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Japanese Journal of Clinical Oncology Advance Access published online on October 8, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn098
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© The Author (2008). Published by Oxford University Press. All rights reserved

Prognostic Factors in Japanese Patients with Advanced Pancreatic Cancer Treated with Single-agent Gemcitabine as First-line Therapy

Tsutomu Tanaka1, Masafumi Ikeda1,2, Takuji Okusaka1, Hideki Ueno1, Chigusa Morizane1, Atsushi Hagihara1, Satoru Iwasa1 and Yasushi Kojima1

1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
2 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan

For reprints and all correspondence: Masafumi Ikeda, Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: masikeda{at}east.ncc.go.jp

Received July 2, 2008; accepted August 24, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: The purpose of the retrospective analysis is to elucidate the treatment efficacy and toxicity as well as to identify prognostic factors in Japanese patients with advanced pancreatic cancer treated with gemcitabine.

Methods: Two hundred and sixty-four patients with pathologically confirmed locally advanced or metastatic pancreatic cancer, who had received gemcitabine monotherapy as first-line chemotherapy for pancreatic cancer, were analyzed. A dose of 1000 mg/m2 gemcitabine was administered intravenously for 30 min on Days 1, 8 and 15 of a 28-day cycle.

Results: One patient achieved a complete response (0.3%) and 27 patients showed a partial response (10.2%), with an overall response rate of 10.6% (95% confidence interval: 6.9–14.3%). The main grade 3/4 toxicities were neutropenia in 94 patients (35.6%) and leukocytopenia in 52 patients (19.7%). The median survival time, 1-year survival proportion and median progression-free survival time were 6.8 months, 21.6% and 3.7 months, respectively. A multivariate analysis using the Cox proportional hazards model demonstrated that a Karnofsky performance status ≥90 (P = 0.01), Stage III (P = 0.01), serum carbohydrate antigen 19-9 level <10 000 U/ml (P = 0.02), serum hemoglobin level ≥10 g/dl (P = 0.01) and serum C-reactive protein level <5.0 mg/dl (P < 0.01) were the independent favorable prognostic factors.

Conclusions: The treatment efficacy, toxicity and prognostic factors of single-agent gemcitabine in Japanese patients with advanced pancreatic cancer are comparable to those that have been reported in Western patients. These results may be useful as reference data in determining treatments strategies and planning for further clinical trials in Japanese patients with advanced pancreatic cancer.

Key Words: pancreatic cancer • gemcitabine • prognostic factor • survival


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
The prognosis for pancreatic cancer remains extremely dismal with an overall 5-year survival proportion of less than 6% (1). It causes around 22 000 deaths per year and is the fifth cause of cancer-related deaths in Japan. The nonspecific nature of its early symptoms results in delayed diagnosis, so that 80% or more of patients initially diagnosed have locally advanced or metastatic disease that is no longer treatable by surgical resection (2). Therefore, effective chemotherapeutic agents are needed to improve the prognosis of pancreatic cancer. A landmark study suggesting that single-agent gemcitabine was superior to 5-fluorouracil in improving survival proportion has been reported by Burris et al. (3). Since then, to improve treatment efficacy, many clinical trials of combination treatments with gemcitabine have been conducted in patients with advanced pancreatic cancer. Of these combinations, gemcitabine plus erlotinib showed prolonged survival in comparison with single-agent gemcitabine for the treatment of this disease (4). However, the difference in the median overall survival between the two regimens was 0.3 months, which may be disregarded clinically. In addition, the incidence of adverse events with gemcitabine plus erlotinib tended to of higher frequencies. Therefore, single-agent gemcitabine is regarded as a standard treatment for advanced pancreatic cancer even now.

In Western countries, there have been many prospective studies on advanced pancreatic cancer treated with single-agent gemcitabine (3–12), the results of which could reliably be used to assess treatment efficacy and toxicity because of the large number of the study populations. On the contrary, in Japan, there has been only one prospective study, which was a phase I trial with 11 patients; the population was too small to assess the results accurately in patients with advanced pancreatic cancer treated with single-agent gemcitabine (13). Furthermore, the treatment efficacy and toxicity of gemcitabine have not been fully evaluated even with retrospective studies in Japan. In addition, in the West, the prognostic factors based on the large population numbers for patients with advanced pancreatic cancer treated with gemcitabine (14,15) have been investigated, but in Japan, no such studies exist. Though we previously reported the prognostic factors in 103 patients with advanced pancreatic cancer (16), the chemotherapeutic regimen was varied among patients and only eight patients were in fact treated with gemcitabine monotherapy. Therefore, in the current analysis, we re-evaluated the prognostic factors based on the large population numbers for patients with advanced pancreatic cancer treated with gemcitabine monotherapy. The analysis of prognostic factors is useful in determining the treatment strategies and planning further clinical trials. The objectives of this current retrospective analysis were to elucidate treatment efficacy and toxicity as well as to identify prognostic factors for advanced pancreatic cancer in Japanese patients treated with single-agent gemcitabine.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Patients
The study subjects consisted of 268 patients with locally advanced or metastatic pancreatic cancer who received single-agent gemcitabine from August, 1998 to March, 2006 at the National Cancer Center Hospital, with no previous chemotherapy for pancreatic cancer. Four patients were excluded from this analysis because of insufficient follow-up records and a total of 264 patients were thus analyzed to elucidate the treatment efficacy and the toxicity of gemcitabine monotherapy, and to identify the prognostic factors in Japanese patients with advanced pancreatic cancer. Overlapping of subjects occurred only in the eight study subjects from our previous report who underwent gemcitabine monotherapy (16).

A pathological confirmation was obtained in all patients by surgical procedure, fine-needle aspiration biopsy or cytological examination. To assess the extent of the disease, imaging modalities such as chest X-ray, abdominal ultrasound and computed tomography (CT) were performed. If necessary, further imaging modalities such as magnetic resonance imaging (MRI) and bone scintigraphy were added. Tumors that extended to the celiac trunk/the superior mesenteric artery, or tumors that occluded the bilateral superior mesenteric-portal venous confluence were regarded as unresectable. The stage of each tumor was judged according to the TNM classification system by the International Union Against Cancer (UICC) 6th edition. Biliary obstruction was controlled before treatment in all patients, by percutaneous transhepatic or endoscopic retrograde biliary drainage or palliative surgical procedures.

Treatment
A dose of 1000 mg/m2 gemcitabine was administered intravenously for 30 min on Days 1, 8 and 15 of a 28-day cycle until disease progression, unacceptable toxicity or patient refusal occurred. In principal, the treatment was suspended to allow recovery from the following toxicities: leukocyte count <2000/mm3, platelet count <70 000/mm3 or grade 3/4 non-hematologic toxicity.

Assessment of Efficacy and Toxicity
All patients underwent physical examination and assessment of toxicity at least once every 1 or 2 weeks until the completion of gemcitabine treatment. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. The antitumor effect of the gemcitabine on the tumor was evaluated by CT/MRI repeated every 4–8 weeks after treatment. Tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) (17). For this analysis, the tumor response was reviewed, and the best overall response was recorded, for each patient.

Factors Analyzed
The various factors were chosen on the basis of previously published reports or our own clinical experience (16). The following variables were divided into two subgroups at the clinically meaningful value: age (<60 or ≥60 years), gender (male or female), prior pancreactomy (present or absent), Karnofsky performance status (70, 80 or 90, 100), location of primary tumor (head or body–tail), locally advanced or metastatic disease (Stage III or IV), serum hemoglobin level (<10 or ≥10 g/dl), serum total bilirubin level (<2.0 or ≥2.0 mg/dl), serum C-reactive protein (CRP) level (<5.0 or ≥5.0 mg/dl), serum carcinoembryonic antigen (CEA) level (<10 or ≥10 ng/ml) and serum carbohydrate antigen 19-9 (CA19-9) level (<10 000 or ≥10 000 U/ml).

Statistical Analysis
Progression-free survival was calculated as the time interval from the first day of treatment to the date of disease progression. If no disease progression was observed, progression-free survival was calculated from the first day of treatment to the last day of the follow-up period or the date of death. Overall survival was calculated as the time interval from the first day of treatment to the date of death or to the last day of the follow-up period. In the univariate analysis, cumulative survival proportions were calculated with the Kaplan–Meier method and any differences were evaluated with the log-rank test. Only variables that achieved statistical significance in the univariate analysis were subsequently evaluated in the multivariate analysis using the Cox's proportional hazards regression model. A P value of less than 0.05 was considered statistically significant and all tests were two-sided. All statistical analyses were performed using the SPSS statistical software program package (SPSS version 11.0 for windows).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Patient Characteristics
Patient characteristics are shown in Table 1. The Karnofsky performance status was 100 in 89 patients (33%), 90 in 129 patients (49%), 80 in 35 patients (13%) and 70 in 11 patients (5%). The performance status was 0–1 in 259 patients (98%) and two in five patients (2%). Two hundred and forty-one patients (91%) were diagnosed as having metastatic pancreatic cancer and 23 patients (9%) had locally advanced pancreatic cancer. The histological diagnosis was adenocarcinoma in 261 patients, adenosquamous carcinoma in two patients and anaplastic carcinoma in one patient. The median number of cycles administered on gemcitabine monotherapy was 2.7 (range: 0–34.7). Fifty-five patients (21%) received second-line chemotherapy, such as S-1 monotherapy (28 patients) and 5-fluorouracil combined with cisplatin (11 patients) or concurrent radiotherapy with 5-fluorouracil (six patients).


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  		Table 1. Patient characteristics

 
Efficacy
Of 264 patients, 243 patients were evaluable for tumor response. One patient achieved a complete response (0.3%) and 27 patients had a partial response (10.2%), with an overall response rate of 10.6% (95% confidence interval: 6.9–14.3%). One hundred and twenty-four patients (47.1%) and 91 patients (34.3%) showed stable disease and progressive disease, respectively. At the time of analysis, 235 patients had died of cancer-related causes. The median survival time, the 1-year survival proportion and median progression-free survival time for all patients were 6.8 months, 21.6% and 3.7 months, respectively. (Fig. 1).


Figure 1
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  		Figure 1. Overall survival and progression-free survival in patients with pancreatic cancer treated with single-agent gemcitabine. Tick marks indicate censored cases.

 
Toxicity
The worst hematological and non-hematological toxicities during entire treatment are summarized in Table 2. With regard to Grade 3/4 hematological toxicities, neutropenia was observed in 94 patients (35.6%), leukocytopenia in 52 patients (19.7%), anemia in 27 patients (10.2%) and thrombocytopenia in 20 patients (7.6%). In the main grade 3/4 non-hematological toxicities, an elevated alkaline phosphatase level was observed in 22 patients (8.3%), and other adverse events occurred in less than 5%. Interstitial pneumonia was observed in three patients (1.1%), but in all of them recovery was achieved with medical treatment such as administration of corticosteroid hormones. Cerebral infarction with incomplete paralysis was observed in two patients (0.8%). There were no other life-threatening toxicities and no treatment-related deaths.


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  		Table 2. Toxicity

 
Prognostic Factor
Table 3 lists the results of univariate analyses of the factors considered to be prognostic for survival. Six factors closely associated with longer survival were as follows: Karnofsky performance status 90, 100 (P = 0.01), stage III (P < 0.01), serum hemoglobin level ≥10 g/dl (P = 0.01), serum CRP level <5.0 mg/dl (P < 0.01), serum CEA level <10 ng/ml (P < 0.01) and serum CA19-9 level <10 000 U/ml (P < 0.01). The multivariate analysis of the independent favorable prognostic factors for survival was as follows (Table 4): Karnofsky performance status 90, 100 (P = 0.01), stage III (P = 0.01), serum CA19-9 level <10 000 U/ml (P = 0.02), serum hemoglobin level ≥10 g/dl (P = 0.01) and serum CRP level <5.0 mg/dl (P < 0.01).


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  		Table 3. Univariate analysis of prognostic factors

 

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  		Table 4. Multivariate analysis of prognostic factors

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
At present, gemcitabine monotherapy has a consensus as first-line therapy for advanced pancreatic cancer world wide. However, reliable data regarding gemcitabine monotherapy for advanced pancreatic cancer in a large number of Japanese patients are lacking because of the lack of prospective studies of gemcitabine except for one trial (13), and no retrospective analysis exists based on a large population of patients with pancreatic cancer. This is the first study that comprises a large number of consecutive Japanese patients with pathological disease confirmation, and in which a unified method for tumor staging and identical procedures for treatment and supportive care were undertaken throughout its the duration, in a single institution.

In Western countries, there have been several randomized controlled trials, including the treatment results of gemcitabine monotherapy (3–12). These studies demonstrated that gemcitabine monotherapy for advanced pancreatic cancer yielded response rates ranging from 4.4 to 17.3% and median overall survival ranging from 5.4 to 7.2 months (Table 5). Comparing these studies with the current study, the baseline patient characteristics such as the rate of performance status and the TNM stage were almost similar. These results of the response rate (10.6%), progression-free survival (median: 3.7 months) and overall survival (median: 6.8 months) in the current study were also similar to those in the Western studies cited. Additionally, adverse events, especially grade 3/4 neutropenia and thrombocytopenia in this study were also equivalent to those cited studies. To sum up, the treatment efficacy and toxicity of gemcitabine monotherapy in Japanese patients with advanced pancreatic cancer is comparable to those that have been reported in the Western literature.


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  		Table 5. A summary of the treatment results of gemcitabine monotherapy for advanced pancreatic cancer

 
The multivariate analysis indicated the following five independent prognostic factors in patients with advanced pancreatic cancer treated with gemcitabine: Karnofsky performance status, TNM stage, serum CA19-9 level, serum CRP level and serum hemoglobin level. Karnofsky performance status (14), TNM stage (14) and serum CA19-9 level (15,16) have been widely recognized as important prognostic factors in patients with advanced pancreatic cancer. Serum CRP level and serum hemoglobin level have also been well recognized as prognostic factors in pancreatic cancer (16,18,19) or other cancers such as stomach, breast, and head and neck (20–22). The kinetics of an elevation in serum CRP level and a decrease in serum hemoglobin level are considered to be tumor-induced activation of the immune and inflammatory systems, which release cytokines including interleukin-6 and tumor necrosis factor alpha (23,24). The activation links to cancer cachexia, characterized by a malnutrition and an accelated starvation state, and results in shorter survival (25). These five prognostic factors in Japanese patients with advanced pancreatic cancer are also similar to those that have been reported in Western patients.

Nowadays, promising regimens superior to gemcitabine monotherapy for advanced pancreatic cancer are being reported. In Western countries, the combination of gemcitabine and erlotinib resulted in a longer survival period compared with gemcitabine monotherapy, although the difference in the median overall survival was trivial (4). In addition, the combination of gemcitabine and axitinib, a selective oral inhibitor of vascular endothelial growth factor receptors, is also a promising strategy (26). On the other hand, in Japan, S-1 monotherapy and the combination of gemcitabine and S-1 have been reported as having a favorable response rate and increased overall survival in patients with advanced pancreatic cancer (27,28). One of these regimens may demonstrate an adequately superior survival time compared with gemcitabine monotherapy in future clinical trials.

In conclusion, this study could confirm the reproducibility of treatment efficacy, toxicity and prognostic factors of single-agent gemcitabine in Japanese patients in comparison with the results in Western patients. These results could be useful as reference data in determining treatment strategies and planning further clinical trials in Japanese patients with advanced pancreatic cancer.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
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