Advertisement

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

  • Zehua Wu
  • Yanhong Deng
Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • 82 Downloads
Part of the following topical collections:
  1. Topical Collection on Lower Gastrointestinal Cancers

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.

Keywords

Capecitabine Fluorouracil infusion Colorectal cancer Meta-analysis 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare they have conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

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

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 14.
    Hoff P, Cassidy J, Schmollc H. The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist. 2001;6:3–11.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 38.
    Review Manager (RevMan). 5.3 ed. Copenhagen: The Nordic Cochrane Centre: The Cochrane Collaboration; 2014.Google Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 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.CrossRefGoogle Scholar
  46. 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.Google Scholar
  47. 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.Google Scholar
  48. 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.CrossRefGoogle Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Medical Oncology Department, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina

Personalised recommendations