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Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis

  • Original Article
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Pathology & Oncology Research

Abstract

Fluoropyrimidine-based regimens are the most common treatments in advanced gastric cancer. We used a Bayesian network meta-analysis to identify the optimal fluoropyrimidine-based chemotherapy by comparing their relative efficacy and safety. We systematically searched databases and extracted data from randomized controlled trials, which compared fluoropyrimidine-based regimens as first-line treatment in AGC. The main outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). A total of 12 RCTs of 4026 patients were included in our network meta-analysis. Pooled analysis showed S-1 and capecitabine had a significant OS benefit over 5-Fu, with hazard ratios of 0.90 (95%CI = 0.81–0.99) and 0.88 (95%CI = 0.80–0.96), respectively. The result also exhibited a trend that S-1 and capecitabine prolonged PFS in contrast to 5-Fu, with hazard ratios of 0.84 (95%CI = 0.66–1.02) and 0.84 (95%CI = 0.65–1.03), respectively. Additionally, all the three fluoropyrimidine-based regimens were similar in terms of ORR and grade 3 or 4 AEs. Compared with regimens based on 5-Fu, regimens based on S-1 or capecitabine demonstrated a significant OS improvement without compromise of AEs as first-line treatment in AGC in Asian population. S-1 and capecitabine can be interchangeable according their different emphasis on AEs.

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References

  1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi:10.3322/caac.20073

    Article  PubMed  Google Scholar 

  2. Rivera F, Vega-Villegas ME, Lopez-Brea MF (2007) Chemotherapy of advanced gastric cancer. Cancer Treat Rev 33(4):315–324. doi:10.1016/j.ctrv.2007.01.004

    Article  CAS  PubMed  Google Scholar 

  3. Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72(1):37–41

    Article  CAS  PubMed  Google Scholar 

  4. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71(3):587–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R (1997) Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8(2):163–168

    Article  CAS  PubMed  Google Scholar 

  6. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol 24(31):4991–4997. doi:10.1200/jco.2006.06.8429

    Article  PubMed  Google Scholar 

  7. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358(1):36–46. doi:10.1056/NEJMoa073149

    Article  CAS  PubMed  Google Scholar 

  8. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S (2010) Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 28(9):1547–1553. doi:10.1200/jco.2009.25.4706

    Article  CAS  PubMed  Google Scholar 

  9. Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A (2009) Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol 10(11):1063–1069. doi:10.1016/s1470-2045(09)70259-1

    Article  CAS  PubMed  Google Scholar 

  10. Cervantes A, Roda D, Tarazona N, Rosello S, Perez-Fidalgo JA (2013) Current questions for the treatment of advanced gastric cancer. Cancer Treat Rev 39(1):60–67. doi:10.1016/j.ctrv.2012.09.007

    Article  CAS  PubMed  Google Scholar 

  11. Pieters A, Laurent S, Dero I, Van Damme N, Peeters M (2008) The role of oral fluoropyrimidines in the treatment of advanced gastric cancer. Acta Gastroenterol Belg 71(4):361–366

    CAS  PubMed  Google Scholar 

  12. Jin M, Lu H, Li J, Shen L, Chen Z, Shi Y, Song S, Qin S, Liu J, Ouyang X (2008) Randomized 3-armed phase III study of S-1 monotherapy versus S-1/CDDP (SP) versus 5-FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC-101 study. J Clin Oncol 26(Suppl 15):4533

    Google Scholar 

  13. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI (2009) Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20(4):666–673. doi:10.1093/annonc/mdn717

    Article  PubMed  Google Scholar 

  14. Lee JL, Kang YK, Kang HJ, Lee KH, Zang DY, Ryoo BY, Kim JG, Park SR, Kang WK, Shin DB, Ryu MH, Chang HM, Kim TW, Baek JH, Min YJ (2008) A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. Br J Cancer 99(4):584–590. doi:10.1038/sj.bjc.6604536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim GM, Jeung HC, Rha SY, Kim HS, Jung I, Nam BH, Lee KH, Chung HC (2012) A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer 48(4):518–526. doi:10.1016/j.ejca.2011.12.017

    Article  CAS  PubMed  Google Scholar 

  16. He MM, Wu WJ, Wang F, Wang ZQ, Zhang DS, Luo HY, Qiu MZ, Wang FH, Ren C, Zeng ZL, Xu RH (2013) S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for advanced gastric carcinoma: a meta-analysis. PLoS One 8(12):e82798. doi:10.1371/journal.pone.0082798

    Article  PubMed  PubMed Central  Google Scholar 

  17. Caldwell DM, Ades AE, Higgins JP (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331(7521):897–900. doi:10.1136/bmj.331.7521.897

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. doi:10.1186/1745-6215-8-16

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23(20):3105–3124. doi:10.1002/sim.1875

    Article  CAS  PubMed  Google Scholar 

  20. Fryback DG, Stout NK, Rosenberg MA (2001) An elementary introduction to Bayesian computing using WinBUGS. Int J Technol Assess Health Care 17(1):98–113

    Article  CAS  PubMed  Google Scholar 

  21. Woods BS, Hawkins N, Scott DA (2010) Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol 10:54. doi:10.1186/1471-2288-10-54

    Article  PubMed  PubMed Central  Google Scholar 

  22. Spiegelhalter DJ, Best NG, Carlin BP, Van Der Linde A (2002) Bayesian measures of model complexity and fit. J Roy Stat Soc B 64(4):583–639. doi:10.1111/1467-9868.00353

    Article  Google Scholar 

  23. Brooks SP, Gelman A (1998) General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7(4):434–455

    Google Scholar 

  24. Higgins J, Jackson D, Barrett J, Lu G, Ades A, White I (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dias S, Welton N, Caldwell D, Ades A (2010) Checking consistency in mixed treatment comparison meta-analysis. Stat Med 29(7–8):932–944

    Article  CAS  PubMed  Google Scholar 

  26. Xu RH, Sun GP, Lu HS, Peng LY, Xu JM, Zhong MZ, Zhang HL, Yu SY, Li W, Hu XH, Wang JJ, Cheng Y, Zhou JT, Guo ZQ, Guan Z (2013) A phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin in patients with advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 31:suppl; abstr 4025

  27. Huang D, Ba Y, Xiong J, Xu N, Yan Z, Zhuang Z, Yu Z, Wan H, Zhang Y, Deng T, Zheng R, Guo Z, Hu C, Wang M, Yu Z, Yao Y, Meng J (2013) A multicentre randomised trial comparing weekly paclitaxel + S-1 with weekly paclitaxel +5-fluorouracil for patients with advanced gastric cancer. Eur J Cancer 49(14):2995–3002. doi:10.1016/j.ejca.2013.05.021

    Article  CAS  PubMed  Google Scholar 

  28. Ocvirk J, Rebersek M, Skof E, Hlebanja Z, Boc M (2012) Randomized prospective phase II study to compare the combination chemotherapy regimen epirubicin, cisplatin, and 5-fluorouracil with epirubicin, cisplatin, and capecitabine in patients with advanced or metastatic gastric cancer. Am J Clin Oncol 35(3):237–241. doi:10.1097/COC.0b013e31820dc0b0

    Article  CAS  PubMed  Google Scholar 

  29. Nishikawa K, Morita S, Matsui T, Kobayashi M, Takeuchi Y, Takahashi I, Sato S, Miyashita Y, Tsuburaya A, Sakamoto J, Kakeji Y, Baba H (2012) A randomized phase-II trial comparing sequential and concurrent paclitaxel with oral or parenteral fluorinated pyrimidines for advanced or metastatic gastric cancer. Gastric Cancer 15(4):363–369. doi:10.1007/s10120-011-0124-3

    Article  CAS  PubMed  Google Scholar 

  30. Sanofi (2011) Docetaxel and Oxaliplatin in Gastric Cancer. ClinicalTrialsgov:NCT00382720

  31. Cocconi G, DeLisi V, Di Blasio B (1982) Randomized comparison of 5-FU alone or combined with mitomycin and cytarabine (MFC) in the treatment of advanced gastric cancer. Cancer Treat Rep 66(6):1263–1266

    CAS  PubMed  Google Scholar 

  32. Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, Kang YK, Shin DB, Kim HT, Kim HJ, et al. (1993) A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 71(12):3813–3818

    Article  CAS  PubMed  Google Scholar 

  33. Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15(1):261–267

    Article  CAS  PubMed  Google Scholar 

  34. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A (2002) Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20(8):1996–2004

    Article  CAS  PubMed  Google Scholar 

  35. Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S (2003) Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan clinical oncology group study (JCOG9205). J Clin Oncol 21(1):54–59

    Article  CAS  PubMed  Google Scholar 

  36. Okines AF, Norman AR, McCloud P, Kang YK, Cunningham D (2009) Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol 20(9):1529–1534. doi:10.1093/annonc/mdp047

    Article  CAS  PubMed  Google Scholar 

  37. Li DH, Pan ZK, Ye F, An HX, Wu JX (2014) S-1-based versus 5-FU-based chemotherapy as first-line treatment in advanced gastric cancer: a meta-analysis of randomized controlled trials. Tumour Biol 35(8):8201–8208. doi:10.1007/s13277-014-2099-2

    Article  CAS  PubMed  Google Scholar 

  38. Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE (2010) Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev (3):Cd004064. doi:10.1002/14651858.CD004064.pub3

  39. Ye JX, Liu AQ, Ge LY, Zhou SZ, Liang ZG (2014) Effectiveness and safety profile of S-1-based chemotherapy compared with capecitabine-based chemotherapy for advanced gastric and colorectal cancer: a meta-analysis. Exp Ther Med 7(5):1271–1278. doi:10.3892/etm.2014.1576

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang J, Zhou Y, Min K, Yao Q, Xu CN (2014) S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: a meta-analysis. World J Gastroenterol 20(33):11886–11893. doi:10.3748/wjg.v20.i33.11886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373(9665):746–758. doi:10.1016/s0140-6736(09)60046-5

    Article  CAS  PubMed  Google Scholar 

  42. Ajani JA, Faust J, Ikeda K, Yao JC, Anbe H, Carr KL, Houghton M, Urrea P (2005) Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 23(28):6957–6965. doi:10.1200/jco.2005.01.917

    Article  CAS  PubMed  Google Scholar 

  43. Daigo S, Takahashi Y, Fujieda M, Ariyoshi N, Yamazaki H, Koizumi W, Tanabe S, Saigenji K, Nagayama S, Ikeda K, Nishioka Y, Kamataki T (2002) A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur. Pharmacogenetics 12(4):299–306

    Article  CAS  PubMed  Google Scholar 

  44. Yoshida R, Nakajima M, Nishimura K, Tokudome S, Kwon JT, Yokoi T (2003) Effects of polymorphism in promoter region of human CYP2A6 gene (CYP2A6*9) on expression level of messenger ribonucleic acid and enzymatic activity in vivo and in vitro. Clin Pharmacol Ther 74(1):69–76. doi:10.1016/s0009-9236(03)00090-0

    Article  CAS  PubMed  Google Scholar 

  45. El Sayed YM, Sadee W (1982) Metabolic activation of ftorafur [R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil]: the microsomal oxidative pathway. Biochem Pharmacol 31(18):3006–3008

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from National Natural Science Foundation of China (grant no. 81272611) and Major Science and Technology Innovation Project of Hangzhou (Grant no. 20112312A01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, No.261, Huansha Road, Shangcheng District, Hangzhou, 310006, People’s Republic of China

    Lucheng Zhu, Jihong Liu & Shenglin MA

  2. Department of Oncology, Hangzhou First People’s Hospital, Hangzhou, 310006, People’s Republic of China

    Lucheng Zhu, Jihong Liu & Shenglin MA

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  1. Lucheng Zhu
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  2. Jihong Liu
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  3. Shenglin MA
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Correspondence to Shenglin MA.

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Electronic supplementary material

S1A Fig.

Comparison of OS between S-1 based (the Left) and 5-Fu based regimens (the right). (JPEG 100 kb)

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S1B Fig.

Comparison of OS between Capecitabine based (the Left) and 5-Fu based regimens (the right). (JPEG 127 kb)

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S1C Fig.

Comparison of OS between S-1 based (the Left) and Capecitabine based regimens (the right). (JPEG 116 kb)

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S2A Fig.

Comparison of PFS between S-1 based (the Left) and 5-Fu based regimens (the right). (JPEG 103 kb)

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S2B Fig.

Comparison of PFS between Capecitabine based (the Left) and 5-Fu based regimens (the right). (JPEG 285 kb)

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S2C Fig.

Comparison of OS between S-1 based (the Left) and Capecitabine based regimens (the right). (JPEG 280 kb)

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S3A Fig.

Comparison of ORR between S-1 based and 5-Fu based regimens. (JPEG 261 kb)

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S3B Fig.

Comparison of ORR between Capecitabine based and 5-Fu based regimens. (JPEG 117 kb)

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S3C Fig.

Comparison of ORR between S-1 based and Capecitabine based regimens. (JPEG 107 kb)

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S4A Fig.

Comparison of Grade 3 or 4 AEs between S-1 based and 5-Fu based regimens. (JPEG 101 kb)

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S4B Fig.

Comparison of Grade 3 or 4 AEs between Capecitabine based and 5-Fu based regimens. (JPEG 106 kb)

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S4C Fig.

Comparison of Grade 3 or 4 AEs between S-1 based and Capecitabine based regimens. (JPEG 107 kb)

High Resolution Image (EPS 301 kb)

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Zhu, L., Liu, J. & MA, S. Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis. Pathol. Oncol. Res. 22, 853–861 (2016). https://doi.org/10.1007/s12253-016-0078-1

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