Japanese Journal of Clinical Oncology Advance Access originally published online on September 26, 2008
Japanese Journal of Clinical Oncology 2008 38(11):786-789; doi:10.1093/jjco/hyn096
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© The Author (2008). Published by Oxford University Press. All rights reserved
Chemotherapy for Gastric Cancer that Recurs After Adjuvant Chemotherapy with S-1
1 Department of Clinical Oncology
2 Department of Gastroenterology
3 Department of Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
For reprints and all correspondence: Kohei Shitara, Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681 Aichi, Japan. E-mail: kouheis0824{at}yahoo.co.jp
Received July 21, 2008; accepted August 20, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We retrospectively analyzed the efficacy of chemotherapy in patients whose gastric cancer recurred after adjuvant chemotherapy with S-1. A total of 51 patients were evaluated. Twenty-one patients received S-1-containing chemotherapy as first-line treatment after recurrence [cohort A: S-1 plus cisplatin (n = 10), S-1 monotherapy (n = 7), S-1 plus irinotecan (n = 3) and S-1 plus docetaxel (n = 1)]. The other 30 patients received a non-S-1-containing regimen [cohort B: paclitaxel or docetaxel (n = 22), irinotecan plus cisplatin (n = 6) and other drugs (n = 2)]. No objective responses occurred in cohort A, while five patients achieved a partial response in cohort B (response rate, 0 versus 16%; P = 0.04). Median progression-free survival was significantly longer in cohort B than in cohort A (4.3 versus 2.3 months, P = 0.02). S-1-containing chemotherapy does not appear to be effective in patients whose gastric cancer recurs after adjuvant S-1 chemotherapy. Other chemotherapeutic agents should be evaluated in this setting.
Key Words: adjuvant chemotherapy • gastric cancer • recurrence • S-1
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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S-1 is a novel oral anticancer drug composed of the 5-FU prodrug tegafur and two 5-FU modulators and showed strikingly high response to gastric cancer in the previous phase II studies (1–5).
Recently, results of two landmark phase III S-1 studies in Japan were reported. In the JCOG 9912 trial, which compared S-1, cisplatin plus irinotecan and 5-FU, S-1 demonstrated non-inferiority compared to 5-FU (6). In another phase III trial that compared S-1 alone to S-1 plus cisplatin (SPIRITS trial), S1 plus cisplatin showed a significantly higher response rate (54 versus 31%), longer progression-free survival (PFS; 6.0 versus 4.0 months) and longer overall survival (OS; 13 versus 11 months) (7). Based on the results from these two trials, S-1 plus cisplatin has become the Japanese standard treatment for patients with unresectable or recurrent gastric cancer. A large worldwide phase III study comparing S-1 plus cisplatin to 5-FU plus cisplatin (FLAGS trial) is ongoing.
The ACTS-GC trial demonstrated that S-1 is also effective as adjuvant chemotherapy for Japanese patients, who have undergone curative gastrectomy for locally advanced gastric cancer (8). However, 
30% of patients still develop recurrence after curative resection followed by adjuvant S-1. As few patients, who received adjuvant chemotherapy, were included in the pivotal phase III trials described above (JCOG 9912/SPIRITS), it is unclear whether patients who develop recurrence after adjuvant S-1 chemotherapy should be treated with S-1-containing or non-containing regimens.
To address this issue, we conducted a following retrospective analysis.
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PATIENTS AND METHODS |
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Endpoints
This retrospective study was designed to evaluate the efficacy of first-line chemotherapy for recurrence in gastric cancer patients, who had undergone curative gastrectomy followed by adjuvant S-1 chemotherapy. In particular, we compared the treatment results of PFS, response rate, disease control rate (DCR) and OS between S-1 containing and non-containing regimens.
Patients
Patients with histopathologically proven recurrent gastric adenocarcinoma after gastrectomy and lymph node dissection with no residual tumor were eligible for analysis. Additional eligibility criteria were (1) Stage II, IIIA or IIIB disease according to the guidelines of the Japanese Gastric Cancer Association at gastrectomy, (2) previous adjuvant S-1 chemotherapy, (3) ECOG performance status 0–2 and (4) adequate bone marrow, hepatic and renal function. Patients were excluded if they discontinued S-1 within 4 weeks due to toxicity. Written informed consent was obtained from each patient prior to treatment initiation.
Evaluation of Treatment and Statistical Analysis
Responses to chemotherapy in measurable lesions were evaluated using the RECIST guidelines every 4–8 weeks or earlier if there were indications of treatment failure due to toxicity. Complete response (CR) and partial response (PR) determination was confirmed by an independent radiologist. DCR represented the percentage of patients with CR, PR or stable disease (SD). PFS was measured from the date of initial chemotherapy for recurrence to date of progressive disease or death from any cause. OS was estimated from the date of initial chemotherapy after recurrence to the date of death or last follow-up visit using the Kaplan–Meier method. PFS and OS in each treatment group were compared using the log-rank test. The Cox proportional-hazards model was used to calculate hazard ratios (HRs). P values for testing differences between proportions and response rates were calculated with chi-square tests for homogeneity or for trend, or with Fisher's exact test. Statistical results were considered to be significant when the P value was less than 0.05. All reported P values are two-sided.
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RESULTS |
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Patient Characteristics
A total of 93 patients with recurrent gastric cancer after curative gastrectomy were treated with chemotherapy at our institution between September 2003 and December 2007. Among them, 53 patients developed recurrence after adjuvant chemotherapy with S-1. Two patients discontinued adjuvant S-1 within 4 weeks due to toxicity; the other 51 patients were included in this analysis and evaluated in detail.
Chemotherapy regimens after diagnosis of recurrence were individually selected by physician. Twenty-one patients received S-1-containing chemotherapy as first-line treatment after recurrence [cohort A: S-1 plus cisplatin (n = 10), S-1 monotherapy (n = 7), S-1 plus irinotecan (n = 3) and S-1 plus docetaxel (n = 1)]. The other 30 patients received a non-S-1-containing regimen as first-line treatment after recurrence [cohort B: paclitaxel or docetaxel (n = 22), irinotecan plus cisplatin (n = 6) and other drugs (n = 2)]. Patient characteristics did not significantly differ between cohorts A and B (Table 1). All patients initially received adjuvant S-1 using a standard dose and schedule (80 mg/m2 for 28 consecutive days followed by a 14-day rest; 42-day cycles to be repeated for 1 year). Ten patients in cohort A and 11 patients in cohort B completed the planned 1 year of adjuvant treatment. Four patients in cohort A and six patients in cohort B discontinued adjuvant chemotherapy with S-1 before planned completion due to toxicity. The remaining patients discontinued adjuvant chemotherapy upon cancer recurrence. The median duration of adjuvant S-1 administration and treatment-free interval (TFI, defined as the date of last administration of adjuvant S-1 to initial date of chemotherapy for recurrence) did not significantly differ between the cohorts (9.7 and 3.5 months in cohort A, 8.7 and 2.8 months in cohort B).
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Tumor Response and PFS with Post-Recurrence Chemotherapy
Of the 21 patients in cohort A, two patients who received S-1 plus irinotecan showed minor tumor shrinkage but did not meet the criteria of partial response. No other patients responded to their S-1-containing chemotherapy [response rate 0%, 95% confidential interval (CI), 0–16.1%]. Ten patients (48%) had progressive disease (Table 1). Of the 30 patients in cohort B, five patients achieved a partial response (paclitaxel in 3, docetaxel in 1 and irinotecan plus cisplatin in 1), with an overall response rate of 16% (95% CI, 5.6–34.7%). Response rate was significantly better in cohort B (P = 0.04). DCR was also significantly better in cohort B (62%) than in cohort A (24%, P < 0.01). Median PFS was significantly longer in cohort B (4.3 months; 95% CI, 3.0–5.5) than in cohort A (2.3 months; 95% CI, 1.9–2.7; HR, 0.50; 95% CI, 0.28–0.90; P = 0.02, Fig. 1).
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Second-Line Chemotherapy After Recurrence
Fifteen patients in cohort A received second-line chemotherapy [paclitaxel (n = 11) or irinotecan (n = 4)], and 16 patients in cohort B received second-line chemotherapy [irinotecan (n = 6), paclitaxel (n = 2), docetaxel (n = 2), 5-FU (n = 2), S-1 plus irinotecan (n = 2), S-1 plus cisplatin (n = 1) or S-1 plus docetaxel (n = 1)]. The proportion of patients who received second-line chemotherapy was higher in cohort A [15 of 21 patients (71%)] than in cohort B [16 of 30 patients (53%)], although it was not statistically significant (P = 0.19). Four patients in cohort B who received S-1-containing regimens as second-line therapy did not have an objective response.
Survival
After a median follow-up of 22.9 months, median OS was 9.1 months (95% CI, 5.2–11.7) in cohort A and 10.1 months (95% CI, 7.6–17.1) in cohort B. Although OS was longer in cohort B, it was not statistically significant (HR, 0.70; 95% CI, 0.37–1.32; P = 0.27; Fig. 1).
Significance of TFI
Nine patients in cohort A and 10 patients in cohort B had a TFI > 6 months. The TFI of the other 32 patients was 
6 months. No significant differences in response rate (10 versus 9%; P = 0.89), PFS (4.2 versus 3.3 months; P = 0.61) or OS (10.2 versus 8.7 months; P = 0.67) were observed in patients with a TFI > 6 months compared with 6 months, respectively.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In this study, we retrospectively compared S-1-containing with non-containing chemotherapy in patients, whose gastric cancer recurred after adjuvant chemotherapy with S-1. Although treatment was individually selected by each physician, there were no major differences between cohorts with respect to treatment regimens, including durations of adjuvant chemotherapy and TFI.
No PRs occurred in patients, who received S-1-containing chemotherapy for recurrent disease, and this group experienced a significantly lower response rate, lower DCR and shorter PFS compared with patients treated with non-S-1-containing chemotherapy. Although reports from studies in other cancer types have suggested the importance of the TFI as a predictive marker of responsiveness to salvage chemotherapy (9,10), no response was observed in the nine patients, who received S-1-containing chemotherapy after a TFI of >6 months. OS did not significantly differ between the groups, perhaps due to the use of second-line chemotherapy including paclitaxel or irinotecan; however, it should be noted that the six patients (28%), who received first-line S-1-containing chemotherapy died of tumor progression before they could receive second-line therapy.
Based on these results, we suggest that chemotherapy agents other than S-1 should be evaluated as first-line treatment of gastric cancer recurrence when S-1 is used as initial adjuvant therapy, since the response rates for irinotecan and taxanes (i.e. paclitaxel and docetaxel) are reported to be 20% for patients with gastric cancer who received prior chemotherapy with fluoropyrimidines and/or cisplatin (11–14). It is not possible to determine whether irinotecan or taxanes would be more effective in S-1-refractory patients based on the results of the current study, although it should be noted that more patients received taxanes than irinotecan. Although combination regimens containing S-1 and other chemotherapeutic agents may potentially have some activity in recurrent disease following S-1 failure, the dose intensity of other agents must be reduced, potentially to a subtherapeutic degree, when they are administered in combination with S-1. In cohort A, two patients, who received S-1 plus irinotecan for their recurrent disease, showed minor tumor shrinkage; it is possible that further tumor shrinkage may have occurred had these patients received a higher dose of irinotecan as monotherapy. The results of an ongoing phase III trial comparing irinotecan monotherapy with S-1 plus irinotecan after progression of S-1-treated gastric cancer and another trial comparing irinotecan and paclitaxel as second-line chemotherapy for gastric cancer are eagerly anticipated.
Although the current study has many limitations (e.g. use of retrospective data, performance at a single center, a heterogeneous TFI and heterogeneous treatment regimens), this is the first report to evaluate the efficacy of chemotherapy in patients with gastric cancer that recurs after adjuvant chemotherapy with S-1. Our data may indicate that S-1 monotherapy and S-1-based combination chemotherapy (particularly S-1 plus cisplatin) are not effective in this setting, which suggest that other chemotherapeutic agents should be evaluated. Further well-defined prospective trials in this important patient population are required to identify optimal treatment regimens.
Conflict of interest statement
None declared.
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References |
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