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Capecitabine Versus Continuous Infusion Fluorouracil for the Treatment of Advanced or Metastatic Colorectal Cancer: a Meta-analysis

  • Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • Published:
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Opinion statement

Nowadays, systemic chemotherapy with intravenous (IV) 5-fluorouracil (5-FU) remains the most commonly prescribed treatment for metastatic colorectal cancers (CRC), in combination with other cytotoxic drugs. 5-FU can be administered through a bolus injection or continuous infusion (cIV), with the latter becoming the preferred administration method and standard of care in recent years. Oral fluoropyrimidines were developed to overcome challenges associated with the IV administration of 5-FU, among which capecitabine has become the most widely used one. However, although capecitabine and other oral fluoropyrimidine-based regimens are more convenient to administer, their efficacy and safety in comparison with IV 5-FU are not well understood. Results from recent randomized controlled trials, observational studies, and meta-analyses have been inconsistent. Safety, in particular, remains controversial. Our review, a first comprehensive meta-analysis comparing the efficacy and safety of cIV 5-FU with capecitabine, the two most widely used fluorouracil modalities in CRC, showed that cIV 5-FU-based regimens are associated with greater response rates compared with capecitabine-based regimens, with no difference in progression-free survival, time to treatment failure, overall survival, or disease-free survival between the two. Furthermore, cIV 5-FU-based regimens showed an improved safety profile compared with capecitabine-based regimens. Our findings suggest that cIV 5-FU remains a more effective and safer modality of fluorouracil administration than capecitabine, thus providing supporting evidence to guide clinical practice in the management of colorectal cancer.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Arnold M, Sierra M, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–91.

    Article  Google Scholar 

  2. Chen W, Zheng R, Zhang S, Zeng H, Zuo T, Xia C, et al. Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin J Cancer Res. 2017;29:1–10.

    Article  Google Scholar 

  3. Zhu J, Tan Z, Hollis-Hansen K, Zhang Y, Yu C, Li Y. Epidemiological trends in colorectal cancer in China: an ecological study. Dig Dis Sci. 2016;62:235–43.

    Article  Google Scholar 

  4. • Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu R-H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO–ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2018;29:44–70. The reference provides different treatment guidelines emphasizing the role of IV 5-FU in the management of CRC and thus highlighting the implications of this meta-analysis.

    Article  CAS  Google Scholar 

  5. • Benson AB, Venook AP, Cederquist L, Chan E, Chen Y-J, Cooper HS, et al. Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15:370–98. The reference provides different treatment guidelines emphasizing the role of IV 5-FU in the management of CRC and thus highlighting the implications of this meta-analysis.

    Article  CAS  Google Scholar 

  6. • Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422. The reference provides different treatment guidelines emphasizing the role of IV 5-FU in the management of CRC and thus highlighting the implications of this meta-analysis.

    Article  Google Scholar 

  7. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–16.

    Article  Google Scholar 

  8. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143–52.

    Article  CAS  Google Scholar 

  9. Lucas AS, O'Neil BH, Goldberg RM. A decade of advances in cytotoxic chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2011;10:238–44.

    Article  CAS  Google Scholar 

  10. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997;15:246–50.

    Article  CAS  Google Scholar 

  11. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. J Clin Oncol. 1992;10:904–11.

    Article  Google Scholar 

  12. Scheithauer W, Rosen H, Kornek G, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. Br Med J. 1993;306:752–5.

    Article  CAS  Google Scholar 

  13. Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol. 1998;16:301–8.

    Article  Google Scholar 

  14. Hoff P, Cassidy J, Schmollc H. The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist. 2001;6:3–11.

    Article  CAS  Google Scholar 

  15. Schüller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45:291–7.

    Article  Google Scholar 

  16. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19:4097–106.

    Article  Google Scholar 

  17. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19:2282–92.

    Article  CAS  Google Scholar 

  18. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang Y-J, Goel R, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008;19:1720–6.

    Article  CAS  Google Scholar 

  19. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011;128:682–90.

    Article  CAS  Google Scholar 

  20. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R. A randomized phase III study of capecitabine plus oxaliplatin (XELOX) versus fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26:2006–12.

    Article  CAS  Google Scholar 

  21. Madi A, Fisher D, Wilson RH, Adams RA, Meade AM, Kenny SL, et al. Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial. Br J Cancer. 2012;107:1037–43.

    Article  CAS  Google Scholar 

  22. Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish cooperative group for the treatment of digestive tumors trial. J Clin Oncol. 2007;25:4224–30.

    Article  Google Scholar 

  23. Pectasides D, Papaxoinis G, Kalogeras KT, Eleftheraki AG, Xanthakis I, Makatsoris T. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic cooperative oncology group phase III trial with collateral biomarker analysis. BMC Cancer. 2012;12:271–81.

    Article  CAS  Google Scholar 

  24. Skof E, Rebersek M, Hlebanja Z, Ocvirk J. Capecitabine plus irinotecan (XELIRI regimen) compared to 5-FU/LV plus irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer. 2009;9:120–9.

    Article  Google Scholar 

  25. Souglakos J, Ziras N, Kakolyris S, Boukovinas I, Kentepozidis N, Makrantonakis P. Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer. 2012;106:453–9.

    Article  CAS  Google Scholar 

  26. Ducreux M, Adenis A, Pignon J-P, Francois E, Chauffert B, Ichante JL, et al. Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). Eur J Cancer. 2013;49:1236–45.

    Article  CAS  Google Scholar 

  27. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011;105:58–64.

    Article  CAS  Google Scholar 

  28. Kohne C-H, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol. 2008;19:920–6.

    Article  Google Scholar 

  29. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol. 2007;25:4779–86.

    Article  CAS  Google Scholar 

  30. Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Boyer M, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol. 2002;13:566–75.

    Article  CAS  Google Scholar 

  31. •• Chionh F, Lau D, Yeung Y, Price T, Tebbutt N. Oral versus intravenous fluoropyrimidines for colorectal cancer. Hoboken: John Wiley & Sons, Ltd; 2017. [The Cochrane Collaboration] A comprehensive and detailed review and meta-analysis from the Cochrane libarary comparing oral with intravenous fluoropyrimidines for the treatment of colorectal cancer.

    Book  Google Scholar 

  32. Zhang L, Xing X, Meng F, Wang Y, Zhong D. Oral fluoropyrimidine versus intravenous 5-fluorouracil for the treatment of advanced gastric and colorectal cancer: meta-analysis. J Gastroenterol Hepatol. 2018;33:209–25.

    Article  CAS  Google Scholar 

  33. Zou XC, Wang QW, Zhang JM. Comparison of 5-FU-based and capecitabine-based neoadjuvant chemoradiotherapy in patients with rectal cancer: a meta-analysis. Clin Colorectal Cancer. 2017;16:e123–e39.

    Article  Google Scholar 

  34. Sasse AD, Sasse EC, dos Santos LV, Lima JS, Nascente CM, Saito HP. Oral fluoropyrimidines versus 5-fluorouracil for colorectal cancer: results of a systematic review and meta-analysis. J Clin Oncol. 2009;27:4111.

    Article  Google Scholar 

  35. Montagnani F, Chiriatti A, Licitra S, Aliberti C, Fiorentini G. Differences in efficacy and safety between capecitabine and infusional 5-fluorouracil when combined with irinotecan for the treatment of metastatic colorectal cancer. Clin Colorectal Cancer. 2010;9:243–7.

    Article  CAS  Google Scholar 

  36. Cao Y, Liao C, Tan A, Liu L, Mo Z, Gao F. Capecitabine plus oxaliplatin vs fluorouracil plus oxaliplatin as first line treatment for metastatic colorectal caner [cancer]: meta-analysis of six randomized trials. Color Dis. 2009;12:16–23.

    Article  Google Scholar 

  37. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article  Google Scholar 

  38. Review Manager (RevMan). 5.3 ed. Copenhagen: The Nordic Cochrane Centre: The Cochrane Collaboration; 2014.

  39. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    Article  Google Scholar 

  40. Deeks J, Higgins J, Altman D, on behalf of the Cochrane Statistical Methods Group. Analysing data and undertaking meta-analyses. In: Cochrane handbook of systematic reviews of interventions. 2011. https://doi.org/10.1002/9780470712184.ch9. Accessed 01 Sept 2018.

  41. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  Google Scholar 

  42. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63.

    Article  CAS  Google Scholar 

  43. de Gramont A, Van Cutsem E, Schmoll H-J, Tabernero J, Clarke S, Moore M, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13:1225–33.

    Article  Google Scholar 

  44. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE study. J Clin Oncol. 2008;26:3523–9.

    Article  CAS  Google Scholar 

  45. Allegra C, Yothers G, O’Connell MJ, Beart RW, Wozniak TF, Pitot HC, et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015;107:djv248.

    Article  Google Scholar 

  46. Martoni AA, Pinto C, Di Fabio F, Lelli G, Rojas Llimpe FL, Gentile AL, et al. Capecitabine plus oxaliplatin (xelox) versus protracted 5-fluorouracil venous infusion plus oxaliplatin (pvifox) as first-line treatment in advanced colorectal cancer: a GOAM phase II randomised study (FOCA trial). Eur J Cancer. 2006;42:3161–8.

  47. Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer.2015;15:384–94.

  48. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO colorectal study group. J Clin Oncol. 2007;25:4217–23.

    Article  CAS  Google Scholar 

  49. Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011;377:1749–59.

    Article  CAS  Google Scholar 

  50. Cassidy J, Saltz L, Twelves C, Van Cutsem E, Hoff P, Kang Y, et al. Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol. 2011;22:2604–9.

    Article  CAS  Google Scholar 

  51. Kripp M, Wieneke J, Kienle P, Welzel G, Brade J, Horisberger K, et al. Intensified neoadjuvant chemoradiotherapy in locally advanced rectal cancer—impact on long-term quality of life. Eur J Surg Oncol. 2012;38:472–7.

    Article  CAS  Google Scholar 

  52. Iacovelli R, Pietrantonio F, Palazzo A, Maggi C, Ricchini F, de Braud F. Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5- fluorouracil: a meta-analysis of published trials. Br J Clin Pharmacol. 2014;78:1228–37.

    Article  CAS  Google Scholar 

  53. Kornblau S, Benson AB, Catalano R, Champlin RE, Engelking C, Field M, et al. Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manag. 2000;19:118–29.

    Article  CAS  Google Scholar 

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Acknowledgements

Writing assistance was provided by Sarah Keyrouz, from Mudskipper Business Consulting (Shanghai) Limited, funded by Baxter (China) Investment Co, Ltd.

Funding

This work was supported by the National Natural Science Foundation of China (grant number 81472249), the Fundamental Research Funds for the Central Universities (grant number 17ykzd25), and Baxter (China) Investment Co, Ltd. Baxter (China) Investment Co, Ltd. supported data collection and analysis. The National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities supported data collection.

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  1. Medical Oncology Department, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, No. 26 Yuan Cun Er Heng Road, Guangzhou, 510655, China

    Zehua Wu MSc & Yanhong Deng MD, PhD

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  1. Zehua Wu MSc
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Correspondence to Yanhong Deng MD, PhD.

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Wu, Z., Deng, Y. Capecitabine Versus Continuous Infusion Fluorouracil for the Treatment of Advanced or Metastatic Colorectal Cancer: a Meta-analysis. Curr. Treat. Options in Oncol. 19, 77 (2018). https://doi.org/10.1007/s11864-018-0597-y

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