not experience significant toxicity
other than peripheral neuropathy of grade 1. Further
studies are needed, however, to determine the optimal
total dosage of cisplatin for treatment of BTC with GC.
Although patients with GBC showed a significantly
higher response rate compared with those with other
types of BTC in the present study, this finding is not par-
ticular to GC. Subgroup analysis of the ABC-02 study
revealed a higher response rate for GBC than for other
forms of BTC in both the gemcitabine arm (21.4 versus
11.7%) and the GC arm (37.7 versus 18.0%) [13]. Fur-
thermore, a previous pooled analysis of clinical trials
revealed that GBC showed a higher response rate to
drugs such as fluoropyrimidines, gemcitabine, and plati-
num compounds administered as single agents or in
combination therapy [17]. These findings may indicate
that BTC comprises a heterogeneous group of carcino-
mas that can be classified crudely as GBC or others. In-
deed, recent studies have suggested that GBC and other
forms of BTC should be considered as distinct diseases
with different clinicopathologic characteristics [18-20].
In summary, our results suggest that GC is effective
and well tolerated in Japanese patients with advanced
BTC even in the clinical practice setting. Most toxicities
observed in our study were hematologic, with such tox-
icities being a major cause of both dose reduction and
treatment delay. Such characterization of GC is impor-
tant for the optimal treatment of patients with BTC in
clinical practice.
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