3.2.1 Treatment-related deaths
Treatment-related deaths were reported in 4 studies.[11,13–15] The accumulated treatment-related mortality rate in Asian patients was 0.4% (2/473) in the S-1-containing group versus 0.2% (1/460) in the 5-FU-containing group, without significant difference (RD = 0.00, 95% CI [−0.01, 0.01], P = 0.68; Table 4); however, the mortality rate in non-Asian patients was 2.5% (13/521) in the S-1-containing group versus 4.9% (25/508) in the 5-FU-containing group, which was a significant difference (RD = −0.02, 95% CI [−0.05, −0.00], P = 0.04; Table 4). Testing for subgroup differences was then performed, showing a significant difference in heterogeneity between Asian and non-Asian subgroups (P of heterogeneity = 0.04, I2 = 76.5%).
3.3 Hematological toxicities
The profile of hematological toxicities was distinct between Asian and non-Asian trials (Table 4). Testing for subgroup differences demonstrated significant difference in heterogeneity between Asian and non-Asian subgroups. In Asian patients, there was a significant increase of hematological toxicities in S-1-containing regimens such as leukopenia (grade 1–4: RR = 1.22, 95% CI [1.08, 1.37], P = 0.001; grade 3–4: RR = 2.21, 95% CI [1.52, 3.21], P < 0.0001), neutropenia (grade 1–4: RR = 1.29, 95% CI [1.11, 1.48], P = 0.0005; grade 3–4: RR = 1.87, 95% CI [1.11, 3.17], P = 0.02), and thrombocytopenia (grade 1–4: RR = 1.71, 95% CI [1.22, 2.41], P = 0.002). Conversely, in non-Asian patients, S-1-containing regimens were found to be associated with lower toxicities for leukopenia (grade 1–4: RR = 0.72, 95% CI [0.66, 0.79], P < 0.0001; grade 3–4: RR = 0.41, 95% CI [0.32, 0.53], P < 0.0001), neutropenia (grade 1–4: RR = 0.74, 95% CI [0.68, 0.80], P < 0.0001; grade 3–4: RR = 0.51, 95% CI [0.44, 0.59], P < 0.0001), febrile neutropenia (grade 1–4: RR = 0.28, 95% CI [0.14, 0.56], P = 0.0003; grade 3–4: RD = −0.05, 95% CI [−0.08, −0.03], P < 0.0001), and thrombocytopenia (grade 1–4: RR = 0.73, 95% CI [0.63, 0.84], P < 0.0001; grade 3–4: RR = 0.62, 95% CI [0.43, 0.89], P = 0.009). However, no significant difference in anemia was found in both subgroups.
3.4 Gastrointestinal toxicities
With regard to nonhematological toxicities, there was no significant heterogeneity between Asian and non-Asian subgroups. Gastrointestinal toxicities were frequent in both groups (Table 5). The incidence of nausea, vomiting, anorexia, diarrhea, and constipation demonstrated no significant differences between groups except that S-1-containing regimens were associated with a significantly decreased incidence of grade 1–4 nausea (RR = 0.80, 95% CI [0.64, 1.00], P = 0.05) and grade 1–4 diarrhea (RR = 0.79, 95% CI [0.67, 0.94], P = 0.006) (Table 4). Of note, S-1-containing regimens were associated with less frequent and less severe mucositis (stomatitis and/or mucosal inflammation), with an incidence of grade 1–4 mucositis of 10.1% versus 60.2% with 5-FU-containing regimens (RR = 0.17, 95% CI [0.13, 0.22], P < 0.001), and grade 3–4 of 1.9% versus 14.7%, respectively (RR = 0.23, 95% CI [0.06, 0.88], P = 0.03).
3.4.1 Other toxicities
Liver impairment (increased bilirubin) was significantly more frequent in S-1-containing than 5-FU-containing regimens (12.1% vs 5.8%, RR = 2.10, 95% CI [1.51, 2.92], P < 0.001). However, the incidence of renal impairment was significantly less frequent in S-1-containing regimens, with 3.8% of patients exhibiting increased creatinine versus 6.4% in 5-FU-containing regimens (RR = 0.61, 95% CI [0.39, 0.95], P = 0.03) and 22.6% of S-1 patients having decreased calculated creatinine clearance versus 40.9% in 5-FU (RR = 0.55, 95% CI [0.46, 0.67], P < 0.001). Some toxicities, including fatigue, infection, weight loss, and neuropathy, were reported infrequently and had similar incidence in both groups (Table 5).
3.5 Sensitivity analysis
Sensitivity analysis showed that the corresponding pooled HRs and ORs were not significantly altered when one study was removed at a time, suggesting stability of the results.
3.6 Publication bias
Begg funnel plot and Egger test were performed to assess the publication bias of the analyzed studies. The shapes of the Begg funnel plots did not reveal evidence of obvious asymmetry (P = 1.00 and 0.76 for OS and ORR, respectively; Fig. 7). Egger test was then used to provide statistical evidence of funnel plot symmetry. The results still suggested no evidence of publication bias (P = 0.91 and 0.20 for OS and ORR, respectively).
Five meta-analyses were identified in the literature search.[6,7,18–20] The main characteristics and results of these analyses were compared with the present study in Table 6. Although 2 published meta-analyses showed the superiority of S-1-containing regimens compared with 5-FU-containing regimens in terms of OS, one contained duplicate material and the other missed a trial which was included in the present analysis. In the present study, the pooled data revealed no significant improvement in OS for S-1-containing regimens (HR = 0.91, 95% CI [0.83–1.01], P = 0.07). It seems difficult to draw firm data-driven conclusion as to survival benefit of S-1. The median OS of S-1 monotherapy was approximately 11 months and the addition of other cytotoxic drugs, such as cisplatin,[16,21] oxaliplatin, paclitaxel, docetaxel,[24,25] or irinotecan[26,27] to S-1, even prolonged median OS beyond 12 months. Several trials comparing these doublets with S-1 monotherapy were conducted and demonstrated that the doublets resulted in a longer OS than that resulting from S-1 monotherapy.[16,21,23,25] However, there are no data indicating which doublets are superior as first-line treatments for AGC.[28–30] Therefore, we suggest that the emphasis should be on further developing S-1 with different cytotoxic drugs and/or biologic agents to anticipate the prolongation of OS in patients with AGC.
Regarding endpoints based on tumor assessments, the pooled data showed that there were no significant differences in ORR and PFS between the 2 groups, whereas S-1-containing regimens were associated with much longer TTF than 5-FU-containing regimens. However, there was significant heterogeneity among trials; therefore, these results should be interpreted with caution. The subgroup meta-analyses showed that there was higher ORR in Asian patients with S-1-containing regimens than 5-FU-containing regimens, but no such difference was found in non-Asian patients. Different stage presentation may affect the efficacy; however, there was no obvious difference in the extent of disease between Asian and non-Asian patients. The profile of stage presentation was remarkably similar in all trials, that is, the majority (above 95%) of patients had metastatic disease and over two-thirds had more than one site of metastasis. In fact, according to the analyzed data in the present study (Tables 2 and 3), the efficacy of S-1 was closely comparable between Asian and non-Asian patients. The median OS was 8.6 months in non-Asian patients versus 8.3 to 15.2 months in Asian patients, PFS 4.8 months versus 3.5 to 5.0 months, TTF 3.8 months versus 2.8 to 5.2 months, ORR 29.1% versus 31.4%; nevertheless, the ORR of 5-FU-containing regimens was evidently high in non-Asian patients (31.9% vs 19.6%), which might be responsible for the difference.
With respect to safety profiles, S-1 monotherapy had a low incidence of grade 3–4 toxicities (usually <5% for each toxicity); however, the addition of other cytotoxic drugs significantly increased the incidence of grade 3–4 toxicities, which remained manageable.[16,21,23,25,27] It is noteworthy that there was significant heterogeneity in the incidence of treatment-related deaths and hematological toxicities between Asian and non-Asian patients. The reported treatment-related mortality was <1% in Asian patients, but was >2.5% in non-Asian patients. Treatment-related deaths were mainly caused by myelosuppression and infection.[11,13] Accordingly, the incidences of grade 3–4 leukopenia, neutropenia, and febrile neutropenia were markedly higher in non-Asian patients, especially in those assigned to 5-FU-containing regimens. Actually, according to the data from Table 4, the incidences of hematological toxicities for S-1-containing regimens were comparable between Asian and non-Asian patients; by contrast, the incidences for 5-FU-containing regimens were relatively low in Asian patients whereas remarkably high in non-Asian patients. As a result, the incidences of hematological toxicities in Asian patients were significantly higher in S-1-containing regimens than those in 5-FU-containing regimens. Conversely, the rates of hematological toxicities in non-Asian patients were significantly less frequent in S-1-containing regimens than 5-FU-containing regimens.
The reason for these differences is complicated and may be related to geographic region, dose, and schedule of cytotoxic drugs and gene polymorphism. A meta-analysis indicated that the Asian trials were associated with lower incidences of grade 3–4 neutropenia and febrile neutropenia, and concluded that geographic region was an independent predictor of safety in chemotherapy for gastric cancer. The dose and schedule of cytotoxic drugs varied among studies due to the individual distinctions and practice culture in different regions. In every chemotherapy cycle, the daily dose of S-1 was usually 80 mg/m2 in Asian patients versus 50 mg/m2 in non-Asian patients; the total dose of 5-FU varied widely among studies, from 2500 mg/m2 to 4000 mg/m2 in Asian patients versus 5000 mg/m2 in non-Asian patients. We observed that the non-Asian patients were administered noticeably lower single doses of S-1 but higher total doses of 5-FU. In addition, the total dose of cisplatin was lower, from 60 mg/m2 to 80 mg/m2 in S-1-containing arms versus 80 mg/m2 to 100 mg/m2 in 5-FU-containing arms; moreover, cisplatin was administered daily at a dose of 20 mg/m2/d intravenously over 4 to 5 days in Asian studies, whereas at the total dose was administered intravenously over 1 to 3 hours in non-Asian studies. However, the metabolic rate of conversion of tegafur to 5-FU differs in various ethnic populations, Cytochrome P450 2A6 (CYP2A6) enzyme is now identified as the principal enzyme responsible for this conversion process. The efficacy of CYP2A6 enzyme is higher in non-Asian patients than in Asian patients, which is attributed to different polymorphisms in the CYP2A6 gene.[35–37] Thus, the conversion rate of tegafur to 5-FU was faster in non-Asian patients, which would cause a lower dose of S-1 in non-Asian patients to achieve a comparable area under the curve of 5-FU with that in Asian patients and provide considerable improved safety without compromising efficacy. Taking all into consideration, the clinical heterogeneity of hematological toxicities between Asian and non-Asian patients would be mainly attributed to higher doses of 5-FU and cisplatin in 5-FU-containing regimens.
With respect to the nonhematological toxicities, S-1-containing regimens significantly reduced the frequency and severity of mucositis compared with 5-FU-containing regimens. A grade 3–4 increase in total bilirubin was the only notable nonhematological toxicity observed more frequently in S-1-containing regimens. However, there were no differences with respect to grade 3–4 elevations in aminotransferases (ALT/AST) or reports of death due to drug-related hepatic toxicity, indicating that there was no evidence of direct hepatotoxicity by S-1.[31,38] Ajani et al acknowledged that the significantly lower rate of renal function abnormalities, such as elevated serum creatinine and impairment of renal clearance in the cisplatin/S-1 arm, could be attributed to lower cisplatin dose (75 mg/m2) than in the cisplatin/infusional fluorouracil arm (100 mg/m2).
Although the data on QOL and cost-effectiveness analysis were limited, S-1-containing regimens seemed to be associated with longer nonhospitalized survival, fewer hospitalizations for drug administration, and lower monetary costs. One abstracts mentioned QOL as secondary endpoints, but no detailed data were reported. Because infusional chemotherapy is commonly performed with hospitalization, we would presume that the nonhospitalized survival reflects a patient's benefit from a QOL point of view. Boku et al reported that S-1 was associated with longer nonhospitalized survival compared with 5-FU (9.3 [interquartile range 4.2–18.0] vs 7.2 [2.7–13.3] months, HR = 0.77, 95% CI [0.63–0.92], P = 0.0025). Moreover, Ajani et al reported that the total number of hospitalizations and percentage of patients hospitalized were lower and the median number of days hospitalized was shorter in S-1-containing arm. In addition to efficacy and safety concerns, expenditure on chemotherapy drugs has recently become a main concern. Unfortunately, few trials compared S-1 with 5-FU from an economic point of view. Only Boku et al offered some information in their discussion section, reporting that in Japan, the cost of S-1 was cheaper than that of 5-FU.
Some limitations should be considered when interpreting the data presented here. First, 2 included studies were abstracts from international conferences with insufficient data on methodological and patient characteristics. In addition, many important estimates, such as PFS, TTF, TTP, and some AEs, were not reported in many of the studies analyzed. These omissions might potentially limit detection of difference. Furthermore, heterogeneity problems were frequently found among the included studies and subgroups, which may have influenced our results. Therefore, we chose to use the random-effects model as well as subgroup analysis to calculate the estimates and explain the causes of heterogeneity, such as differences in geographic region, dose, and schedule of cytotoxic drugs. In addition, most of the studies included were performed in Asia, with only one non-Asian study. We noticed significant differences in efficacy and safety profiles, such as median OS, treatment-related mortality, and incidence of hematological toxicities. However, future studies are needed to determine the mechanism underlying this phenomenon.
In conclusion, S-1-containing regimens could not improve survival outcomes, but increase some hematological toxicities in Asian patients, compared with 5-FU-containing regimens. Therefore, special attention on hematological toxicities should be paid to Asian patients because S-1 is administered on an outpatient basis. Moreover, whether S-1 could provide advantages in terms of QOL and monetary costs needs to be clarified by further trials.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
Efficacy; fluorouracil; heterogeneity; meta-analysis; S-1; stomach neoplasms; toxicity