Japanese Journal of Clinical Oncology 32:90-94 (2002)
© 2002 Foundation for Promotion of Cancer Research
A Phase II Study of Doxifluridine in Elderly Patients with Advanced Gastric Cancer: The Japan Clinical Oncology Group Study (JCOG 9410)
1Department of Internal Medicine, Mitoyo General Hospital, Mitoyo-gun, Kagawa, 2Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 3Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, 4Department of Internal Medicine, Tonan Hospital, Sapporo, 5Department of Internal Medicine, Yamagata Prefectural Hospital, Yamagata, 6Department of Internal Medicine, Kitasato University East Hospital, Sagamihara, Kanagawa, 7Department of Internal Medicine, National Nagoya Hospital, Nagoya and 8JCOG Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: A previous phase II study of doxifluridine in non-elderly patients with advanced gastric cancer demonstrated a favorable survival with mild toxicity, despite a low response rate. The objectives of this study were to evaluate efficacy and feasibility of this agent for elderly patients.
Methods: This study protocol required elderly patients, aged 76–80 years, with advanced gastric cancer and having no prior chemotherapy. Doxifluridine, at a dose of 1400 mg/m2/day, was administered for four consecutive days followed by a 10-day rest.
Results: Between October 1994 and March 1998, 18 patients were registered. The study was then closed because of poor accrual. Toxicity was moderate; three patients suffered from grade 3 anemia and one patient each had grade 3 thrombocytopenia, nausea/vomiting and grade 4 diarrhea. There was one partial response, seven with no change and 10 with progressive disease, yielding a response rate of 5.6%. The median progression-free survival and median survival time for the 18 patients were 55 and 164 days, respectively, with a 1-year survival rate of 5.6%.
Conclusions: Although the number of patients was too small to draw any definitive conclusions, this study failed to demonstrate the survival advantage of doxifluridine.
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INTRODUCTION |
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Chemotherapy for advanced gastric cancer appears to have a palliative impact. There have been three small studies comparing the outcomes of combination chemotherapy with those of best supportive care (1–3). In each study, survival was moderately, but significantly, prolonged for the group receiving chemotherapy. However, these studies were conducted in patients aged 75 years or younger and the impact of chemotherapy for elderly patients (over 75 years) has not been elucidated.
Doxifluridine is an oral fluoropyrimidine derivative that is converted to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). Since this enzyme has higher activity in tumors than in normal tissues, the concentration of 5-FU in tumor tissues is considered to be higher than in normal tissue (4,5). Doxifluridine is commercially available in Japan and its registration-directed phase II trial for Japanese non-elderly patients with advanced gastric cancer revealed preferable survival with a median survival time of 371 days and mild toxicity, despite a low response rate of 12% (20/161 patients) (6). We assumed that the efficacy/safety balance of this agent would be more beneficial for elderly patients.
Based on this background, the Japan Clinical Oncology Group (JCOG) (7) conducted a phase II study of elderly patients with advanced gastric cancer. Regarding dose and schedule of doxifluridine, there had been published a randomized phase II study comparing a continuous schedule of 800 mg/m2/day with an intermittent schedule of 1400 mg/m2/day for four consecutive days followed by a 3-day rest (8). This study demonstrated a lower incidence of gastrointestinal toxicities such as nausea/vomiting and diarrhea in the intermittent group than in the continuous group, while the response results were almost equivalent between the two groups. We then selected the intermittent schedule with a reduction of dose intensity, 1400 mg/m2/day for 4 days followed by a 10-day rest, since the target population of this study was elderly patients. This dose and schedule were the same as those used in our previous study in combination with cisplatin (9), which resulted in favorable response and survival.
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PATIENTS AND METHODS |
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Patient Eligibility
In the present study, all patients had to have histologically proven unresectable or recurrent gastric cancer with measurable or evaluable lesions and had to be between 76 and 80 years old. No prior chemotherapy was allowed. Patients were required to have an ECOG performance status of 2 or better and to have adequate bone marrow (WBC
4000/µl, platelets 100 000/µl), liver (AST and ALT within three times the upper limit, thus excluding patients with liver metastasis; bilirubin 
2.0 mg/dl) and renal function (serum BUN 25 mg/dl; creatinine 1.5 mg/dl). A life expectancy of 8 weeks or longer and oral or written informed consent were also required. Patients with serious complications including massive ascites or pleural effusion were excluded from the study. The study protocol was approved by the Japan Clinical Oncology Group (JCOG) Clinical Trial Review Committee.
Administration Schedule
Doxifluridine at a dose of 1400 mg/m2/day was administered orally three times per day after meals for four consecutive days followed by a 10-day rest. Administration was continued until disease progression or patient refusal. When an adverse event of grade 2–4 diarrhea or grade 3–4 leukocytopenia occurred, administration was suspended until recovery and the following dose of doxifluridine was reduced to 1000 mg/m2/day. The administration was terminated if the recovery from the above adverse events required 6 weeks from the suspension of the agent. No other anti-cancer drugs or biological response modifiers were allowed during the protocol treatment.
Evaluation of Response and Toxicity
Pretreatment evaluation of the disease was done by gastroscopy, barium gastrography, abdominal CT scan and chest X-ray. To evaluate an objective tumor response, the response criteria of the Japanese Research Society for Gastric Cancer (10) were adopted. Briefly, a complete response (CR) was defined as the complete disappearance of all measurable and evaluable lesions for a minimum of 4 weeks. A partial response (PR) was defined as a 50% reduction in the sum of the products of the longest diameter of measurable lesions for a minimum of 4 weeks. No change (NC) was defined as the failure to observe a partial or complete response and progressive disease for at least 4 weeks. Progressive disease (PD) was defined as one with a 25% increase in the sum of the products of the longest perpendicular diameters of measurable lesions or the appearance of new lesions. The response for primary tumors was assessed by the same Japanese criteria based on roentgenographic and endoscopic findings. Evaluation of the response was repeated every 6–8 weeks. These response evaluations were confirmed in the extramural review. Adverse events were evaluated according to the toxicity criteria of the JCOG (11), which were modified from the National Cancer Institute Common Toxicity Criteria. Evaluation of adverse reactions, including blood analyses, were monitored every 2 weeks.
Study Design
The primary endpoint of this study was objective tumor response. In this study, Simon’s optimal two-stage design was used to determine the sample size and the decision criteria (12). The required sample size was calculated based on the assumption of an expected response rate of 15% and a minimum response rate of 5% with alpha and beta errors of 0.1, which resulted in 66 in total and 28 in the first stage. When there would be no responder in the initial 28 patients, the study would be closed. The secondary endpoints of this study were overall survival and progression-free survival. Overall survival was calculated from the date of registration to the date of last follow-up or death. Progression-free survival was measured from the date of registration to the date when disease progression was confirmed or the date when death occurred. Overall and progression-free survival were estimated using the Kaplan–Meier method.
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RESULTS |
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Patients’ Characteristics
Between October 1994 and March 1998, 18 patients were enrolled in the study. Because of poor accrual, the study was terminated early before completion of planned one-stage accrual and finally analyzed at March 2000 with an updated survival follow-up. All 18 registered patients were eligible and their characteristics are shown in Table 1. Their median age was 77 years and most patients had good performance status of 0 or 1. Seven and 11 patients had histological diagnosis of intestinal and diffuse types of cancer, respectively and three patients had a history of prior gastrectomy. The major metastatic sites were abdominal (para-aortic) lymph nodes in 13 patients and the liver in seven patients. The median number of courses of drug administration was four, ranging from one to 16. Reasons for discontinuing treatment consisted of disease progression in 17 patients and patient’s refusal not associated with toxicity in one patient.
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Adverse Events
Adverse events are listed in Table 2. Grade 3 or 4 non-hematological adverse events occurred in four (22%) patients, although grade 3 or 4 liver dysfunction that developed in two of the four patients seemed to be caused by tumor progression. One patient had grade 3 fever of unknown cause and the remaining one patient was associated with grade 3 nausea/vomiting, hyponatremia and grade 4 diarrhea, which were considered to be treatment-related. Grade 3 thrombocytopenia and anemia were also observed in one and three patients, respectively. Three patients died within 30 days from the last administration date; all of them were caused by tumor progression.
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Response and Survival
Of the 18 patients, an objective response was observed in only one patient, giving a response rate of 5.6% (95% confidence interval 0.1–27.3%). There were seven NCs and 10 PDs. The patient achieving PR was a 77-year-old woman with a primary lesion and liver metastases. She achieved an objective response in the liver metastasis after two courses of treatment. This treatment continued up to 12 courses of treatment, giving a response duration of 168 days. All patients had already died at final analysis. The median survival time of all patients was 164 days, with a 1-year survival rate of 5.6% (Fig. 1), and the median progression-free survival was 55 days (Fig. 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Because of the poor accrual, this study failed to obtain a sufficient number of patients to draw any conclusions. Although an investigation of predictive patient accrual in all participating institutions revealed a sufficient number of patients, the number of actually registered patients was less than one-third that expected. Since this study was the first one of elderly patients in our group, we failed to estimate an adequate number of patients. The poor accrual might have been caused by overestimation of patient numbers, low rate of eligible patients in the elderly population or less interest in or toxicity of the agent used, and it is difficult to specify the main cause among these. Regarding the low rate of eligible patients in the elderly population, Sasaki et al. reported that only a small population of elderly patients could fulfil the eligibility criteria of the usual clinical studies for non-elderly patients (13). Thus, the eligibility criteria of this study might have been too strict to recruit elderly patients. Whatever the main cause was, this study could not provide any definitive conclusions because of the failure to recruit sufficient patients.
The previous industrial phase II study of this agent resulted in a median survival time of 371 days in 140 patients with advanced gastric cancer despite a low response rate of 14% (6,14). This result appeared to be superior to those from various phase II studies, which usually resulted in a median survival of 6–10 months. Some investigators have reported that the anti-cachectic effects of this agent might cause this longer survival time (14,15). Based on in vivo studies, the mechanism of action of this agent might be explained as follows: various cytokines such as interleukins-1 and -6, tumor necrotizing factor and interferon induce general cachexia and high PyNPase activity in cancer cells, which suggest a high susceptibility to doxifluridine in patients with cachexia (15,16). Additionally, there were no significant differences in survival between patients aged 70 years and those younger than 70 years in the previous phase II study (15). Based on these backgrounds, we conducted the present study for elderly patients.
The present study demonstrated a low response rate of 5.6% (1/18) and a short median survival time of 164 days associated with a high PD rate and a short progression-free survival. The low response rate in this study is comparable to the findings of the previous study (6). However, the present study did not provide the favorable survival seen in the previous study. The different populations and different administration schedules between the previous and the present study might have caused this poor outcome. With respect to different population by age, although no prospective studies indicating treatment results for elderly patients with advanced gastric cancer have been published, some reports have suggested that there are no significant differences in treatment results between patients aged <70 and >70 years for various cancers (17–19). However, compared with many of the phase II and III studies in non-elderly patients with advanced gastric cancer, the present results do not seem to demonstrate any benefits in terms of survival. Regarding administration dose and schedule, we adopted an intermittent schedule as described in the Introduction. The dose intensity of this schedule was calculated to be 400 mg/m2/day (~600 mg/day), which was considerably lower than the continuous schedule in the previous study (6), mostly ranging from 800 to 1200 mg/day. This lower dose intensity might have caused shorter progression-free and overall survival in this study. However, incidences of gastrointestinal toxicities, such as nausea/vomiting and diarrhea, appeared to be moderate and it seemed to be difficult to increase the dose intensity of this agent at least for elderly patients.
Although we cannot draw conclusions as to whether doxifluridine as a monotherapy has any advantages, particularly with respect to response and survival, because of the failure to recruit sufficient patients, this small study in elderly patients with advanced gastric cancer did not demonstrate any favorable effects on survival as shown in the previous phase II study of non-elderly patients.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported by Grants-in-Aid (5S-1, 8S-1, 11S-3, 11S-4) from the Ministry of Health, Labor and Welfare, Japan. The authors thank Miyuki Niimi and Seiichiro Yamamoto (JCOG Data Center) for data management and helpful comments. The participating investigators and institutions were as follows: Dr Tetsuri Imamura, Sapporo Kosei Hospital, Sapporo; Dr Hiroshi Sasagawa, Rumoi Municipal Hospital, Rumoi; Dr Yasushi Tsuji, Tonan Hospital, Sapporo; Dr Hiroshi Saito, Yamagata Prefectural Hospital, Yamagata; Dr Atsushi Ohtsu, National Cancer Center Hospital East, Kashiwa; Dr Yasuhiro Shimada, National Cancer Center Hospital, Tokyo; Dr Wasaburo Koizumi, Kitasato University East Hospital, Sagamihara; Dr Hiroaki Iwase, National Nagoya Hospital, Nagoya; Dr Kazuo Hayakawa, Meitetsu Hospital, Nagoya; Dr Nobumasa Ikeda, Mitoyo General Hospital, Kagawa; and Dr Ichinosuke Hyodo, National Shikoku Cancer Center, Matsuyama.
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FOOTNOTES |
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+ For reprints and all correspondence: Atsushi Ohtsu, Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, 6–5–1, Kashiwanoha, Kashiwa 277-8577, Japan. E-mail: aohtsu@east.ncc.go.jp
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received October 12, 2001; accepted December 12, 2001.
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