Japanese Journal of Clinical Oncology Advance Access originally published online on March 24, 2009
Japanese Journal of Clinical Oncology 2009 39(5):332-335; doi:10.1093/jjco/hyp018
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© The Author (2009). Published by Oxford University Press. All rights reserved
Activity of S-1 in Advanced or Recurrent Gastric Cancer Patients after Failure of Prior Chemotherapy, Including Irinotecan + Cisplatin or Fluorouracil (Except S-1)
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
For reprints and all correspondence: Akira Ono, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimnagakubo, Nagaizumi, Sunto-gun, Shizuoka, Japan. E-mail: a.ono{at}scchr.jp
Received February 6, 2009; accepted February 9, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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We retrospectively reviewed to investigate the efficacy and toxicity of monotherapy with S-1 in patients with advanced or recurrent gastric cancer after failure of first-line chemotherapy. Twenty-one patients were evaluated. The median number of treatment cycles was 2 (range 1–19). There were no cases showing either complete or partial response, and 10 patients (47.6%) showed stable disease. The median progression-free survival was 89 days. Sixteen patients (76%) received third-line chemotherapy. The median survival time was 271 days after the initiation of S-1, with a 1-year survival rate of 32%. Hematological toxicities were Grade 4 anemia (9.5%), Grade 3 or 4 neutropenia (9.5%) and leukopenia (4.7%). As for non-hematological toxicities, Grade 3 or 4 diarrhea and anorexia were noted in 9.5% and 14.2% of the patients, respectively. S-1 was found to show no efficacy and cannot be recommended for second-line chemotherapy against gastric cancer.
Key Words: S-1 • gastric cancer • second-line
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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In Japan, several randomized trials have been performed during the last decade. The Japan Clinical Oncology Group (JCOG) conducted a Phase III trial to compare continuous infusion of 5-fluorouracil (5-FUci), 5-FU + cisplatin (CDDP) (FP) and uracil and tegafur (UFT) + mitomycin (UFTM) in patients with advanced gastric cancer (1). Combined chemotherapy with either FP or UFTM yielded no survival benefit when compared with that obtained with 5-Fuci; furthermore, 5-FUci was associated with significantly lesser toxicity. Thus, 5-FUci was adopted as the control arm for the subsequent Phase III trials.
The endpoint in many clinical studies is the overall survival, even in those evaluating the effects of first-line treatment. On the other hand, with the emergence of many potent antitumor agents, some of them have been used in the second-line setting, after failure of first-line chemotherapy, with disease progression. In a Phase III trial (JCOG9912) comparing S-1 monotherapy and combination chemotherapy with irinotecan (CPT-11) + CDDP to 5-FUci, the activity of S-1 was confirmed in the first-line setting in patients with unresectable advanced gastric cancer. In this study, while the median time-to-treatment failure of 5-FUci, CPT-11 + CDDP and S-1 monotherapy was not so long (2.3, 3.7 and 4.0 months, respectively), the median survival times (MSTs) were 10.8, 12.3 and 11.4 months, respectively. These differences between the time-to-treatment failure and overall survival seemed to be larger than those reported from other recent Phase III trials (2). Moreover, the overall survival times in patients treated with 5-FUci in the JCOG9912 trial was remarkably longer than that in those treated in the JCOG9205 trial. After the completion of the JCOG9205 trial, not a few number of active agents, such as S-1, CPT-11 and taxanes, have been approved and used in clinical practice in Japan. The results of use of these agents suggest that second-line chemotherapy with these newly approved agents may improve the survival after failure of first-line chemotherapy in advanced gastric cancer patients.
Several Phase II trials and some retrospective analyses of second-line chemotherapy for gastric cancer have been conducted (3–7). However, there have been no reports of evaluation of the efficacy/tolerability of S-1 monotherapy in the second-line setting for advanced gastric cancer. We retrospectively reviewed to evaluate the activity of S-1 in advanced or recurrent gastric cancer patients with a previous history of chemotherapy, including with CPT-11 + CDDP or regimens containing a fluoropyrimidine other than S-1.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Subjects
A total of 25 patients with advanced or recurrent gastric cancer were treated with S-1 in the second-line setting at our institution between September 2002 and October 2006. Twenty-one of the 25 patients had a history of failure of first-line chemotherapy with CPT-11 + CDDP or regimens containing a fluoropyrimidine other than S-1. The reasons for the failure of the first-line chemotherapy included disease progression in 17 patients, unacceptable toxicities in 3 patients and refusal to continue treatment in 1 patient. The subjects of this study were these 21 patients who satisfied the following criteria: (i) histologically confirmed adenocarcinoma of the stomach; (ii) 75 years or lower in age; (iii) performance status of 0 or 1 on the ECOG PS; (iv) adequate bone marrow, hepatic and renal functions; and (iv) absence of other serious medical conditions. Two of the four patients excluded had previously been treated with S-1-containing regimens and the remaining two were >75 years old.
Treatment
The treatment schedule comprised oral administration of S-1 twice daily at 40 mg/m2/day for 28 consecutive days, followed by a 14-day rest. The treatment cycles were repeated until disease progression or the appearance of unacceptable toxicities. The actual doses of S-1 according to the body surface area (BSA) were: BSA < 1.25 m2, 80 mg/body/day; 1.25 m2 
BSA < 1.5 m2, 100 mg/body/day; and 1.5 m2 BSA, 120 mg/body/day. The dose of S-1 was reduced by one level in the event of development of Grade 4 hematological toxicities, febrile neutropenia, Grade 2 liver or renal dysfunction, or of other complicated medical conditions judged as necessitating dose reduction by the attending physician.
Evaluation
Laboratory parameters and symptoms were checked at least every 2 weeks, and adverse events were graded according to the CTCAE ver. 3.0. Tumor responses were evaluated by computed tomography, and endoscopic examination was also conducted where judged necessary. Objective tumor responses were assessed as complete response, partial response, stable disease or progressive disease, according to RECIST guideline.
Statistical Analysis
Overall survival was calculated from the date of initiation of S-1 monotherapy to the date of death. Progression-free survival (PFS) was counted to the earlier date of disease progression or of deciding treatment discontinuation for any reason. Survival curves were estimated by the Kaplan–Meier method.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient's Characteristics
Most were male (90%), and the median age was 62 years. Thirteen (62%) and eight (38%) patients showed an ECOG PS 0 and 1, respectively. The number of metastatic sites, including liver, lymph nodes, peritoneum and other sites, was 1 in 11 patients and 2 in the remaining 10 patients. The histological type of the cancer was the intestinal type in 10 patients and the diffuse type in the remaining 11 patients. All the patients had at least one target lesion. In regard to the first-line therapy used, 17 (81%) patients had received chemotherapy with CPT-11 + CDDP and 4 (19%) patients had been treated with a 5-FU-containing regimen. There were no complete and six partial responses to chemotherapy with CPT-11 + CDDP, and one partial response to treatment with a 5-FU-containing regimen (Table 1).
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Treatment
The median number of cycles administered was 2 (range 1–5), and dose reduction was required in two patients due to the appearance of Grade 4 hematological toxicity. Monotherapy with S-1 was discontinued due to progressive disease in 18 patients (85%) and due to the appearance of adverse events in 3 patients, including Grade 3 dermatitis in 1, bleeding from the primary lesion in 1 and diarrhea in 1 patient. Third-line chemotherapy was administered with paclitaxel in 13 patients (61.9%), docetaxel in 1 patient (4.7%), CPT-11 + CDDP in 1 patient and hepatoarterial infusion of 5-FU in 1 patient (Table 1).
Efficacy
Of the 21 patients, there were no cases showing complete or partial response, and 10 patients (47%) showed stable disease (Table 1). The median PFS was 91 days, and the MST was 275 days after the initiation of S-1 administration, with a 1-year survival rate of 32% (Fig. 1).
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Toxicities
In regard to hematological toxicities, Grade 4 anemia was observed in two patients (9.5%); there were no cases of Grade 4 neutropenia or leukopenia, or of febrile neutropenia. As for non-hematological toxicities, Grade 3 or 4 anorexia was observed in three patients (14.2%), diarrhea in two patients (9.5%) and nausea, vomiting, rush hot flush and fatigue in one patient each. There were no early deaths within 30 days of the last administration of S-1 and no treatment-related deaths.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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S-1 is a newly developed oral fluoropyrimidine, composed of a mixture of tegafur, 5-chloro-2,4-dehydroxypyridine and potassium oxonate in a molar ratio of 1:0.4:1 (8). The results of a few Phase II trials of monotherapy with S-1 in the first-line setting among Japanese patients with advanced gastric cancer have been encouraging. They reported a response rate (RR) of 44% and 49%, respectively, at the recommended doses, and an MST of 207 and 250 days, respectively. Thus, treatment with S-1 was concluded to be very feasible and convenient in both trials (9,10).
In regard to second-line chemotherapy for gastric cancer, the guideline for the treatment of gastric cancer in Japan (11) does not recommend any particular chemotherapeutic regimen, because none has been demonstrated to yield survival benefit. In practice, there are four active agents, fluoropyrimidine, cisplatin, irinotecan and taxanes, that are available for the treatment of gastric cancer in Japan, and many gastric cancer patients receive second-line chemotherapy with some of these drugs. There have been many reports of second-line chemotherapy after failure of S-1 therapy. Ueda et al. (6) reported a retrospective study, in which 32 patients treated with CPT-11 (70 mg/m2) + CDDP (80 mg/m2) repeated every 4 weeks showed an RR of 25%, PFS of 3.4 months and MST of 9.4 months. Hironaka (3) reported that weekly paclitaxel (80 mg/m2, repeated weekly three times for 4 weeks) yielded an RR of 23%, PFS of 2.1 months and MST of 5 months in 38 patients who were treated with fluorouracil agents, including S-1, CDDP + fluoropyrimidine, or 5-FU + methotrexate. Giuliani et al. (7) reported a Phase II study of CPT-11 + mitomycin C (MMC) administered every 4 weeks in patients who had received CDDP, taxane- or fluoropyrimidine/anthracycline-based regimens, which yielded an RR of 32%, PFS of 4 months and MST of 8 months. It is believed that second-line chemotherapy with irinotecan or taxanes can yield tumor shrinkage in some patients.
In this study, 81% of the subjects had been treated with CPT-11 + CDDP in the first-line setting. S-1 did not show any efficacy in the second-line setting. This result indicates that S-1 does not cause tumor shrinkage. It has been reported that S-1 yielded no efficacy in the third-line setting for colorectal cancer either. It is considered that the ability of S-1 to produce tumor shrinkage in the second-line setting might not be as strong as that of other antitumor agents, such as CPT-11 or taxanes. The disease control rate, which was defined as the rate of partial response plus the rate of stable disease, was 47.6% and PFS was 91 days in this study. This means that more than half of the patients receiving second-line chemotherapy showed progressive disease at the first evaluation.
The MST in this study seemed to be longer than that reported from other trials (3,7). The MST is influenced by the patients' medical condition, such as the performance status and tumor burden, especially in the second-line setting. The subjects of this study could take S-1 orally and more than half of them could also receive third-line chemotherapy, which means that the medical condition of the subjects in this analysis was relatively good. It is considered that the good survival time in this study may have been related to the patient selection.
In this study, Grade 3 or 4 anemia was observed in 38%, neutropenia in 10%, thrombocytopenia in 10%, diarrhea in 10%, nausea in 5% and vomiting in 5% of the patients. There were no unexpected or life-threatening toxicities. The incidences of Grade 3 or 4 leukopenia and neutropenia have been reported to be 75% and 81%, respectively, for CPT-11 + CDDP, 8% and 21%, respectively, for CPT-11 + MMC and 29% and 32%, respectively, for weekly paclitaxel. Although S-1 seemed to be less toxic when compared with other agents in the second-line setting, it produced substantial toxicity in the absence of tumor shrinkage
In conclusion, monotherapy with S-1 cannot be recommended for the treatment of unresectable or recurrent gastric cancer in the second-line setting.
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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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