Japanese Journal of Clinical Oncology Advance Access published online on November 8, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn119
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© The Author (2008). Published by Oxford University Press. All rights reserved
Oral Fluoropyrimidines (Capecitabine or S-1) and Cisplatin as First Line Treatment in Elderly Patients with Advanced Gastric Cancer: A Retrospective Study
1 Division of Hematology-Oncology
2 Division of Gastroenterology, Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
For reprints and all correspondence: Joo Seop Chung, Hematology-oncology Division, Department of Internal Medicine, Pusan National University Hospital, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea. E-mail: hemon{at}pusan.ac.kr
Received August 10, 2008; accepted September 29, 2008
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Abstract |
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Background: This study aimed to evaluate the safety and efficacy of oral fluoropyrimidines and cisplatin therapy in elderly patients with untreated advanced gastric cancer (AGC) retrospectively. In addition, we evaluated the relative activity and toxicity of these agents in this patient population.
Methods: Clinical data from 72 patients with previously untreated AGC, who were treated with capecitabine/cisplatin and S-1/cisplatin, were reviewed. Oral fluoropyrimidines were administered orally twice a day on Days 1–14. The dose of capecitabine was 1250 mg/m2 and that of S-1 was 50 mg [body surface area (BSA) < 1.5 m3] or 60 mg (BSA > 1.5 m3) twice a day. Cisplatin was administered intravenously on Day 1 (before the first dose of capecitabine or S-1) at a dose of 70 mg/m2 over a 2 h period. The chemotherapy cycle was of 3 weeks (with oral capecitabine or S-1).
Results: Thirty-two and 40 patients received the S-1 and capecitabine regimens, respectively, and were included in the analysis. The S-1 protocol had a response rate of 40.6%, a median time-to-progression (TTP) of 5.4 months and a median survival of 9.6 months. The capecitabine had a response rate of 55%, a median TTP of 5.9 months and a median survival of 10.2 months. Each protocol had a similar incidence of Grade 3 or 4 adverse events. However, there was a higher rate of the hand–foot syndrome (6 versus 37%) and diarrhea (25 versus 32%) in the capecitabine group.
Conclusion: Oral fluoropyrimidines and cisplatin in elderly patients with untreated AGC showed encouraging results. The treatment was well tolerated with a manageable toxicity profile. The comparison of S-1 with capecitabine showed that capecitabine had a slightly higher response rate (statistically not significant) in addition to a higher rate of adverse events such as the hand–foot syndrome and diarrhea. These data should be warranted with further prospective studies.
Key Words: oral fluoropyrimidines • cisplatin • elderly • advanced gastric cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Worldwide, gastric cancer ranks second in all causes of death from cancer, with
700 000 confirmed deaths annually; the majority of cases occur in the elderly population (seventh and eighth decade of life) (1,2). To date, palliative chemotherapy has been the only reasonable therapeutic option for these patients with recurrent or unresectable advanced gastric cancer (AGC). The median survival for this population has been reported to be 6–9 months (3–6). However, demographic analysis of Phases II and III chemotherapy trials shows that only a minority of treated patients were >65 years of age (7,8). Consequently, there is uncertainly about the type and the extent of systemic palliative chemotherapy that should be offered to elderly patients. Among the agents with known antitumor activity, 5-fluorouracil (5-FU) and cisplatin have been extensively used in the treatment of AGC. Although several new drugs (docetaxel, irinotecan and oxaliplatin) have been tested in the general population during the past decade, the number of responders, progression-free survival and overall survival have not been reported to have markedly improved; with the median survival not exceeding 12 months (9–11). Furthermore, the rate of toxicity secondary to these agents has been shown to be greater in the elderly than in younger patients (12–14).
The recent introduction of two new generation oral fluoropyrimidines, capecitabine and S-1, has been shown to be equivalent (or possibly slightly better) to fluorouracil and can be used safely in elderly patients; their doses can easily be adjusted when toxicity occurs (15–23). Oral fluoropyrimidine-based combination therapy with other promising drugs such as cisplatin, irinotecan and taxanes is expected to yield good results. The combination of oral fluoropyrimidines and cisplatin has shown high efficacy and is expected to be the standard therapy for AGC (24).
On this basis, we investigated the safety and efficacy of combination oral fluoropyrimidines in elderly patients with untreated AGC. In addition, we evaluated the relative activity and toxicity of these agents in this patient population.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients were eligible for this study if they had histologically confirmed AGC, metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction, and the patient was >70-years old. The patients were eligible if they had at least one measurable lesion and no prior chemotherapy except postoperative adjuvant chemotherapy that was received more than 6 months before entry into the study. Other eligibility criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2, adequate organ function and an expected survival of at least 3 months. The exclusion criteria included pre-existing peripheral neuropathy, concurrent or prior malignancy, brain metastasis, or an active infection with concurrent treatment that interfered with the study’s evaluation.
Treatment Schedule
Before chemotherapy, all patients had a complete history and physical examination, a complete blood count, serum chemistries (liver and renal function tests and electrolytes), ECG, chest radiograph, computed tomography (CT) scanning of the abdomen and pelvis, and if indicated, CT scans of the chest and a bone scan. Capecitabine was administered orally at a dose of 1250 mg/m2 twice a day according to the standard intermittent schedule (14 days of treatment followed by a 7-day rest period, every 3 weeks). S-1 was administered orally twice a day according to the standard intermittent schedule (14 days of treatment followed by a 7-day rest period, every 3 weeks). The dosage of S-1 was determined by the patient’s body surface area (BSA); 50 mg twice a day (BSA < 1.5 m3), 60 mg twice a day (BSA >1.5 m3). Cisplatin was administered intravenously on Day 1 (before the first dose of capecitabine or S-1) at a dose of 70 mg/m2 over a 2 h period. Immediately before treatment, all patients received antiemetic therapy with a 5-HT3 antagonist followed by a dopamine antagonist. Cisplatin was allowed for the patients who had an ECOG performance of 0 or 1 and was repeated every 21 days. G-CSF or GM-CSF was administered when the absolute neutrophil count decreased to 500 cells/µl. Treatment was continued until disease progression or unacceptable toxicity, or if the patient chose to discontinue treatment.
Dose Modification for Adverse Events
Toxicity evaluation was carried out before each treatment cycle according to the National Cancer Institute of Canada Common Toxicity Criteria (NCI-CTC) version 3.0.
Oral fluoropyrimidines and cisplatin treatment interruption or dose reduction was not indicated for the first occurrence of Grade 1 toxicity. For hematological toxicity, treatment was interrupted in patients with Grade 3 or 4 events. The next treatment cycle could start only when the patient recovered to Grade 1 or 0 toxicity. The dose of oral fluoropyrimidines and cisplatin was reduced by 25% if the granulocyte nadir in the preceding cycle was <0.5 x 109/l for >7 days and/or there was an associated fever (
38.5°C) or if the thrombocyte nadir in the preceding cycle was <25 x 109/l. If the neutrophil count was <1.5 x 109/l on Day 21, then treatment had to be postponed for 1 week. For non-hematological toxicities, oral fluoropyrimidines and cisplatin doses were reduced by 25% for patients who had their first occurrence of a Grade 3 event or a second occurrence of a specific Grade 3 event. Treatment was permanently discontinued with Grade 4 non-hematological toxicity. For non-hematological toxicities more severe than Grade 2, the oral fluoropyrimidine treatment was interrupted and could not be continued unless the toxicity resolved to Grade 1 or less. For Grade 3 non-hematological toxicities, cisplatin was suspended for a maximum of 3 weeks from the scheduled date of re-infusion until the toxicity resolved. After recovery from Grade 3 toxicity to Grade 2 or less, the dose of cisplatin was reduced by 25% in subsequent cycles. The dose of cisplatin was reduced by 50% in the subsequent cycle if the creatinine clearance, as calculated according to the Cockcroft–Gault formula, was between 40 and 59 ml/min.
Follow-up Studies and Response Evaluation
Physical examination, chest X-rays, complete blood counts and biochemical tests were performed before each chemotherapy cycle. CT scans were performed every two to three cycles until the tumor progressed. Tumor response was classified according to the response evaluation criteria defined by the RECIST guidelines (25). Confirmation of the response was not required for this study; repeat CT scanning after 4 weeks was not practical in the clinical setting.
Statistical Analysis
Time-to-progression (TTP) was defined as the time-to-disease progression. The survival time was defined as the duration from the initiation of chemotherapy until death. Survival curves were calculated according to the Kaplan–Meier method. Data were analyzed with the SPSS Windows 12.0 system.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Characteristics
Between March 2004 and March 2008, 32 patients were assigned to treatment with S-1 and 40 patients were assigned to treatment with capecitabine. There were no significant differences between the two groups with respect to laboratory and clinical features at diagnosis or trial entry (Table 1). About two-thirds were men in both groups and the median age was 73 (range 70–85) and 74 years (range 70–82) in the S-1- and capecitabine-treated groups, respectively. The percentage of patients with 1, 2 or 3 or more organs involved was similar in both groups.
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Chemotherapy
The median follow-up was 18.9 and 19.2 months in the S-1 and capecitabine groups, respectively. The median number of cycles administered was six in each group. The mean number of days of delay in treatment per patient was not significantly different in the two groups (S-1 versus capecitabine, 6.4 versus 6.7 days, respectively; P = 0.436). The percentage of patients undergoing at least one dose reduction in the regimen was similar in both groups (S-1, 22%; capecitabine, 20%).
Objective Tumor Responses and TTP
Among the 72 patients with measurable disease, confirmed responses were recorded in 35 patients, i.e. 48.6% responded. Among the 32 patients assigned to S-1, none of the patients had a complete response and 10 patients had a partial response, i.e. 40.6% of these patients responded. Among the 40 patients assigned to capecitabine treatment, none of the patients had a complete response and 18 had a partial response, i.e. 55% of these patients responded. The difference between the proportions of responders between the two groups was not statistically significant (P = 0.246) (Table 2). The median time-to-disease progression was not significantly different between the two groups (S-1 versus capecitabine, 5.4 versus 5.9 months; P = 0.640; Fig. 1A).
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Overall Survival
The median overall survival was not significantly different between the two groups [S-1 versus capecitabine, 9.6 (IQR 2–31) versus 10.8 months (IQR 2–38); P = 0.343; Fig. 1B]. Survival at 12 months was 41.6% in the patients assigned to S-1 and 47.3% in the patients assigned to capecitabine, and at 24 months it was 7% in the patients assigned to S-1 and 8% in the patients assigned to capecitabine. Events occurred in 27 (84%) of the 32 patients assigned to S-1 and in 33 (82%) of the 40 patients assigned to capecitabine.
Toxicity
We recorded a similar incidence of Grade 3 or 4 adverse events, including leucopenia, neutropenia, anemia, nausea and anorexia in both groups (Table 3). A higher rate of hand–foot syndrome (6 versus 37%) and diarrhea (25 versus 32%) was noted in the capecitabine group. The median relative dose intensity was 92.6% for scheduled cycles of treatment in patients assigned to S-1, and 90.2% in those assigned to capecitabine. Treatment was delayed for at least 1 week in five (15%) of the 32 patients assigned to S-1 and in eight (20%) of the 40 patients assigned to capecitabine. The reasons for the delay of treatment were myelosuppression, nausea, vomiting, anorexia, fatigue and diarrhea.
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The reasons for discontinuation of treatment are shown in Table 4.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Gastric cancer predominantly afflicts elderly patients, and the world’s population is aging (1,2). Older patients have a higher incidence of comorbidity and end-organ dysfunction. The presence of these factors leads to heterogeneity of responses to the effects of chemotherapy toxicity seen clinically. The provision of optimal care for older patients with gastric cancer is a highly relevant issue. However, there has, in general, been an exclusion of the elderly from clinical trials, particularly those involving chemotherapy protocols (26,27). This has led to a paucity of data available for the clinician to make rational treatment decisions for this group of patients.
Treatment with oral fluoropyrimidines appears to offer new hope for elderly patients with gastric cancer. A trial that compared treatment with fluorouracil plus cisplatin with capecitabine plus cisplatin confirmed that the efficacy of capecitabine was equivalent to that of fluorouracil (15). Furthermore, capecitabine at the recommended does of 1250 mg/m2 twice daily, on Days 1–14 every 21 days, was better tolerated than FU administered as per the Mayo Clinic schedule (425 mg/m2 Days 1–5 every 28 days); hand–foot syndrome was more common with the capecitabine therapy and myelosuppression more common with the FU therapy (16–21).
S-1 is a new oral anticancer drug that is composed of tegafur, 5-chloro-2,4 dihydroxypyrimidine and oteracil potassium. This drug was designed to enhance the efficacy of tegafur, a prodrug of fluorouracil. Early Phase II studies have shown encouraging findings with responses ranging from 40 to 50%, a 1-year survival of 30% and a 2-year survival of 15% (21). The findings of the Japan Clinical Oncology Group (JCOG) 9912 trial that compared fluorouracil alone versus irinotecan plus cisplatin versus S-1 alone, suggested that S-1 was no worse than fluorouracil or irinotecan plus cisplatin; these findings led to the use of S-1 monotherapy as the standard chemotherapy regimen for patients with inoperable and recurrent gastric cancer in Japan (23). However, according to a recent study (24,28), the median progression-free and overall survivals were significantly longer with S-1 plus cisplatin than with S-1 monotherapy. Therefore, treatment with combined S-1 plus cisplatin has become the standard of care. Currently, combination chemotherapy is considered to be more effective than single-agent therapy in patients with metastatic gastric cancer. To improve efficacy as well as improve tolerability and patient quality of life, patients received cisplatin plus oral fluoropyrimidines alternatives to i.v. 5-FU in our study. The combination of oral fluoropyrimidines and cisplatin resulted in a response rate of 48.6%. The S-1 resulted in a response rate of 40.6%, a median TTP of 5.4 months and a median survival of 9.6 months. The capecitabine resulted in a response rate of 55%, a median TTP of 5.9 months and a median survival of 10.2 months. These findings of the response rate and toxicity were similar to those reported from the previous studies on oral fluoropyrimidines (S-1) and cisplatin therapy in patients of all ages with metastatic gastric cancer (24). Perhaps due to the combination of cisplatin, the response rate and TTP in our study were slightly superior to a prior study on oral fluoropyrimidines monotherapy in elderly patients with metastatic gastric cancer (29). Therefore, it is important to consider determining when to provide combination regimens to elderly patients with AGC. As such patients represent a heterogeneous population, treatment should be individualized on the basis of the possible risks and benefits expected for each patient.
The safety of oral fluoropyrimidine and cisplatin in the current study was favorable, with only 12% of patients developing Grade 3 and 4 adverse events. The toxicity profile was similar in both groups. However, there was a higher rate of hand–foot syndrome (2 versus 37%) and diarrhea (25 versus 32%) in the capecitabine group. Due to the paucity of events, the determination of prognostic factors for adverse events could not be assessed. However, despite 80% of the patients having comorbid disorders and 29% of the patients being, 80 years of age, we did not detect any higher rate of adverse events in them. There was an approximately 34% incidence of Grade 3–4 GI toxicity observed in both groups, mainly consisting of diarrhea. In practice, when using oral fluoropyrimidines, this side effect might be reduced with the more aggressive use of loperamide at the first sign of diarrhea, with repeated doses every 2 h. The frequency of neutropenia was low, which resulted mainly in uncomplicated episodes of Grade 3–4 diarrhea. In addition, we did not observe any severe hand–foot syndrome in this study that could potentially contribute to increased rates of falling. Based on the results of this study, the combination of oral fluoropyrimidines and cisplatin in elderly patients with untreated AGC showed encouraging results and was well tolerated with a manageable toxicity profile. A comparison between S-1 and capecitabine showed that capecitabine had a slightly higher response rate (statistically not significant), but also had a higher rate of adverse events such as the hand–foot syndrome and diarrhea. Additional studies are needed to identify the potential predictive factors to choose the best oral fluoropyrimidime treatment and to develop more effective treatment strategies based on capecitabine or S-1 in elderly patients with AGC.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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