Effectiveness and safety of S-1-based therapy compared with 5-fluorouracil-based therapy for advanced colorectal cancer: a meta-analysis.
1. IntroductionDespite advances in diagnosis and treatment, colorectal cancer remains the third leading cancer, with approximated 1,233,700 new cases and 608,700 deaths worldwide each year [1]. For the patients with advanced colorectal cancer (ACRC), acquiring curative therapy by surgery or radiotherapy is complex; therefore, systemic chemotherapy is the main effective treatment, which can prolong survival and enhance life quality of patients [2].
For many years, traditional continuous-infusion 5-fluorouracil (5-FU) in combination with leucovorin (LV) has been the backbone of palliative therapy for ACRC [2], and the combination of 5-FU and LV with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) has been recognized as standard first-line therapies for ACRC [3]. However, administration of the traditional 5-FU regimens is time-consuming, uncomfortable, and inconvenient for the patients, because continuous infusion requires an indwelling central venous catheter with the associated increased risk of infection and thrombosis and regular hospital visits.
As substitute of 5-FU, S-1 (Taiho Pharmaceutical Company, Tokyo, Japan), an oral fluoropyrimidine, is a combined form of three pharmacological compounds (tegafur, gimeracil [CDHP], and oteracil potassium [Oxo]) at a molar ratio of 1: 0.4: 1. Tegafur is a prodrug that is mainly converted by liver enzyme cytochrome P450(CYP)2A6 to 5-FU, CDHP is an inhibitor of dihydropyrimidine dehydrogenase, which can prolong the half-life of 5-FU, and Oxo can reduce the toxic effects of 5-FU by inhibiting the phosphorylation of 5FU to fluorouridine monophosphate in the gastrointestinal tract [4]. S-1-based therapy (SBT) has found to have similar efficacy and safety to 5-fluorouracil-based therapy (FBT) in the treatment of advanced gastric cancer (AGC) [5] and has been approved for the treatment of patients with AGC in japan.
The question that whether SBT has similar efficacy and safety to FBT in the treatment of ACRC is well worth exploring and studying. Recently, there have been a series of trials comparing S-1 with 5-FU in mono or combined therapy for ACRC [6-17]. However, single study may not be powered sufficiently to comprehensively assess the efficacy and safety of them, and so far there still has been not a meta-analysis of SBT versus FBT for ACRC. Consequently, we performed the present meta-analysis of all eligible studies to compare both treatment approaches and to evaluate their clinical efficacy and safety for patients of ACRC.
2. Methods
2.1. Literature Search. We conducted a comprehensive search by examining the PubMed, Embase, and the Cochrane Library Database for randomized controlled trials (RCTs) from inception to November 15, 2013, using various combinations of different terms "colorectal cancer," "S-1" "5-FU" "randomized controlled trial" and their synonyms or similar words (the "appendix" showed the search strategy of Embase, and the search strategy was also referred in other electronic databases). In addition, all abstracts from the American Society of Clinical Oncology (ASCO) conferences from inception to 2013 were also searched for relevant RCTs, and references cited in the identified articles were searched manually. The search was done without restriction on language.
2.2. Inclusion and Exclusion Criteria. Inclusion and exclusion criteria were delineated before the commencement of the literature search. Eligible studies were included in this meta-analysis if they met all the following criteria: (1) that participants were the patients of histologically confirmed, advanced, recurrent, or metastatic colorectal cancer and did not have severe basic diseases, (2) that only RCT was considered, (3) trials comparing SBT with FBT: mono or combined therapy of S-1 versus 5-FU and not confused by additional drugs or interventions (i.e., the experimental and control arms had difference only by S-1 and 5-FU components in the combination therapy). Accordingly, studies meeting the following criteria were excluded: (1) crossover studies and (2) the studies about loses visit rate >20%.
2.3. Data Extraction. Essential data was carefully extracted from all eligible studies independently by two investigators (Jia-Xiang Ye, Lian-Ying Ge), and discrepancies were finally resolved by consensus between the two authors (Jia-Xiang Ye, Lian-Ying Ge). From each study, we collected information on the following items: the first author's name, published year, country/region of origin, study design, characteristics of participants, interventions, and outcomes. When there were some updated results about the same study, we extracted the updated results. For the included studies with only abstract, we also acquired relevant clinical trial information by ClinicalTrials.gov Database (http://www.clinicaltrials.gov/).
2.4. Quality Assessment for Included Studies. Two authors (Jia-Xiang Ye, Lian-Ying Ge) assessed the quality of the eligible studies independently, with disagreements solved by a third author (Shao-Zhang Zhou) until agreement was obtained. With the guidance of the Cochrane Collaboration's tool for assessing risk of bias of RCTs (5.1.0) [20], we considered the following criteria to appraise the RCTs: random sequence generation, allocation concealment, binding of participants and personnel, binding of outcome assessment, incomplete outcome data, selecting reporting, and other bias. In all cases, high risk, low risk, or unclear risk was used to evaluate the risk of bias, and if insufficient detail was reported of what happened in the study, the judgment would usually be unclear risk of bias.
2.5. Statistical Analysis. Statistical analysis of the hazards ratio (HR) and 95% confidence interval (CI) for overall survival (OS) and progression-free survival (PFS), the odds ratio (OR) and 95% CI for overall response rate (ORR), disease control rate (DCR), one- or two-year survival rate (SR), and grade 3-4 adverse events (AEs) were calculated using RevMan 5.1.0 software. ORR was defined as the sum of partial and complete response rates according to the Response Evaluation Criteria in Solid Tumors, and the DCR was the sum of ORR and stable disease rate [21]. A fixed-effect model was used first, the Q test and I2 statistic was performed to assess the heterogeneity, and P < 0.1 or I2 > 50% was considered as heterogeneity between studies. If the heterogeneity existed, sensitivity analysis or random-effect model was applied. Visual inspection of asymmetry in funnel plots was used to estimate the potential publication bias [22]. In order to supplement the funnel plot, Begg's test [23] and Egger's test [24] methods were performed using Stata version 12.0 software (Stata Corporation, College Station, TX).
3. Results
3.1. Study and Patient Characteristics. The search strategy yielded 400 records. Of these, 79 duplicates were eliminated and 302 articles were excluded due to irrelevancy by reviewing their titles and abstracts. The remaining 19 records were obtained to further determine eligibility. We ruled out another five articles: two articles due to single arm trials [25, 26], one article due to pooled analysis [27], and two trials not comparing SBT with FBT [28, 29]. So ten full texts [6,7, 9,11-17] and four abstracts 8,10,18,19] were identified according to the inclusion criteria, of which the trial reported by Otsuji et al. [19] was the updated study of partial result of the trial reported by Ojima et al. [10], and the trial reported by Baba et al. [18] was the updated study of partial result of the trial reported by Muro et al. [9]. Thus, only twelve studies [6-17] assessing 1625 participants qualified to be included for this meta-analysis, as described in the flow chart (Figure 1). Table 1 displayed the characteristics of these twelve individual trials with respect to author (year), country, demographic data, duration, intervention, outcome measure, and study design.
3.2. Quality of Eligible Studies. All included studies undertook detailed assessments. All of the studies included the term "random," but only three RCTs [6,9,16] reportedthe methods of random sequence generation, and only two RCTs [9, 16] reported the allocation concealment in detail. Moreover, although the three full texts [9, 12, 16] were open-label and other nine trials did not mention whether the blind method was adopted or not, these were unlikely to affect the quality assessment results. Two RCTs [9,16] adequately described the missing data or missing reasons and took intention to treat analysis of all randomized patients. Eight RCTs [6,7,11-15,17] reported complete outcome data. The ten RCTs had no other bias. Two trials [8,10] were abstracts and included insufficient information regarding the outcome data, selective reporting and other bias (Figures 2 and 3).
3.3. Overall Survival. Three of the four trials provided OS data [16,18,19]. The pooled HR of OS showed no significant difference between SBT and FBT yielding HR of 0.94 (95% CI 0.80-1.10) by using a fixed-effect model, and there was no significant heterogeneity across studies (P = 0.50, [I.sup.2] = 0%) (Figure 4).
3.4. One- or Two-Year Survival Rate. Three trials provided SR data [9, 10, 16, 19]. The pooled OR of one- or two-year SR showed there was no significant difference between SBT and FBT (1-year SR: OR = 0.99,95% CI = 0.74-1.33; 2-year SR: OR = 1.01,95% CI = 0.76-1.35) by using a fixed-effect model, with no heterogeneity across studies (1-year SR: P = 0.66, [I.sup.2] = 0%; 2-year SR: P = 0.37, [I.sup.2] = 0%) (Figure 5).
3.5. Progression-Free Survival. Three trials provided PFS data [10, 16, 18]. The pooled HR of PFS showed there was no significant difference between SBT and FBT (HR = 1.03, 95% CI = 0.91-1.18), and the pooled HR of PFS was performed by using fixed-effects model, with no heterogeneity (P = 0.69, [I.sup.2] = 0%) (Figure 6).
3.6. Overall Response Rate or Disease Control Rate. All included studies provided the information on ORR [6-17]. As shown in Figure 7, the pooled OR of ORR in fixed-effect model was 1.23 (95% CI: 1.00-1.53) with little evidence of heterogeneity (P = 0.62, I2 = 0%), which indicated there was no significant difference between SBT group and FBT group. Eleven trials reported DCR data [6-8, 10-17], the meta-analysis of the pooled data demonstrated that DCR was not different between the two groups (OR = 1.37, 95% CI = 0.99-1.89), and there was no heterogeneity across the trials (P = 0.80, [I.sup.2] = 0%) (Figure 8).
3.7. Safety. Results of graded 3 and 4 AEs analyses were shown in Table 2.
Neutropenia in hematologic toxicity: meta-analysis of four trials [9-11, 16] including 541 patients in the SBT group and 533 patients in the FBT group showed graded 3-4 neutropenia was less likely to happen in the SBT group (OR = 0.35, 95% CI = 0.27-0.47), and yet there was significant heterogeneity across these trials (P < 0.1, [I.sup.2] = 69%). Sensitivity analysis suggested that the trial reported by Yamada et al. [16] was the main source of heterogeneity. After removing this study, the heterogeneity was eliminated (P = 0.73, [I.sup.2] = 0.0%), and the pooled result of the three trials applying fixed-effect model also showed that graded 3-4 neutropenia was significantly less likely to happen in patients of SBT than FBT (OR = 0.49, 95% CI = 0.35-0.68) (Figure 4(b)).
Leucopenia: meta-analysis of ten trials [6, 7, 9, 11-17] about graded 3-4 leucopenia, which included 734 patients in the SBT group and 726 patients in the FBT group, showed no significant difference between the two groups (OR = 0.75, 95% CI = 0.55-1.04), with no significant heterogeneity across studies (P = 0.28, [I.sup.2] = 18%).
Anemia: nine trials [6, 7, 9,11,12,14-17] reported graded 3-4 anemia assessing 1417 participants (SBT, n = 712;FBT, n = 705), meta-analysis of the pooled data showed no significant difference between the two groups (OR = 1.33, 95% CI = 0.83-2.15), and there was no significant heterogeneity across studies (P = 0.40, [I.sup.2] = 3%).
Thrombocytopenia: the pooled OR of graded 3-4 thrombocytopenia of nine trials [6, 7, 9, 12-17] assessing 1411 participants (SBT, n = 709; FBT, n = 702) showed no significant difference between the two groups (OR = 1.05,95% CI = 0.51-2.15), and there was no significant heterogeneity across studies (P = 0.28, [I.sup.2] = 21%).
Diarrhea in nonhematologic toxicity: all included studies provided the information on grade 3-4 diarrheas. Metaanalysis of twelve trials showed a significant heterogeneity across the trials (P < 0.10, [I.sup.2] = 64%). Sensitivity analysis did not find the main source of heterogeneity. So meta-analysis of twelve trials assessing 1625 participants (SBT, n = 820; FBT, n = 805) in random-effect model showed no significant difference between the two groups (OR = 1.25,95% CI = 0.582.69).
Nausea/vomit: meta-analysis of ten trials [6-9, 12-17] assessing 1471 participants (sBt, n = 739; FBT, n = 732) in fixed-effect model showed no significant difference between the two groups (OR = 0.41, 95% CI = 0.23-0.72), with no heterogeneity (P = 0.56, [I.sup.2] = 0%).
Stomatitis: nine trials [6-9,12,13,15-17] reported graded 3-4 stomatitis assessing 1426 participants (SBT, n = 716; FBT, n = 710), meta-analysis of the pooled data showed no significant difference between the two groups (OR = 2.21,95% CI = 0.83-5.88), and there was no significant heterogeneity across studies (P = 0.24, [I.sup.2] = 28%).
Treatment-related death (TRD): data on the TRD were available for five trials [8, 9, 11, 16, 17] including 1087 participants (SBT, n = 545; FBT, n = 542) in the metaanalysis. The pooled OR of five trials showed TRD was not significantly different between the two groups (OR = 0.72, 95% CI = 0.24-2.19), and there was no heterogeneity among the studies (P = 0.71, [I.sup.2] = 0%).
3.8. Publication Bias. The visual inspection of the funnel plots suggested a roughly symmetrical distribution for the study (Figure 9), which showed no evidence of publication bias. Moreover, according to Begg's test (P = 0.49) and Egger's test (P = 0.40), publication bias was also not found.
4. Discussion
To our knowledge, this was the first meta-analysis to evaluate the efficacy and safety of SBT versus FBT for aCrC. A total of 1625 patients from twelve RCTs including 820 patients in the SBT group and 805 patients in the FBT group were analyzed. With respect to ORR, DCR, and one- or two-year SR, our meta-analysis showed no significant difference between SBT and FBT group, which suggested that SBT was noninferior to FBT for the patients of ACRC. And the pooled analysis showed that SBT had similar PFS and OS to FBT as well. All these results indicated SBT had similar efficacy to FBT for patients of ACRC.
For safety profile, Our meta-analysis showed grade 34 toxicity such as anemia, leucopenia, thrombocytopenia, diarrhea, and TRD was similar between two groups, but the graded 3-4 neutropenia (OR = 0.49, 95% CI = 0.350.68) and nausea/vomit (OR = 0.41, 95% CI = 0.23-0.72) were less likely to happen in the SBT group than in the FBT group. Thus, compared with FBT, SBT could reduce some toxicity for patients of ACRC. Owing to significant heterogeneity in grade 3-4 neutropenia, sensitivity analysis was performed to find the contributors of heterogeneity, the trial reported by Yamada et al. [16], and the main source of heterogeneity might be attributable to the different therapy regimens; for instance, the therapy regimen of the trial reported by Yamada et al. had a biological targeted drug (bevacizumab), but the therapy regimens of the other studies of meta-analysis did not include bevacizumab. Regarding grade 3-4 diarrhea, a sensitivity analysis was also performed, but the factors contributing to the heterogeneity could not be identified; these might be associated with variations in age, performance status of patients, dose, and the regimen of therapy between the trials. Thus, a random-effect model was applied to compensate for this.
Capecitabine is another oral fluorouracil-derivative drug designed to simulate a continuous intravenous infusion of 5-FU [30], whose efficacy and safety had been found to be at least equivalent to that of 5-FU for ACRC by many studies [31]. And yet, in 2012 the phase 3 trial reported by Hong et al. showed the noninferiority of oxaliplatin and S-1(SOX) versus oxaliplatin and capecitabine (XELOX) for ACRC, with median PFS of 8.5 months in the SOX group and 6.7 months in the XELOX group (HR = 0.79, 95% CI 0.601.04), and manageable toxicities in both groups [28]. Later the results of a randomized phase II study also suggested that both SOX and XELOX regimens were active and were well tolerated regimens in patients with ACRC [29]. These studies suggested indirectly that S-1-based chemotherapy (SBCT) could be regarded as an alternate chemotherapy strategy to 5-FU-based chemotherapy (FBCT) for the patients of ACRC.
Recently 5-FU-based chemotherapy plus bevacizumab (FBCT + Bev) has been widely used for first-line treatment of ACRC [32, 33], but S-1-based chemotherapy plus bevacizumab (SBCT + Bev) is still at the research stage. In 2013, Yamada et al. performed a randomised phase 3 trial, showing that SBCT + Bev was noninferior to FBCT + Bev in the firstline treatment for ACRC, with median PFS of 11.7 months in SBT group and 11.5 months in FBT group, and AEs in both groups were tolerable [16]. Moreover, the median PFS of SBCT + Bev was about 2 months longer than that of similar SBCT without bevacizumab in the treatment of patients with similar characteristics in the phase III trial reported by Hong et al. [28]. What is more, SBCT + Bev did not require a long infusion process and reduced the inconvenience for patients. Therefore, compared with FBCT + Bev, SBCT + Bev provided a great advantage and was a promising regimen for patients of ACRC.
Of note, S-1 had different optimal doses and safety among patients in different regions and populations. Since the gene polymorphic variants of liver enzyme CYP2A6 converting tegafur to 5-FU were less frequent in the Caucasians than in East Asians, the tolerable dose of S-1 might be lower for Caucasian patients than for patients in East Asia; in other words, toxic effects were more common in Caucasian patients exposed to the same dose of S-1 [34, 35]. Besides, variation in creatinine clearance was associated with S-1 toxicity as well, which meant dose adjustment should be considered when S-1 was used for patients with compromised renal function [16]. Thus, the use of different dose of S-1 should be clarified for suitable population.
There were several limitations in this meta-analysis. First, since all the studies included in this analysis were from East Asia, the results needed confirmation in other countries. Second, the quality of the studies was not considered to be high, only three RCTs [6, 9,16] reported the methods of random sequence generation, and two RCTs [9,16] reported the allocation concealment in detail. More RCTs with improved methodological quality should be provided to update this study. Third, two studies in the meta-analysis were abstracts [8, 10], whose incomplete information might potentially limit estimate of SBT effects. Moreover, information of each individual patient for each trial was not obtained to make comprehensive analysis. Last, there was one heterogeneous result about AEs.
In summary, our meta-analysis indicated that SBT had similar efficacy and better safety than FBT for patients of ACRC. Given its advantages of simplicity and convenience to administer, SBT would be an attractive alternative to FBT for patients of ACRC, especially for outpatients. Owing to the variation of S-1 tolerance in different regions and populations, further high-quality RCTs and different population studies in future would be needed to confirm it.
http://dx.doi.org/ 10.1155/2014/146530
Appendix
EMBASE search terms:
(1) "colorectal": ab, ti OR "rectal": ab, ti OR "colon": ab, ti OR "intestinal": ab, ti OR "colorectal carcinoma"/exp OR "colorectal tumor"/exp;
(2) "tegafur gimeracil oteracil potassium": ab, ti OR "S1": ab, ti OR "TS-1": ab, ti OR "gimeracil plus oteracil potassium plus tegafur"/exp;
(3) "fluorouracil": ab, ti OR "5-FU": ab, ti OR "fluorouracil"/exp;
(4) "trial": ab, ti OR "randomized": ab, ti OR "randomly": ab, ti OR "random": ab, ti OR "groups": ab, ti OR "placebo": ab, ti OR "randomized controlled trial"/exp OR "randomized controlled trial (topic)"/exp;
(5) #1 AND #2 AND #3 AND #4.
Conflict of Interests
The authors declare that they have no conflict of interests.
Authors' Contribution
Jiaxiang Ye and Jiawei Chen contributed equally to this work.
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Jiaxiang Ye, Jiawei Chen, Lianying Ge, Aiqun Liu, and Shaozhang Zhou
Department of Medical Oncology, The Cancer Institute, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
Correspondence should be addressed to Lianying Ge; gelianying2013@163.com
Received 8 April 2014; Accepted 4 November 2014; Published 30 November 2014
Academic Editor: Daiming Fan
TABLE 1: Main characteristics of the studies included in the meta-
analysis.
Number of
Patients
Study Country Duration (A/B)
PS (score)
Muro et al. 2010 [9], Japan Jan. 2006-Jan. 2008 213/213
Baba et al. 2011 [18]
Katoetal. 2011 [8] Japan July 2007-Mar. 2010 30/30
Ojima et al. 2011 [10], Japan July 2008-July 2009 56/49
Otsuji et al. 2012 [19] 0-1
Yamada et al. 2013 Japan Feb. 2009-Mar. 2011 256/255
[16] 0-1
Yang and Li 2013 [17] China Jan. 2010-Jun. 2012 30/28
Xie et al. 2013 [14] China Mar. 2009-Sep. 2012 23/22
Wang et al. 2013 [13] China Mar. 2008-Dec. 2012 22/21
Wang et al. 2012 [12] China NA 18/18
>70a
Tian 2011 [11] China Jun 2009-May 2011 25/24
Bian et al. 2013 [6] China Jan. 2011-Dec. 2012 90/90
0-1
Xiong et al. 2012 [15] China Mar. 2010-Jun 2011 35/30
Gao et al. 2013 [7] China Jan. 2010-Jun 2012 31/33
Study Regimen (group A and group B)
Muro et al. 2010 [9], A: irinotecan 125 mg/[m.sup.2] dldl5, S-l
Baba et al. 2011 [18] 40-60 mg (according to body surface area) bid
dl-14, q4 w B: LV 200 mg/[m.sup.2] dl,
irinotecan 150 mg/[m.sup.2] dl, 5-FU 400
mg/[m.sup.2] dl and 2400 mg/[m.sup.2] civ 46
h, q2 w
Katoetal. 2011 [8] A: irinotecan 150 mg/[m.sup.2] dl, S-l 80
mg/[m.sup.2] d3-16, bevacizumab 7.5 mg/kg, q3
w
B: irinotecan 150 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, bevacizumab 5
mg/kg, q2 w
Ojima et al. 2011 [10], A: S-l 40-60 mg bid dl-7, oral LV 25 mg bid
Otsuji et al. 2012 [19] dl-7, oxaliplatin 85 mg/[m.sup.2] dl, q2 w B:
oxaliplatin 85 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q2 w
Yamada et al. 2013 A: oxaliplatin 130 mg/[m.sup.2] dl, S-l 40-60
[16] mg (according to body surface area) bid
dl-14, bevacizumab 7.5 mg/kg, q3 w
B: bevacizumab 5 mg/kg, LV 200 mg/[m.sup.2]
dl, oxaliplatin 85 mg/[m.sup.2] dl, 5-FU 400
mg/[m.sup.2] dl and 2400 mg/[m.sup.2] civ 46
h, q2 w
Yang and Li 2013 [17] A: irinotecan 180 mg/[m.sup.2] dl, S-l 80
mg/[m.sup.2] dl-14, q3 w
B: irinotecan 180 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q2 w
Xie et al. 2013 [14] A: S-l 80 mg/[m.sup.2] dl-14, oxaliplatin 100
mg/[m.sup.2] dl, q3 w
B: oxaliplatin 100 mg/[m.sup.2] dl, LV 400
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q2 w
Wang et al. 2013 [13] A: S-l 80 mg/[m.sup.2] dl-14, oxaliplatin 130
mg/[m.sup.2] dl, q3 w
B: oxaliplatin 130 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q3 w
Wang et al. 2012 [12] A: S-l 80 mg/[m.sup.2] dl-14, oxaliplatin 85
mg/[m.sup.2] dl, q4 w B: oxaliplatin 85
mg/[m.sup.2] dl, LV 200 mg/[m.sup.2] dl, 5-FU
300 mg/[m.sup.2] dl-5, q4 w
Tian 2011 [11] A: irinotecan 125 mg/[m.sup.2] dldl5, S-l
40-60 mg (according to body surface area) bid
dl-14, q4 w
B: irinotecan 150 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q2 w
Bian et al. 2013 [6] A: S-l 80 mg/[m.sup.2] dl-14, oxaliplatin 85
mg/[m.sup.2] dl, q4 w
B: oxaliplatin 85 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 300 mg/m.2 dl-5, q4 w
Xiong et al. 2012 [15] A: S-l 80 mg/[m.sup.2] dl-14, oxaliplatin 100
mg/[m.sup.2] dl, q3 w
B: oxaliplatin 100 mg/[m.sup.2] dl, LV 400
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] dl and
2400 mg/[m.sup.2] civ 46 h, q2 w
Gao et al. 2013 [7] A: irinotecan 100 mg/[m.sup.2] dld8, S-l 40
mg/[m.sup.2] dl-14, q3 w
B: irinotecan 180 mg/[m.sup.2] dl, LV 200
mg/[m.sup.2] dl, 5-FU 400 mg/[m.sup.2] iv
dld2 and 600 mg/[m.sup.2] civ 22 h, dld2, q2
w
Study Outcome measures
Muro et al. 2010 [9],
Baba et al. 2011 [18] ORR, PFS, OS,
toxicities
Katoetal. 2011 [8]
ORR, toxicities
Ojima et al. 2011 [10], ORR, PFS, SR, OS,
Otsuji et al. 2012 [19] toxicities
Yamada et al. 2013 ORR, PFS, OS,
[16] toxicities
Yang and Li 2013 [17] ORR, toxicities
Xie et al. 2013 [14] ORR, TTP, toxicities
Wang et al. 2013 [13] ORR, toxicities
Wang et al. 2012 [12] ORR, TTP, MST,
toxicities
Tian 2011 [11]
ORR, TTP, toxicities
Bian et al. 2013 [6] ORR, toxicities
Xiong et al. 2012 [15]
ORR, toxicities
Gao et al. 2013 [7]
ORR, toxicities
Study Study design
Muro et al. 2010 [9],
Baba et al. 2011 [18] Randomized phase
II/III study
Katoetal. 2011 [8]
Randomized pilot study
Ojima et al. 2011 [10], Randomized phase II
Otsuji et al. 2012 [19] trial
Yamada et al. 2013 Randomized phase III
[16] trial
Yang and Li 2013 [17] Randomized controlled
trial
Xie et al. 2013 [14] Randomized controlled
trial
Wang et al. 2013 [13] Randomized controlled
trial
Wang et al. 2012 [12] Randomized controlled
trial
Tian 2011 [11]
Randomized controlled
trial
Bian et al. 2013 [6] Randomized controlled
trial
Xiong et al. 2012 [15]
Randomized controlled
trial
Gao et al. 2013 [7]
Randomized controlled
trial
Note: LV: leucovorin; 5-FU: 5-fluorouracil; PS: performance status;
ORR: overall response rate; OS: overall survival; PFS: progression-
free survival; MST: median survival time; TTP: time to progression;
SR: survival rate; dl-14: days 1-14; q3 w: every 3 weeks; q4 w: every
4 weeks; q6 w: every 6 weeks; bid: twice a day; NA: not available;
civ: continuous intravenous infusion; (a)Karnofsky method.
TABLE 2: Outcome of toxicity meta-analysis comparing S-1 versus 5-FU
in advanced colorectal cancer.
Toxicity Trials SBT FBT
Grade 3-4 neutropenia 3 96/291 143/284
Grade 3-4 leucopenia 10 79/734 100/726
Grade 3-4 anemia 9 41/712 31/705
Grade 3-4 thrombocytopenia 9 15/709 14/702
Grade 3-4 diarrhea 12 92/820 49/805
Grade 3-4 nausea/vomit 10 15/739 38/732
Grade 3-4 stomatitis 9 11/716 4/710
Treatment-related death 5 4/545 6/542
Toxicity Heterogeneity
P value [I.sup.2] (%)
Grade 3-4 neutropenia 0.73 0
Grade 3-4 leucopenia 0.28 18
Grade 3-4 anemia 0.40 3
Grade 3-4 thrombocytopenia 0.28 21
Grade 3-4 diarrhea <0.1 64
Grade 3-4 nausea/vomit 0.56 0
Grade 3-4 stomatitis 0.24 28
Treatment-related death 0.71 0
Toxicity OR (95% CI)
Grade 3-4 neutropenia 0.49 [0.35, 0.68]
Grade 3-4 leucopenia 0.75 [0.55,1.04]
Grade 3-4 anemia 1.33 [0.83, 2.15]
Grade 3-4 thrombocytopenia 1.05 [0.51, 2.15]
Grade 3-4 diarrhea 1.25 [0.58, 2.69]
Grade 3-4 nausea/vomit 0.41 [0.23, 0.72]
Grade 3-4 stomatitis 2.21 [0.83, 5.88]
Treatment-related death 0.72 [0.24, 2.19]
Toxicity Model P value
Grade 3-4 neutropenia Fixed <0.01
Grade 3-4 leucopenia Fixed 0.08
Grade 3-4 anemia Fixed 0.24
Grade 3-4 thrombocytopenia Fixed 0.89
Grade 3-4 diarrhea Random 0.57
Grade 3-4 nausea/vomit Fixed <0.01
Grade 3-4 stomatitis Fixed 0.11
Treatment-related death Fixed 0.57
Notes: NA: not available; OR: odds ratio; CI: confidence interval;
FBT: 5-fluorouracil-based therapy; SBT: S-1-based therapy.
FIGURE 2: Risk of bias summary: review authors' judgements about each
risk of bias item for each included study.
Yang and Li 2013 Yamada et al., 2013
Random sequence generation (?) (+)
(selection bias)
Allocation concealment (?) (+)
(selection bias)
Blinding of participants and (b) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (+)
(attrition bias)
Selective reporting (reporting (+) (+)
bias)
Other bias (+) (+)
Xiong et al., 2012 Xie et al., 2013
Random sequence generation (?) (?)
(selection bias)
Allocation concealment (?) (?)
(selection bias)
Blinding of participants and (+) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (+)
(attrition bias)
Selective reporting (reporting (+) (+)
bias)
Other bias (+) (+)
Wang et al., 2013 Wang et al., 2012
Random sequence generation (?) (?)
(selection bias)
Allocation concealment (?) (?)
(selection bias)
Blinding of participants and (+) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (+)
(attrition bias)
Selective reporting (reporting (+) (+)
bias)
Other bias (+) (+)
Tian 2011 Ojima et al., 2011
Random sequence generation (?) (?)
(selection bias)
Allocation concealment (?) (?)
(selection bias)
Blinding of participants and (+) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (?)
(attrition bias)
Selective reporting (reporting (+) (?)
bias)
Other bias (+) (?)
Muro et al., 2010 Kato et al., 2011
Random sequence generation (+) (?)
(selection bias)
Allocation concealment (+) (?)
(selection bias)
Blinding of participants and (+) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (?)
(attrition bias)
Selective reporting (reporting (+) (?)
bias)
Other bias (+) (?)
Gao et al., 2013 Bian et al., 2013
Random sequence generation (?) (+)
(selection bias)
Allocation concealment (?) (?)
(selection bias)
Blinding of participants and (+) (+)
personnel (performance bias)
Blinding of outcome assessment (+) (+)
(detection bias)
Incomplete outcome data (+) (+)
(attrition bias)
Selective reporting (reporting (+) (+)
bias)
Other bias (+) (+)
Note: yellow = (?) and green = (+)
FIGURE 4: Forest plot of hazard ratio of overall survival.
Study or subgroup Weight Hazard ratio Hazard ratio
IV, fixed, 95% CI IV, fixed, 95% CI
Muro et al., 2010 56.5% 0.90 [0.73, 1.12]
Ojima et al., 2011 9.0% 0.76 [0.45, 1.30]
Yamada et al., 2013 34.5% 1.05 [0.80, 1.38]
Total (95% CI) 100.0% 0.94 [0.80, 1.10]
Heterogeneity: [chi square] = 1.39, df =2 (P = 0.50); [I.sup.2] = 0%
Test for overall effect: Z = 0.82 (P = 0.41)
FIGURE 5: Forest plot of odds ratio of one- or two-year survival rate.
Study or subgroup S-1 5-FU
Events Total Events Total Weight
4.1.1 1-year survival rate
Muro et al., 2010 125 213 126 213 57.4%
Ojima et al., 2011 48 56 39 49 6.6%
Yamada et al., 2013 218 256 220 255 36.1%
Subtotal (95% CI) 525 517 100.0%
Total events 391 385
Study or subgroup Odds ratio Odds ratio
M-H, fixed, 95% CI M-H, fixed, 95% CI
4.1.1 1-year survival rate
Muro et al., 2010 0.98 [0.67, 1.44]
Ojima et al., 2011 1.54 [0.55, 4.27]
Yamada et al., 2013 0.91 [0.56, 1.50]
Subtotal (95% CI) 0.99 [0.74, 1.33]
Total events
Heterogeneity: [chi square] = 0.82, df =2 (P = 0.66); [I.sup.2] = 0%
Test for overall effect: Z = 0.05 (P = 0.96)
4.1.2 2-year survival rate
Muro et al., 2010 24 213 24 213 23.3%
Ojima et al., 2011 40 56 29 49 9.7%
Yamada et al., 2013 89 256 94 255 67.1%
Subtotal (95% CI) 525 517 100.0%
Total events 153 147
4.1.2 2-year survival rate
Muro et al., 2010 1.00 [0.55, 1.82]
Ojima et al., 2011 1.72 [0.76, 3.89]
Yamada et al., 2013 0.91 [0.64, 1.31]
Subtotal (95% CI) 1.01 [0.76, 1.35]
Total events
Heterogeneity: [chi square] = 1.96, df =2 (P = 0.37); [I.sup.2] = 0%
Test for overall effect: Z = 0.08 (P = 0.94)
FIGURE 6: Forest plot of hazard ratio of progression-free survival.
Hazard ratio Hazard ratio
Study or subgroup Weight IV, fixed, 95% CI IV, fixed, 95% CI
Muro et al., 2010 45.90% 1.06 [0.87, 1.29]
Ojima et al., 2011 6.50% 0.83 [0.49, 1.40]
Yamada et al., 2013 47.70% 1.04 [0.86, 1.27]
Total (95% CI) 100.00% 1.03 [0.91, 1.18]
Heterogeneity: [chi square] = 0.73, df = 2 (P = 0.69); [I.sup.2] = 0%
Test for overall effect: Z = 0.50 (P = 0.62)
FIGURE 7: Forest plot of odds ratio of overall response rate.
S-1 5-FU
Study or subgroup Events Total Events Total Weight
Bian et al., 2013 57 90 38 90 9.4%
Gao et al., 2013 20 31 15 33 3.5%
Kato et al., 2011 17 29 16 28 4.5%
Muro et al., 2010 34 181 29 174 16.1%
Ojima et al., 2011 31 56 26 49 8.3%
Tian 2011 5 25 4 24 2.2%
Wang et al., 2012 11 18 8 18 2.1 %
Wang et al., 2013 10 22 8 21 3.0%
Xie et al., 2013 11 23 12 22 4.3%
Xiong et al., 2012 19 35 14 30 4.6%
Yamada et al., 2013 144 234 146 233 37.8%
Yang and Li 2013 20 30 18 28 4.2%
Total (95% CI) 774 750 100.0%
Total events 379 334
Odds ratio Odds ratio
Study or subgroup M-H, fixed, 95% CI M-H, fixed, 95% CI
Bian et al., 2013 2.36 [1.30, 4.30]
Gao et al., 2013 2.18 [0.80, 5.96]
Kato et al., 2011 1.06 [0.37, 3.04]
Muro et al., 2010 1.16 [0.67, 2.00]
Ojima et al., 2011 1.10 [0.51, 2.37]
Tian 2011 1.25 [0.29, 5.35]
Wang et al., 2012 1.96 [0.52, 7.41]
Wang et al., 2013 1.35 [0.40, 4.57]
Xie et al., 2013 0.76 [0.24, 2.47]
Xiong et al., 2012 1.36 [0.51, 3.61]
Yamada et al., 2013 0.95 [0.66, 1.39]
Yang and Li 2013 1.11 [0.38, 3.28]
Total (95% CI) 1.23 [1.00, 1.53]
Total events
Heterogeneity: [chi square] = 9.02, df =11 (P = 0.62); [I.sup.2] = 0%
Test for overall effect: Z = 1.91 (P = 0.06)
FIGURE 8: Forest plot of odds ratio of disease control rate.
Study or subgroup S-1 5-FU Weight
Events Total Events Total
Bian et al., 2013 75 90 66 90 17.4%
Gao et al., 2013 26 31 24 33 5.9%
Kato et al., 2011 28 29 26 28 1.4%
Ojima et al., 2011 52 56 42 49 5.1%
Tian 2011 19 25 16 24 6.2%
Wang et al., 2012 15 18 12 18 3.2%
Wang et al., 2013 17 22 15 21 5.5%
Xie et al., 2013 16 23 19 22 9.4%
Xiong et al., 2012 29 35 23 30 6.7%
Yamada et al., 2013 209 234 208 233 35.2%
Yang and Li 2013 27 30 24 28 3.9%
Total (95% CI) 593 576 100.0%
Total events 513 475
Study or subgroup Odds ratio Odds ratio
M-H, fixed, 95% CI M-H, fixed, 95% CI
Bian et al., 2013 1.82 [0.88, 3.75]
Gao et al., 2013 1.95 [0.57, 6.64]
Kato et al., 2011 2.15 [0.18, 25.19]
Ojima et al., 2011 2.17 [0.59, 7.90]
Tian 2011 1.58 [0.45, 5.53]
Wang et al., 2012 2.50 [0.51, 12.14]
Wang et al., 2013 1.36 [0.34, 5.38]
Xie et al., 2013 0.36 [0.08, 1.63]
Xiong et al., 2012 1.47 [0.43, 4.98]
Yamada et al., 2013 1.00 [0.56, 1.81]
Yang and Li 2013 1.50 [0.30, 7.39]
Total (95% CI) 1.37 [0.99, 1.89]
Total events
Heterogeneity: [chi square] = 6.23, df =2 (P = 0.80); [I.sup.2] = 0%
Test for overall effect: Z = 1.92 (P = 0.06)
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| Author: | Ye, Jiaxiang; Chen, Jiawei; Ge, Lianying; Liu, Aiqun; Zhou, Shaozhang |
|---|---|
| Publication: | Gastroenterology Research and Practice |
| Article Type: | Report |
| Date: | Jan 1, 2014 |
| Words: | 7486 |
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