Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang & Geng Liu To cite this article: Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang & Geng Liu (2015) Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia, Journal of Chemotherapy, 27:4, 227-234 To link to this article: http://dx.doi.org/10.1179/1973947815Y.0000000013
Published online: 20 Mar 2015.
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Date: 17 March 2016, At: 05:21
Anticancer Original Research Paper
Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang, Geng Liu
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Department of General Surgery, The Second Hospital of Tianjin Medical University, Tianjin Medical University, People’s Republic of China Introduction: After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer. Methods: Relevant trials were identified by searching databases. Five trials were selected in this article. The indicators we used were overall response rate, disease control rate, 1-year survival rate and haematological toxicities. Results: Meta-analysis of the pooled data demonstrated that the overall response rate (risk ratio, RR52.52, 95% confidence interval, CI: 1.85–3.42, Pv0.00001) and disease control rate (RR51.24, 95% CI: 1.12– 1.37, Pv0.0001) were significantly different for the GS and GEM alone chemotherapies. Among the group of patients, 43.4% in the GS group and 31.4% in the GEM group survived more than a year. According to this, patients who use the GS regiment may have a better prognosis than the GEM regiment (RR51.62, 95% CI: 1.12–2.33, P50.04). The combination chemotherapy with GEM and S-1 group had higher haematological toxicities including neutropaenia (RR51.58, 95% CI: 1.17–2.14, P50.003) and thrombocytopaenia (RR51.85, 95% CI: 1.28–2.67, P50.001). The incidence of anaemia was much the same in the two groups (RR51.22, 95% CI: 0.87–1.70, P50.24). Discussion: Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone. Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients, at least in Asia. Mini Abstract: This systematic review analysing randomized controlled trials (RCTs) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response, disease control and 1-year survival proportion. Keywords: Pancreatic cancer, Chemotherapy, Gemcitabine, S-1, Meta-analysis
Introduction Pancreatic cancer is one of the most frequently observed gastrointestinal cancers and is becoming a leading cause of cancer-related death worldwide.1 The incidence of the disease is nearly equivalent to the death rate associated with the diagnosis of Correspondence to: Jinjin Sun, Department of General Surgery, The Second Hospital of Tianjin Medical University, Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin, China. Email: [email protected]
ß 2015 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947815Y.0000000013
pancreatic cancer. Among a majority of patients present with locally advanced or metastatic disease, the median life expectancy is 3–6 months for metastatic disease and 6–10 months for non-metastatic disease.2 Some patients are eligible for surgery at diagnosis, but the outcome of advanced pancreatic cancer remains dismal. So, development of more effective treatment is essential to improve patient survival. In recent years, the systemic administration of gemcitabine (GEM) has been accepted as a standard
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first-line treatment for patients with advanced pancreatic cancer.3 However, patients who receive this therapy have a median overall survival (OS) of only 5.65 months. There is a clear need to improve its efficacy by combining it with other anticancer drugs. FOLFIRINOX, GEM/cisplatin/epirubicin/ 5-FU(PEFG), GEM/NAB-paclitaxel(NAB-P), GEM/erlotinib+ bevacizumab, GEM/capecitabine and GEM/oxaliplatin were associated with statistically significant improvements in OS and progression free survival relative to GEM alone.4 S-1 is a new oral anticancer agent that consists of a 5-FU prodrug (tegafur) and two modulators of 5-FU metabolism, gimeracil and oteracil, in a 1:0.4:1 molar concentration ratio.5 Recently, S-1 has demonstrated single-agent activity in advanced pancreatic cancer, with a 21–37.5% overall response rate.6 Many studies have shown that GS is reportedly well tolerated and active against advanced pancreatic cancer.1,7 There are a large number of clinical trials involving GS in the management of advanced pancreatic cancer. However, it is not fully clear whether overall response rate, disease control rate and 1-year survival rate using combination chemotherapy with GEM and S-1 (GS) are superior to that using GEM alone. Therefore, we conducted a meta-analysis to assess the efficacy and safety of GS therapy in patients with locally advanced or metastatic pancreatic cancer.
Methods Search strategy Trials were identified by searching MEDLINE, EMBASE, ISI Web of Science and the Cochrane Central Register of Controlled Trials from 1966 to July 2014. In addition, references of selected articles and previous systematic reviews were scanned for any other relevant trials, and original trialists were contacted for possible unpublished trials. The search strategy for these trials included the following search keys: ((‘pancreas’ or ‘pancreatic’) and (‘cancer’ or ‘carcinoma’ or ‘tumour’) and(‘ S-1’ or ‘gemcitabine’ or ‘chemotherapy’)) or((‘pancreas’ or ‘pancreatic’) and (‘cancer’ or ‘carcinoma’)and (‘non-metastatic’ or ‘non-metastatic’) and (‘unresectable’ or ‘non-resectable’ or ‘locally advanced’)), without language restriction. Randomized controlled trials (RCTs) are the most appropriate.
Selection criteria To be eligible for inclusion, trials were required to be properly RCTs including patients treated with GS or GEM alone. Well designed trials are the best. Patients with locally advanced or metastatic disease were included in the study, and histologic or confirmation of pancreatic cancer was required.
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If a trial included concomitant interventions such as radiotherapy or radioisotope treatment that differed systematically between the investigated arms, the trial was excluded. If patients in trials had active coronary artery disease, unstable diabetes mellitus or an active concomitant malignancy, the trials were excluded too. Only randomized trials were included, and randomisation must have started on or after 1 January 1965. The deadline for eligible trial publication was 30 July 2014.
Data collection Two authors (Yanxun Li and Zhijia Jiang.) independently identified trials for inclusion, extracted data related to the specified outcomes, and assessed the risk of bias in the trials. If one of the reviewers determined that an abstract was eligible, the full text of article was retrieved and reviewed in detail by all reviewers. The authors also cross-checked all data collected against the original articles. All differences of opinion were resolved by discussion between authors.
Statistical analysis The primary outcome measurements were overall response rate, disease control rate and 1-year survival rate, while the secondary endpoint was haematological toxicities. Toxicities recorded by the original research group were recorded in our analysis, and the most frequent events were analyzed. Trial level risk ratio (RR) and 95% confidence interval (CI) were obtained for each survival outcome. A general variance-based method was used to estimate the pooled RR and 95% CI.7 All statistical tests were two-sided, and P-values of 0.05 or less were considered to be statistically significant. Funnel plot analysis was used for an appraisal of publication bias. Judgements about each risk of bias item for each included study were accessed by the Cochrane Collaboration’s tool.8 Heterogeneity of the effect across trials was assessed by the chi-square statistic. A fixed effect approach was adopted unless there was evidence of significant unexplained heterogeneity, in which case a random effects approach was used. All statistical analyses were conducted with Review Manager 5.2.
Results The results of the search strategy for studies are summarized in Fig. 1. The literature search uncovered 188 articles. Primary screening led to the exclusion of 146 articles for the following reasons: case reports (57), reviews (37), other cancers or diseases (18), other agents/regimens (17) and radiotherapy/chemoradiotherapy (17). The remaining 46 papers were retrieved for more detailed evaluation. Of these, 28 articles were excluded because combination chemotherapy with S-1 and GEM was not mentioned,
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Figure 1 Flow chart for trials selection in the meta-analysis.
2 for biliary tract cancer and 11 because the design was not controlled. In the end, a total of five randomized clinical trials were eligible for inclusion in our analysis.9–13 Table 1 shows the basic characteristics of the eligible trials. Each study of chemotherapy regimens are shown in Table 2. There is only a little difference among chemotherapy regiments. For example, Ozaka M. used GS regiment: 1000 mg/m2 GEM on days 1 and 8, combined with 80 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks; and Nakai Y. used GS regiment: 1000 mg/m2GEM on days 1 and 15, combined with 80–120 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks. The above differences we have considered and have no effect on our study.
response. The overall response rate was reported in the five trials, which comprised 909 patients with pancreatic cancer, of whom 476 received GEM alone and 433 received the GS combination. Meta-analysis of the pooled data demonstrated that the overall response rate was significantly different for the GS and GEM alone chemotherapies (RR52.52, 95% CI: 1.85–3.42, Pv0.00001, Fig. 2). This suggested that GS can remarkably improve overall response rate compared with GEM alone in pancreatic cancer.
Efficacy
One-year survival rate After processing the data, we use 1-year survival rate to evaluate survival rate of patients. Out of this, 43.4% in the GS group and 31.4% in the GEM
Overall response rate The overall response rate was defined as the proportion of patients who had a complete response or partial
Disease control rate The disease control rate was defined as the proportion of patients who had a complete response, partial response or stable disease. This result demonstrated that GS may be more effective than GEM alone (RR51.24, 95% CI: 1.12–1.37, Pv0.0001, Fig. 3).
Table 1 Characteristics of the eligible trials included in the meta-analysis
Trial
No. of pts Regimens (per arm)
Ozaka et al.9
112
Nakai et al.10
106
Suzuki et al.
107
Ueno et al.12
552
Sudo et al.13
101
11
GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM
No. of pts (per arm) 53 59 53 53 34 73 275 277 51 50
Male (%) Median age (range) ECOG ps (0–2) (%) M* (%) 60.4 59.3 79.2 62.3 41.2 58.9 57.5 61.4 52.9 68.0
64 (45-77) 64 (41-79) 63 (40-82) 67 (42-84) 66.5 (48-84) 68.3 (43-83) i65 (50.2%) i65 (51.6%) 66 (50-77) 67 (45-73)
100 100 100 100 100 100 100 100 100 100
75.5 69.5 71.7 75.5 52.9 52.1 75.3 76.2 64.7 62
GEM: gemcitabine; ECOG ps: Eastern Cooperative Oncology Group performance status; M*: metastatic disease.
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Table 2 Regimens of the trials included in this analysis Trial
Arm
Regimens
Ozaka et al.9
GEMzS-1
Nakai et al.10
GEM GEMzS-1
Suzuki et al.11
GEM GEMzS-1
Ueno et al.12
GEM GEMzS-1
1000 mg/m2GEM on days 1 and 8, combined with 80 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 15,combined with 80–120 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 8, combined with 40 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 8, combined with 60–100 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 8 and 15, combined with 60 mg/m2 oral S-1 twice daily on days 1–15, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks
GEM Sudo et al.13
GEMzS-1
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GEM
Figure 2 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – overall response rate.
Figure 3 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – disease control rate.
group of patients survived more than a year. According to this, patients who used the GS regiment may have a better prognosis than GEM regiment (RR51.62, 95% CI: 1.12–2.33, P50.04, Fig. 4).
Haematology toxicity The major grade 3–4 adverse events regarding haematological toxicities are compared in Figs. 5–7. These results suggested that GS group have higher haematological
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toxicities including neutropaenia (RR51.58, 95% CI: 1.17–2.14, P50.003, Fig. 5) and thrombocytopaenia (RR51.85, 95% CI: 1.28–2.67, P50.001, Fig. 7). The incidence of anaemia was much the same in the two groups (RR51.22, 95% CI: 0.87–1.70, P50.24, Fig. 6). Although the frequency of grade 3–4 adverse events in the GS group was higher than that in the GEM group regarding haematological toxicities, the toxicities were predictable and manageable.
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Figure 4 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – 1-year survival rate.
Figure 5 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3 –4 adverse events: neutropaenia.
Figure 6 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3 –4 adverse events: anaemia.
Figure 7 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3– 4 adverse events: thrombocytopaenia.
Examination of the funnel plots revealed evidence of bias, possibly publication bias, but this is difficult to interpret in view of the small number of studies within each comparison. This analysis ruled out possible issues related to publication bias. Furthermore, judgements about the
risk of bias, as well as other factors affecting the quality of evidence such as publication bias, were considered when interpreting the results of our systematic review. A detailed report in is provided in Fig. 8. Although some projects had high risk of bias, this had little influence on our results.
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Figure 8 Judgements about each risk of bias item for each included study.
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Discussion Pancreatic adenocarcinoma is among the most challenging of solid malignancies to treat on account of its propensity for late presentation with inoperable disease, aggressive tumour biology and resistance to chemotherapy.14 There have been no real medical breakthroughs with regard to improving the prognosis of this dismal disease.15 Despite our increasing knowledge about numerous genetic alterations, such as mutations of oncogenes, tumour suppressor genes, altered pathways of apoptosis, etc., all known drugs targetting these defects do not really prolong life expectancy. Development of more effective treatment is essential to improve patient survival and quality of life. Gemcitabine monotherapy is accepted as a standard first-line treatment for locally advanced unresectable or metastatic pancreatic cancer.16 Recently, Sultana A. et al. concluded that there was insufficient evidence of a survival difference between GEM and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR 0.75; 95% CI, 0.42–1.31).17 Compared with GEM alone, GEM combination chemotherapy can markedly improve the survival of patients (HR 0.91; 95% CI, 0.85–0.97).. This study suggested that there was a significant survival benefit for chemotherapy over best supportive care and GEM combinations over GEM alone, supporting the use of GEMbased combination chemotherapy in the treatment of advanced pancreatic cancer. S-1 is a new oral anticancer agent that consists of a 5-FU prodrug (tegafur) and two modulators of 5-FU metabolism, gimeracil and oteracil, in a 1:0.4:1 molar
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concentration ratio.5 Worthy to note, tegafur is gradually converted to 5-FU in the liver after oral ingestion and gimeracil is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in the catabolism of 5-FU. Moreover, oteracil preferentially localizes in the gut and inhibits phosphorylation of 5-FU. On another front, S-1 and GEM combination chemotherapy is challenging but promising. In the past few decades, many trials evaluated GEM combined with various cytotoxic or targetted agents to try to ameliorate prognosis of patients with pancreatic cancer. Intriguingly, some of these studies have reported enhanced median OS and 1year survival rates.1,15,17 Two RCTs comparing chemoradiation therapy with GEM alone have been conducted. A French group reported an inferior outcome with radiation therapy plus 5-FU and cisplatin compared to chemotherapy with GEM alone.18 The ECOG study demonstrated that radiation therapy plus GEM had a superior survival outcome to GEM alone.19 Thus, these two recent RCTs comparing chemoradiation therapy with GEM alone have verified a conflicting survival results. It remains unclear whether chemoradiation therapy or chemotherapy alone has a better outcome in patients with locally advanced pancreatic cancer. This clinical question should also be evaluated in the future. However, the question of whether GS is better than GEM monotherapy is still unclear. This review of chemotherapy in pancreatic cancer aimed to assess the key issues, including overall response rate, disease control rate, 1-year survival rate and haematological toxicities in GS group and GEM group. Our analysis showed that the overall response rate (Pv0.00001), disease control rate (Pv0.0001) and 1-year survival (P50.0004) in the GS group were overwhelmingly better than those in the GEM group. Our findings of improved response rate and 1-year survival are in agreement with the meta-analyses of Sultana A et al.20 Furthermore, we used grade 3–4 adverse events to analysis safety as well. In this study, haematological toxicities including anaemia, neutropaenia and thrombocytopaenia were conducted in a comprehensive analysis insinuating that the GS group has higher haematological toxicities, such as neutropaenia and thrombocytopaenia. Although the frequency of grade 3–4 adverse events in the GS group was higher than that in the GEM group regarding haematological toxicities, the toxicities were predictable and manageable. Last but not least, some studies are consistent with our results.21,22 Currently, there are a lot of combined chemotherapy of pancreatic cancer. It is very
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important especially in combination chemotherapy of GEM. Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with GEM monotherapy.23 Overall survival was significantly improved (HR 0.83, Pv0.01; HR 0.87, P?5?0.03; HR 0.80, P50.01; respectively) and objective response rate (ORR) was significantly increased (OR 0.51, Pv0.01; OR 0.66, P50.03; OR 0.35, Pv0.01; respectively) in the GEMz5FU/CAP/S-1, GEMzCAP and GEMzS-1 groups compared to the GEM alone group.24 Besides, addition of an agent against EGFR to GEMbased chemotherapy improved the OS and ORR compared to GEM-based chemotherapy alone in patients with advanced pancreatic cancer.25 In addition, GEM plus erlotinib for treating advanced pancreatic cancer may provide better efficacy and safety.26 All in all, compared with GEM monotherapy, combinations of two or more drugs may improve outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings. However, not all GEM combination therapy is superior to the GEM monotherapy. The combination SUNGEM was not sufficiently superior in locally advanced or metastatic PDAC compared to GEM alone associated with more toxicity.27 According to some RCTs, we demonstrated GS may offer greater benefits than GEM alone. In the future, we will continue to face a lot of challenges in the treatment of pancreatic cancer. H. A. Al and T. E. Adrian give us some advice; it is clear that to really make an impact on this disease, it will be necessary to address three different problems with targetted therapeutics.28 First, it is of great importance to eradicate pancreatic cancer stem cells that will result in recurrence. Second, reducing the peritumoral stroma is of great significance or profundity, as peritumoral stroma provides the tumours with growth support and provides a barrier to access of therapeutic agents. Finally, it is important to address the marked cachexia and metabolic derangement that contribute to morbidity and mortality and further complicate therapeutic intervention. In conclusion, this analysis has elucidated that overall response rate and disease control rate as well as 1-year survival in patients who received GS were superior to those treated with GEM alone. This study suggests that GS may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. In addition, more detailed meta-analyses are required to better illuminate the comparative benefits and harms of combination chemotherapy regimens.
Meta-analysis of pancreatic cancer chemotherapy in Asia
Disclaimer Statements Contributors Guarantor of integrity of entire study : Yanxun Li, Jinjin Sun Study concepts : Yanxun Li, Jinjin Sun. Study design : Yanxun Li, Jinjin Sun. Literature research : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Data acquisition : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Data analysis/interpretation : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Statistical analysis : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Manuscript preparation : Yanxun Li, Jinjin Sun. Manuscript definition of intellectual content : Yanxun Li, Jinjin Sun. Manuscript editing : Yanxun Li, Jinjin Sun. Manuscript revision/review : Yanxun Li, Jinjin Sun. Manuscript fnal version approval : Yanxun Li, Jinjin Sun.
Funding Funding was received fromt the Welcome Trust.
Conflicts of interest There was no conflict among the authors.
Ethics approval This paper is a meta-analysis. The literatures we selected have obtained ethics committee approval.
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cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29(31):4105–12. Sultana A, Tudur SC, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses. Br J Cancer. 2008;99(1):6–13. Song H, Han B, Park CK, Kim JH, Jeon JY, Kim IG, et al. Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2013;72(4):845–52. Yanagimoto H, Ishii H, Nakai Y, Ozaka M, Ikari T, Koike K, et al. Improved survival with combined gemcitabine and S-1 for locally advanced pancreatic cancer: pooled analysis of three randomized studies. J Hepatobiliary Pancreat Sci. 2014;21(10):761–6. Sun C, Ansari D, Andersson R, Wu DQ. Does gemcitabinebased combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol. 2012;18(35): 4944–58. Li Q, Yan H, Liu W, Zhen H, Yang Y, Cao B. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomized controlled trials. PLoS One. 2014;9(8):e104346. Tian W, Ding W, Kim S, Xu X, Pan M, Chen S. Efficacy and safety profile of combining agents against epidermal growth factor receptor or vascular endothelium growth factor receptor with gemcitabine-based chemotherapy in patients with advanced pancreatic cancer: a meta-analysis. Pancreatology. 2013;13(4):415–22. Yang ZY, Yuan JQ, Di MY, Zheng DY, Chen JZ, Ding H, et al. Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis. PLoS One. 2013;8(3):e57528. Bergmann L, Maute L, Heil G, Russel J, Weidmann E, Koberle D, et al. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Eur J Cancer. 2015;51(1):27–36. Al HA, Adrian TE. Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma. Expert Opin Investig Drugs. 2014;23(11):1499–515.
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang & Geng Liu To cite this article: Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang & Geng Liu (2015) Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia, Journal of Chemotherapy, 27:4, 227-234 To link to this article: http://dx.doi.org/10.1179/1973947815Y.0000000013
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Date: 17 March 2016, At: 05:21
Anticancer Original Research Paper
Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang, Geng Liu
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Department of General Surgery, The Second Hospital of Tianjin Medical University, Tianjin Medical University, People’s Republic of China Introduction: After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer. Methods: Relevant trials were identified by searching databases. Five trials were selected in this article. The indicators we used were overall response rate, disease control rate, 1-year survival rate and haematological toxicities. Results: Meta-analysis of the pooled data demonstrated that the overall response rate (risk ratio, RR52.52, 95% confidence interval, CI: 1.85–3.42, Pv0.00001) and disease control rate (RR51.24, 95% CI: 1.12– 1.37, Pv0.0001) were significantly different for the GS and GEM alone chemotherapies. Among the group of patients, 43.4% in the GS group and 31.4% in the GEM group survived more than a year. According to this, patients who use the GS regiment may have a better prognosis than the GEM regiment (RR51.62, 95% CI: 1.12–2.33, P50.04). The combination chemotherapy with GEM and S-1 group had higher haematological toxicities including neutropaenia (RR51.58, 95% CI: 1.17–2.14, P50.003) and thrombocytopaenia (RR51.85, 95% CI: 1.28–2.67, P50.001). The incidence of anaemia was much the same in the two groups (RR51.22, 95% CI: 0.87–1.70, P50.24). Discussion: Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone. Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients, at least in Asia. Mini Abstract: This systematic review analysing randomized controlled trials (RCTs) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response, disease control and 1-year survival proportion. Keywords: Pancreatic cancer, Chemotherapy, Gemcitabine, S-1, Meta-analysis
Introduction Pancreatic cancer is one of the most frequently observed gastrointestinal cancers and is becoming a leading cause of cancer-related death worldwide.1 The incidence of the disease is nearly equivalent to the death rate associated with the diagnosis of Correspondence to: Jinjin Sun, Department of General Surgery, The Second Hospital of Tianjin Medical University, Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin, China. Email: [email protected]
ß 2015 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947815Y.0000000013
pancreatic cancer. Among a majority of patients present with locally advanced or metastatic disease, the median life expectancy is 3–6 months for metastatic disease and 6–10 months for non-metastatic disease.2 Some patients are eligible for surgery at diagnosis, but the outcome of advanced pancreatic cancer remains dismal. So, development of more effective treatment is essential to improve patient survival. In recent years, the systemic administration of gemcitabine (GEM) has been accepted as a standard
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first-line treatment for patients with advanced pancreatic cancer.3 However, patients who receive this therapy have a median overall survival (OS) of only 5.65 months. There is a clear need to improve its efficacy by combining it with other anticancer drugs. FOLFIRINOX, GEM/cisplatin/epirubicin/ 5-FU(PEFG), GEM/NAB-paclitaxel(NAB-P), GEM/erlotinib+ bevacizumab, GEM/capecitabine and GEM/oxaliplatin were associated with statistically significant improvements in OS and progression free survival relative to GEM alone.4 S-1 is a new oral anticancer agent that consists of a 5-FU prodrug (tegafur) and two modulators of 5-FU metabolism, gimeracil and oteracil, in a 1:0.4:1 molar concentration ratio.5 Recently, S-1 has demonstrated single-agent activity in advanced pancreatic cancer, with a 21–37.5% overall response rate.6 Many studies have shown that GS is reportedly well tolerated and active against advanced pancreatic cancer.1,7 There are a large number of clinical trials involving GS in the management of advanced pancreatic cancer. However, it is not fully clear whether overall response rate, disease control rate and 1-year survival rate using combination chemotherapy with GEM and S-1 (GS) are superior to that using GEM alone. Therefore, we conducted a meta-analysis to assess the efficacy and safety of GS therapy in patients with locally advanced or metastatic pancreatic cancer.
Methods Search strategy Trials were identified by searching MEDLINE, EMBASE, ISI Web of Science and the Cochrane Central Register of Controlled Trials from 1966 to July 2014. In addition, references of selected articles and previous systematic reviews were scanned for any other relevant trials, and original trialists were contacted for possible unpublished trials. The search strategy for these trials included the following search keys: ((‘pancreas’ or ‘pancreatic’) and (‘cancer’ or ‘carcinoma’ or ‘tumour’) and(‘ S-1’ or ‘gemcitabine’ or ‘chemotherapy’)) or((‘pancreas’ or ‘pancreatic’) and (‘cancer’ or ‘carcinoma’)and (‘non-metastatic’ or ‘non-metastatic’) and (‘unresectable’ or ‘non-resectable’ or ‘locally advanced’)), without language restriction. Randomized controlled trials (RCTs) are the most appropriate.
Selection criteria To be eligible for inclusion, trials were required to be properly RCTs including patients treated with GS or GEM alone. Well designed trials are the best. Patients with locally advanced or metastatic disease were included in the study, and histologic or confirmation of pancreatic cancer was required.
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If a trial included concomitant interventions such as radiotherapy or radioisotope treatment that differed systematically between the investigated arms, the trial was excluded. If patients in trials had active coronary artery disease, unstable diabetes mellitus or an active concomitant malignancy, the trials were excluded too. Only randomized trials were included, and randomisation must have started on or after 1 January 1965. The deadline for eligible trial publication was 30 July 2014.
Data collection Two authors (Yanxun Li and Zhijia Jiang.) independently identified trials for inclusion, extracted data related to the specified outcomes, and assessed the risk of bias in the trials. If one of the reviewers determined that an abstract was eligible, the full text of article was retrieved and reviewed in detail by all reviewers. The authors also cross-checked all data collected against the original articles. All differences of opinion were resolved by discussion between authors.
Statistical analysis The primary outcome measurements were overall response rate, disease control rate and 1-year survival rate, while the secondary endpoint was haematological toxicities. Toxicities recorded by the original research group were recorded in our analysis, and the most frequent events were analyzed. Trial level risk ratio (RR) and 95% confidence interval (CI) were obtained for each survival outcome. A general variance-based method was used to estimate the pooled RR and 95% CI.7 All statistical tests were two-sided, and P-values of 0.05 or less were considered to be statistically significant. Funnel plot analysis was used for an appraisal of publication bias. Judgements about each risk of bias item for each included study were accessed by the Cochrane Collaboration’s tool.8 Heterogeneity of the effect across trials was assessed by the chi-square statistic. A fixed effect approach was adopted unless there was evidence of significant unexplained heterogeneity, in which case a random effects approach was used. All statistical analyses were conducted with Review Manager 5.2.
Results The results of the search strategy for studies are summarized in Fig. 1. The literature search uncovered 188 articles. Primary screening led to the exclusion of 146 articles for the following reasons: case reports (57), reviews (37), other cancers or diseases (18), other agents/regimens (17) and radiotherapy/chemoradiotherapy (17). The remaining 46 papers were retrieved for more detailed evaluation. Of these, 28 articles were excluded because combination chemotherapy with S-1 and GEM was not mentioned,
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Figure 1 Flow chart for trials selection in the meta-analysis.
2 for biliary tract cancer and 11 because the design was not controlled. In the end, a total of five randomized clinical trials were eligible for inclusion in our analysis.9–13 Table 1 shows the basic characteristics of the eligible trials. Each study of chemotherapy regimens are shown in Table 2. There is only a little difference among chemotherapy regiments. For example, Ozaka M. used GS regiment: 1000 mg/m2 GEM on days 1 and 8, combined with 80 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks; and Nakai Y. used GS regiment: 1000 mg/m2GEM on days 1 and 15, combined with 80–120 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks. The above differences we have considered and have no effect on our study.
response. The overall response rate was reported in the five trials, which comprised 909 patients with pancreatic cancer, of whom 476 received GEM alone and 433 received the GS combination. Meta-analysis of the pooled data demonstrated that the overall response rate was significantly different for the GS and GEM alone chemotherapies (RR52.52, 95% CI: 1.85–3.42, Pv0.00001, Fig. 2). This suggested that GS can remarkably improve overall response rate compared with GEM alone in pancreatic cancer.
Efficacy
One-year survival rate After processing the data, we use 1-year survival rate to evaluate survival rate of patients. Out of this, 43.4% in the GS group and 31.4% in the GEM
Overall response rate The overall response rate was defined as the proportion of patients who had a complete response or partial
Disease control rate The disease control rate was defined as the proportion of patients who had a complete response, partial response or stable disease. This result demonstrated that GS may be more effective than GEM alone (RR51.24, 95% CI: 1.12–1.37, Pv0.0001, Fig. 3).
Table 1 Characteristics of the eligible trials included in the meta-analysis
Trial
No. of pts Regimens (per arm)
Ozaka et al.9
112
Nakai et al.10
106
Suzuki et al.
107
Ueno et al.12
552
Sudo et al.13
101
11
GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM GEMzS-1 GEM
No. of pts (per arm) 53 59 53 53 34 73 275 277 51 50
Male (%) Median age (range) ECOG ps (0–2) (%) M* (%) 60.4 59.3 79.2 62.3 41.2 58.9 57.5 61.4 52.9 68.0
64 (45-77) 64 (41-79) 63 (40-82) 67 (42-84) 66.5 (48-84) 68.3 (43-83) i65 (50.2%) i65 (51.6%) 66 (50-77) 67 (45-73)
100 100 100 100 100 100 100 100 100 100
75.5 69.5 71.7 75.5 52.9 52.1 75.3 76.2 64.7 62
GEM: gemcitabine; ECOG ps: Eastern Cooperative Oncology Group performance status; M*: metastatic disease.
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Table 2 Regimens of the trials included in this analysis Trial
Arm
Regimens
Ozaka et al.9
GEMzS-1
Nakai et al.10
GEM GEMzS-1
Suzuki et al.11
GEM GEMzS-1
Ueno et al.12
GEM GEMzS-1
1000 mg/m2GEM on days 1 and 8, combined with 80 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 15,combined with 80–120 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 8, combined with 40 mg/m2 oral S-1 twice daily on days 1–14, repeated every 4 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 1 and 8, combined with 60–100 mg/m2 oral S-1 twice daily on days 1–14, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks 1000 mg/m2GEM on days 8 and 15, combined with 60 mg/m2 oral S-1 twice daily on days 1–15, repeated every 3 weeks 1000 mg/m2 GEM on days 1, 8, and 15, repeated every 4 weeks
GEM Sudo et al.13
GEMzS-1
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GEM
Figure 2 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – overall response rate.
Figure 3 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – disease control rate.
group of patients survived more than a year. According to this, patients who used the GS regiment may have a better prognosis than GEM regiment (RR51.62, 95% CI: 1.12–2.33, P50.04, Fig. 4).
Haematology toxicity The major grade 3–4 adverse events regarding haematological toxicities are compared in Figs. 5–7. These results suggested that GS group have higher haematological
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toxicities including neutropaenia (RR51.58, 95% CI: 1.17–2.14, P50.003, Fig. 5) and thrombocytopaenia (RR51.85, 95% CI: 1.28–2.67, P50.001, Fig. 7). The incidence of anaemia was much the same in the two groups (RR51.22, 95% CI: 0.87–1.70, P50.24, Fig. 6). Although the frequency of grade 3–4 adverse events in the GS group was higher than that in the GEM group regarding haematological toxicities, the toxicities were predictable and manageable.
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Figure 4 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – 1-year survival rate.
Figure 5 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3 –4 adverse events: neutropaenia.
Figure 6 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3 –4 adverse events: anaemia.
Figure 7 Results for combination chemotherapy with gemcitabine (GEM) and S-1 (GS) versus GEM – grade 3– 4 adverse events: thrombocytopaenia.
Examination of the funnel plots revealed evidence of bias, possibly publication bias, but this is difficult to interpret in view of the small number of studies within each comparison. This analysis ruled out possible issues related to publication bias. Furthermore, judgements about the
risk of bias, as well as other factors affecting the quality of evidence such as publication bias, were considered when interpreting the results of our systematic review. A detailed report in is provided in Fig. 8. Although some projects had high risk of bias, this had little influence on our results.
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Figure 8 Judgements about each risk of bias item for each included study.
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Discussion Pancreatic adenocarcinoma is among the most challenging of solid malignancies to treat on account of its propensity for late presentation with inoperable disease, aggressive tumour biology and resistance to chemotherapy.14 There have been no real medical breakthroughs with regard to improving the prognosis of this dismal disease.15 Despite our increasing knowledge about numerous genetic alterations, such as mutations of oncogenes, tumour suppressor genes, altered pathways of apoptosis, etc., all known drugs targetting these defects do not really prolong life expectancy. Development of more effective treatment is essential to improve patient survival and quality of life. Gemcitabine monotherapy is accepted as a standard first-line treatment for locally advanced unresectable or metastatic pancreatic cancer.16 Recently, Sultana A. et al. concluded that there was insufficient evidence of a survival difference between GEM and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR 0.75; 95% CI, 0.42–1.31).17 Compared with GEM alone, GEM combination chemotherapy can markedly improve the survival of patients (HR 0.91; 95% CI, 0.85–0.97).. This study suggested that there was a significant survival benefit for chemotherapy over best supportive care and GEM combinations over GEM alone, supporting the use of GEMbased combination chemotherapy in the treatment of advanced pancreatic cancer. S-1 is a new oral anticancer agent that consists of a 5-FU prodrug (tegafur) and two modulators of 5-FU metabolism, gimeracil and oteracil, in a 1:0.4:1 molar
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concentration ratio.5 Worthy to note, tegafur is gradually converted to 5-FU in the liver after oral ingestion and gimeracil is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in the catabolism of 5-FU. Moreover, oteracil preferentially localizes in the gut and inhibits phosphorylation of 5-FU. On another front, S-1 and GEM combination chemotherapy is challenging but promising. In the past few decades, many trials evaluated GEM combined with various cytotoxic or targetted agents to try to ameliorate prognosis of patients with pancreatic cancer. Intriguingly, some of these studies have reported enhanced median OS and 1year survival rates.1,15,17 Two RCTs comparing chemoradiation therapy with GEM alone have been conducted. A French group reported an inferior outcome with radiation therapy plus 5-FU and cisplatin compared to chemotherapy with GEM alone.18 The ECOG study demonstrated that radiation therapy plus GEM had a superior survival outcome to GEM alone.19 Thus, these two recent RCTs comparing chemoradiation therapy with GEM alone have verified a conflicting survival results. It remains unclear whether chemoradiation therapy or chemotherapy alone has a better outcome in patients with locally advanced pancreatic cancer. This clinical question should also be evaluated in the future. However, the question of whether GS is better than GEM monotherapy is still unclear. This review of chemotherapy in pancreatic cancer aimed to assess the key issues, including overall response rate, disease control rate, 1-year survival rate and haematological toxicities in GS group and GEM group. Our analysis showed that the overall response rate (Pv0.00001), disease control rate (Pv0.0001) and 1-year survival (P50.0004) in the GS group were overwhelmingly better than those in the GEM group. Our findings of improved response rate and 1-year survival are in agreement with the meta-analyses of Sultana A et al.20 Furthermore, we used grade 3–4 adverse events to analysis safety as well. In this study, haematological toxicities including anaemia, neutropaenia and thrombocytopaenia were conducted in a comprehensive analysis insinuating that the GS group has higher haematological toxicities, such as neutropaenia and thrombocytopaenia. Although the frequency of grade 3–4 adverse events in the GS group was higher than that in the GEM group regarding haematological toxicities, the toxicities were predictable and manageable. Last but not least, some studies are consistent with our results.21,22 Currently, there are a lot of combined chemotherapy of pancreatic cancer. It is very
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important especially in combination chemotherapy of GEM. Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with GEM monotherapy.23 Overall survival was significantly improved (HR 0.83, Pv0.01; HR 0.87, P?5?0.03; HR 0.80, P50.01; respectively) and objective response rate (ORR) was significantly increased (OR 0.51, Pv0.01; OR 0.66, P50.03; OR 0.35, Pv0.01; respectively) in the GEMz5FU/CAP/S-1, GEMzCAP and GEMzS-1 groups compared to the GEM alone group.24 Besides, addition of an agent against EGFR to GEMbased chemotherapy improved the OS and ORR compared to GEM-based chemotherapy alone in patients with advanced pancreatic cancer.25 In addition, GEM plus erlotinib for treating advanced pancreatic cancer may provide better efficacy and safety.26 All in all, compared with GEM monotherapy, combinations of two or more drugs may improve outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings. However, not all GEM combination therapy is superior to the GEM monotherapy. The combination SUNGEM was not sufficiently superior in locally advanced or metastatic PDAC compared to GEM alone associated with more toxicity.27 According to some RCTs, we demonstrated GS may offer greater benefits than GEM alone. In the future, we will continue to face a lot of challenges in the treatment of pancreatic cancer. H. A. Al and T. E. Adrian give us some advice; it is clear that to really make an impact on this disease, it will be necessary to address three different problems with targetted therapeutics.28 First, it is of great importance to eradicate pancreatic cancer stem cells that will result in recurrence. Second, reducing the peritumoral stroma is of great significance or profundity, as peritumoral stroma provides the tumours with growth support and provides a barrier to access of therapeutic agents. Finally, it is important to address the marked cachexia and metabolic derangement that contribute to morbidity and mortality and further complicate therapeutic intervention. In conclusion, this analysis has elucidated that overall response rate and disease control rate as well as 1-year survival in patients who received GS were superior to those treated with GEM alone. This study suggests that GS may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. In addition, more detailed meta-analyses are required to better illuminate the comparative benefits and harms of combination chemotherapy regimens.
Meta-analysis of pancreatic cancer chemotherapy in Asia
Disclaimer Statements Contributors Guarantor of integrity of entire study : Yanxun Li, Jinjin Sun Study concepts : Yanxun Li, Jinjin Sun. Study design : Yanxun Li, Jinjin Sun. Literature research : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Data acquisition : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Data analysis/interpretation : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Statistical analysis : Yanxun Li, Jinjin Sun, Zhijia Jiang, Linqiang Zhang. Manuscript preparation : Yanxun Li, Jinjin Sun. Manuscript definition of intellectual content : Yanxun Li, Jinjin Sun. Manuscript editing : Yanxun Li, Jinjin Sun. Manuscript revision/review : Yanxun Li, Jinjin Sun. Manuscript fnal version approval : Yanxun Li, Jinjin Sun.
Funding Funding was received fromt the Welcome Trust.
Conflicts of interest There was no conflict among the authors.
Ethics approval This paper is a meta-analysis. The literatures we selected have obtained ethics committee approval.
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