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Cancer Res Treat. 2008;40(1):22-26
Gemcitabine versus Gemcitabine Combined with Cisplatin
Treatment Locally Advanced or Metastatic Pancreatic Cancer:
A Retrospective Analysis
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Jae-Hyuk Choi, M.D. , Sung Yong Oh, M.D. , Hyuk-Chan Kwon, M.D. , Jung Hwan Kim, M.D. , Jae
Hoon Lee, M.D.1, Suee Lee, M.D.1, Dong Mee Lee, M.D.1, Sung-Hyun Kim, M.D.1, Myung Hwan Rho,
M.D.1, Young-Hoon Kim, M.D.2, Mee-Sook Rho, M.D.3 and Hyo-Jin Kim, M.D.1
Departments of 1Internal Medicine, 2Surgery and 3Pathology, Dong-A University College of Medicine, Busan, Korea
Purpose: Gemcitabine is the most active agent to treat
unresectable pancreatic cancer. The superiority of com bining other drugs with cisplatin is still controversial;
therefore, we performed a retrospective analysis of gem citabine versus gemcitabine combined with cisplatin to
determine the treatment outcomes for patients with locally advanced or metastatic pancreatic cancer.
Materials and Methods: From 2001 to 2007, we enrolled
60 patients who were treated with gemcitabine or gemcitabine combined with cisplatin for locally advanced or
metastatic pancreatic cancer. Gemcitabine 1, 000 mg/m2
(G) was administrated at day 1 and day 8 every 3 weeks.
Cisplatin 60 mg/m2 was added at day 1 every 3 weeks to
the gemcitabine schedule (GP).
Results: Number of G: GP was 34: 26, locally advanced
to metastatic ratio was 35% to 65% in group G and 46%
to 54% in group GP. Median follow up duration was 29
months. The median number of chemotherapy cycles
was 4 (range: 2∼11) for the G group, and 4 (range: 1∼
11) for the GP group. The response rate of the G and GP
groups was 17% and 11%, respectively. The progression
free survival (PFS) was 4.5 months and 2.8 months, re spectively, for the G and GP groups. The overall survival
(OS) was 10.7 and 8.7 months respectively, for the G and
GP groups, but there is no statistically significant difference of the PFS (p=0.2396) and OS (p=0.4643) between
the 2 groups. The hematological toxicity profile was sim ilar (the grade III neutropenia and thrombocytopenia was
4.4% and 3.1%, respectively, in G group, and 7.5% and
2.8%, respectively, in the GP group). But non-hematological toxicities such as skin rash, abnormal liver function
and nausea/vomiting were observed in 3 patients of the
GP group. On the prognostic factor analysis, no factors
predicted a longer PFS and OS for both the G and GP
groups.
Conclusions: Gemcitabine single treatment might be
more tolerable and it had the same efficacy compared to
cisplatin combination treatment in this retrospective
study. (Cancer Res Treat. 2008;40:22-26)
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Key Words: Gemcitabine, Cisplatin, Pancreatic neoplasm
Those symptoms have a substantial negative effect on the
patients' performance status (PS) and quality of life. The median
survival for these patients ranges from 3 months to 6 months (2).
Chemotherapy is widely used for the treatment of patients
with advanced stage pancreatic cancer in an attempt to improve
survival and to control the disease-related symptoms (3,4).
Gemcitabine is currently the most active agent to treat locally
advanced or metastatic pancreatic cancer (2,5). Many attempts
have been made to increase the overall objective response rate
and the survival of patients with locally advanced or metastatic
pancreatic cancer, and particularly by combining gemcitabine
with other drugs. It has been shown that cisplatin has a 21%
overall objective response rate with a median overall survival
(OS) of only 4 months for patients with locally advanced or
metastatic pancreatic cancer (6).
Although the activity of cisplatin alone may be overestimated, it has been shown that the gemcitabine-cisplatin combination is synergistic in vitro because gemcitabine is able to
inhibit DNA repair after cisplatin-induced damage, and cisplatin
INTRODUCTION
Pancreatic cancer is the cause of 5.7 per 100,000 estimated
deaths in Korea, and it was the fifth leading cause of cancer
deaths in the year 2002 (1).
The only curative treatment option for pancreatic cancer is
complete surgical resection, but only 5% to 25% of these
patients who present with pancreatic cancer are candidates for
resection. At the time of diagnosis, most patients have locally
advanced and/or metastatic disease and they experience severe
pain, nausea and emesis, anorexia and significant weight loss.
Correspondence to: Hyo-Jin Kim, Department of Internal Medicine,
Dong-A University College of Medicine, 3-1, Dongdaesin-dong,
Seo-gu, Busan 602-715, Korea. (Tel) 82-51-240-2951, (Fax) 82-51240-2088, (E-mail) [email protected]
Received January 27, 2008, Accepted March 12, 2008
22
Jae-Hyuk Choi, et al：G versus GP Treatment in Pancreatic Cancer 23
is able to influence gemcitabine catabolism through the inhibition of ribonucleotide reductase (7,8). Yet the effectiveness
of combining cisplatin with gemcitabine is still controversial
(9,10).
Therefore, we performed a retrospective analysis of the treatment outcomes of gemcitabine versus gemcitabine combined
with cisplatin for patients with locally advanced or metastatic
pancreatic cancer.
MATERIALS AND METHODS
1) Patients
From 2001 to 2007, we enrolled 60 patients who were administered gemcitabine or gemcitabine combined with cisplatin as
treatment for locally advanced or metastatic pancreatic cancers.
They met the following inclusion criteria; 1) they had an
imaging diagnosis of locally advanced and/or metastatic pancreatic carcinoma; 2) they had measurable disease, as defined
by the Response Evaluation Criteria in Solid Tumors (RECIST)
(11); 3) they were 18 years or older in age 4) they had an
adequate baseline bone marrow reserve (white blood cell count
≥4,000/mm3, hemoglobin level≥10 g/dl, platelets≥100,000/
mm3), adequate hepatic function (a level of transaminases≤2.5
times the normal values) and adequate renal function (defined
as a serum creatinine concentration≤1.5 mg/dl and a blood
urea nitrogen level≤50 mg/dl) and 5) they had a Eastern
Cooperative Oncology Group (ECOG) PS of 0, 1 or 2.
2) Treatment schedule
Gemcitabine (G) was diluted in normal saline and it was
2
administrated at 1,000 mg/m on day 1 and day 8 every 3 weeks.
Cisplatin was added at 60 mg/m2 on day 1 every 3 weeks to
the gemcitabine schedule (GP). The WHO toxicity criteria were
used in this study and we recorded the incidence of grade III∼
IV toxicity.
3) Pretreatment and follow-up studies
Imaging studies were done by performing abdominal
computed tomography scans (CT), and this documented the
patients' measurable disease before treatment. Obtaining the
medical history, physical examinations, complete blood cell
counts, a serum chemistry panel and chest X-rays were carried
out before each cycle of therapy. Abdominal CT was carried
out each 3 cycles of chemotherapy.
4) Response evaluation
The responses to chemotherapy were graded according to the
RECIST criteria (11). A complete response (CR) was defined
as disappearance of all measurable lesions, no new lesions and
normalization of the tumor markers for at least 4 weeks. A
partial response (PR) was defined as a 30% decrease in the sum
of the longest diameter of the measurable lesions from baseline,
non-progressive disease in the non-targeted lesions and no
lesions. Progressive disease (PD) was defined as a 20% increase in the sum of the longest diameter of the measurable
lesions or the appearance of new lesions. Stable disease (SD)
was defined as small changes that do not meet the above
criteria. The dose intensity (mg/m2/week) was calculated as the
total cumulative dose divided by the duration of treatment. The
relative dose-intensity (RDI) was calculated by dividing the
dose-intensity by the planned dose-intensity, and this was
expressed as a percentage. The planned dose-intensities, expressed as mg/m2/week, were 667 for gemcitabine and 20 for
cisplatin.
5) Statistical methods
All analyses were performed with the use of SPSS software
(version 12.0, Chicago-IL). The differences in the clinical
characteristics between the two groups for the OR rates were
analyzed by a chi-square test. Statistical analysis was performed
by the log-rank test to compare differences in progression free
survival (PFS) and OS between the two groups. Survival curves
were constructed by using the Kaplan-Meier method.
RESULTS
1) Patient characteristics and the disease status
Sixty patients were enrolled in this study. The patients'
characteristics and disease status are listed in Table 1. Thirty
four patients received gemcitabine (G) and 26 patients received
gemcitabine combined with cisplatin (GP). The locally advanced
disease and metastatic disease percentages were 35% and 65%
in group G, and 46% and 54% in group GP. Twenty patients
were male (58%), and 14 patients were female (42%) in group
G, and 16 patients were male (61%) and 10 patients were
female (39%) in group GP. Ten patients in group G (29%) and
5 patients in group GP (19%) had undergone a previous
palliative operation. Twenty six patients in group G (76%) and
18 patients in group GP (69%) showed a recorded rise of their
Table 1. Patient characteristics
G* (%)
34
No. of patients
20：14
61
12：22
31
10
26
Male：Female
Median age (range) years
Locally advanced：Metastatic disease
Performance status (ECOG‡) 0/1
Palliative operation history
CA19-9＞normal limit
*gemcitabine single,
†
gemcitabine＋cisplatin,
‡
(58：42)
(39∼75)
(35：65)
(91)
(29)
(76)
Eastern Cooperative Oncology Group.
GP† (%)
26
16：10
58
12：14
22
5
18
(61：39)
(37∼78)
(46：54)
(84)
(19)
(69)
24 Cancer Res Treat. 2008;40(1)
Table 2. Treatment response
Cycles of chemotherapy
Median chemotherapy
cycles (range)
Response
PR‡
SD§
PD∥
Unevaluable
Table 3. Toxicity profile (WHO toxicities Grades III-IV)
G* (%)
159
4 (2∼11)
6 (17)
13 (39)
15 (44)
0
†
GP (%)
106
4 (1∼11)
3
10
10
3
(11)
(39)
(39)
(11)
‡
Hematologic toxicity (n=265)
Anemia
Leucopenia
Thrombocytopenia
Non-hematologic toxicity§ (n=60)
Nausea/vomiting
Abnormal liver function
Skin eruption
†
G* (%)
GP† (%)
159
0
7 (4.4)
5 (3.1)
34
0
0
0
106
1 (0.9)
8 (7.5)
3 (2.8)
26
1 (3.8)
1 (3.8)
1 (3.8)
‡
per cycle, §per
*gemcitabine single, †gemcitabinecisplatin, ‡partial response, §stable
disease, ∥progressive disease.
*gemcitabine single,
persons.
Fig. 1. Time to progression curve (p=0.2396) (G: gemcitabine, GP:
gemcitabine＋cisplatin).
Fig. 2. Overall survival curve (p=0.4643) (G: gemcitabine, GP:
gemcitabine＋cisplatin).
CA 19-9 level.
cumulative doses were 940 mg/m2 gemcitabine (range: 750∼
11,000) in group G, and 966 mg/m2 gemcitabine (range: 750∼
9,000)- 57 mg/m2 cisplatin (range: 45∼540) in group GP. Dose
reductions were required 8 times each in both groups. The dose
2
intensity for group G was 626 gemcitabine mg/m /week and
2
that for group GP was 644 mg/m gemcitabine/week- 19 mg/m2
cisplatin/week, and the RDI of group G was 94.8% and that
for group GP was gemcitabine 97.5%- cisplatin 95%.
The toxicities observed during the treatment are listed in Table
3. The hematological toxicity profile was similar in both
groups: grade III-IV neutropenia and thrombocytopenia was
observed in 4.4% and 3.1%, respectively, of the patients in
group G and in 7.5% and 2.8%, respectively of the patients in
group GP. But non-hematological toxicities (skin rash, abnormal
liver function test, nausea/vomiting) were observed in 3 patients
of group GP.
2) Treatment, the response and survival
The median follow-up duration was 29 months (range: 7∼64
months). The response rates are showed in Table 2. The median
number of administered cycles in group G and group GP was
4 (range: 1∼11 cycles) and 4 (range: 2∼11 cycles), respectively. The PR rate of group G was 17% and that of group
GP was 11%. The SD rate was 39% in both groups. The PD
rate of group G was 44% and that of group GP was 39% (p=
0.719). The total number of chemotherapy cycles for group G
was 159 and that of group GP was 106 (p=0.410).
The median PFS was 4.5 months (95% CI: 3.6∼5.4) for
group G and 2.8 months (95% CI: 1.4∼4.2) for group GP. The
median OS was 10.7 months (95% CI: 1.1∼20.3) for group
G and 8.7 months (95% CI: 5.0∼12.4) for group GP. Yet there
was statistical difference in the PFS (p=0.2396) (Fig. 1) and
OS (p=0.4643) between the 2 groups (Fig. 2).
3) Toxicities
Sixty patients received a total of 265 treatment cycles. Thirty
four patients received a total of 159 cycles with gemcitabine
treatment and 26 patients received a total of 106 cycles with
gemcitabine combined with cisplatin treatment. The median
gemcitabine＋cisplatin,
4) Prognostic factor analysis
By log-rank testing, there were no factors that predicted a
longer median PFS, including age, PS, gender, palliative operation, metastasis of disease and an increase of the CA 19-9 level
(Table 4). By the same testing, no factors predicted a longer
OS (Table 5).
Jae-Hyuk Choi, et al：G versus GP Treatment in Pancreatic Cancer 25
Table 4. Prognostic factors of progression free survival (months)
G*
Gender
Male
Female
Age
≥60
＜60
Performance status
≤1
2
Disease status
Distant metastasis
Locally advanced
Palliative operation
(−)
(＋)
CA19-9
＞normal
≤normal
*gemcitabine single,
†
GP
Table 5. Prognostic factors of overall survival (months)
p value
4.5
3.9
2.6
4.1
0.5579
0.4580
4.5
4.5
2.3
3.2
0.1487
0.9529
4.8
4.5
2.8
2.3
0.3345
0.5427
4.5
3.9
4.4
2.3
0.4931
0.3820
4.5
3.3
2.6
5.8
0.0628
0.3665
4.5
4.5
2.6
2.8
0.3948
0.3325
†
gemcitabine＋cisplatin.
DISCUSSION
Gemcitabine is currently considered by most oncologists as
the standard treatment for patients with advanced pancreatic
carcinoma, and this is based on the results obtained in phase
II-III trials, These trials reported a clinical, beneficial response
in 23∼40% of the patients, a major OR rate ranging from 5.4%
to 16.6%, disease stabilization in 19∼40% of the patients, and
a median OS ranging from 3.9 months to 6.3 months (12).
To improve the clinical results of gemcitabine for treating
advanced pancreatic carcinoma, some recent phase II-III trials
have evaluated the efficacy of combinations of gemcitabine
with other drugs such as 5-FU, cisplatin, topoisomerase I inhibitors etc., and these drugs have been shown to be synergistic
in vitro (13). Some trials demonstrated that gemcitabine-based
combination chemotherapy improved the response rate, the PFS
and the median OS compared with gemcitabine alone. On
comparing gemcitabine plus erlotinib with gemcitabine plus
placebo, the one-year survival and progression-free survival
were significantly longer for the patients who were administered erlotinib plus gemcitabine (14). In patients with a good
PS, gemcitabine-doublelets may be the new standard treatment.
On comparing gemcitabine with gemcitabine plus capecitabine,
the patients with good a KPS (score of 90 to 100) showed a
significant prolongation of their median OS duration in the
gemcitabine plus capecitabine group compared with the patients
in the gemcitabine group (15). Yet there have not been enough
phase III studies, so a single agent is now considered as the
standard treatment for patients with advanced pancreatic cancer.
In our study, gemcitabine single treatment was more tolerable
and it had the same efficacy as compared with gemcitabine and
cisplatin combination treatment: there were no significant differences in the PFS and OS. None of the predictive factors
Gender
Male
Female
Age
≥60
＜60
Performance status
≤1
2
Disease status
Distant metastasis
Locally advanced
Palliative operation
(−)
(＋)
CA 19-9
＞normal
≤normal
*gemcitabine single,
G*
GP†
p value
9.3
17.4
6.9
28.4
0.2177
0.1182
9.1
10.7
7.6
8.7
0.5906
0.4532
9.3
20.6
7.6
9.7
0.9967
0.2485
17.4
10.7
9.9
7.6
0.1508
0.6849
10.6
39.2
9.9
6.9
0.8272
0.2324
9.1
10.7
8.7
6.9
0.9655
0.0986
†
gemcitabine＋cisplatin.
favored combination therapy. The hematological toxicity profile
was similar for both groups, but the non-hematological
toxicities were higher for the GP group for nausea/vomiting,
abnormal LFT and skin eruption. The results presented here
show that the GP group seems to experience more toxicity than
the G group.
CONCLUSION
The gemcitabine plus cisplatin combination had no significant
survival benefit and had toxicities that of gemcitabine alone in
patients with locally advanced or metastatic pancreatic cancer.
Our study had limitations as a retrospective analysis of
treatment, the stratification of both groups, the small sample
size (the required number of patients was ＞500), and the short
duration of the survival gain (2 wks∼2 mos). Therefore, well
designed prospective, large scale studies that will focus on
gemcitabine versus gemcitabine combination treatment are
needed in the future.
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