Skip to main content
SpringerLink
Log in

Safety of Bevacizumab in Treating Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis of All Randomized Clinical Trials

  • Systematic Review
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and objective

The incidence rates of colorectal cancer (CRC) are increasing in a number of different regions, and recent studies have indicated that addition of bevacizumab to CRC therapy is beneficial. To better understand the relative risk (RR) of adverse events associated with use of bevacizumab, we systematically reviewed published clinical trials that studied use of bevacizumab in treatment of patients affected by metastatic CRC (mCRC).

Methods

The National Library of Medicine PubMed, MEDLINE, Ovid, Cochrane Library and Chinese Biomedicine databases were searched. The RR and number needed to harm (NNH) values for major side effects with 95 % confidence intervals (CIs) were calculated in a fixed-effects model and a random-effects model, where appropriate.

Results

Fifteen controlled trials totalling 6,937 patients were eligible for this analysis. Compared with the control group, the bevacizumab treatment group had a slightly higher risk of any severe adverse event (pooled RR 1.07 [95 % CI 1.02–1.12]). The pooled risk difference was 5 % [95 % CI 2–9 %], with an NNH of 20 treated patients. Analyses showed a statistically significantly higher risk of secondary endpoints, including the discovery that bevacizumab was associated with a threefold higher risk of hypertension (pooled RR 3.06 [95 % CI 2.45–3.83]), a twofold higher risk of gastrointestinal haemorrhage/perforation and a lower risk of neutropenia (pooled RR 0.75 [95 % CI 0.26–2.19]).

Conclusion

Bevacizumab has efficacy in all treatment regimens for advanced CRC. However, our meta-analysis raises safety concerns regarding an increased risk of serious adverse events associated with use of bevacizumab among patients with mCRC. Our findings warrant cautious use of bevacizumab in clinical oncology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Ferrarotto R, Hoff PM. Antiangiogenic drugs for colorectal cancer: exploring new possibilities. Clin Colorectal Cancer. 2013;12(1):1–7.

    Google Scholar 

  3. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  4. Renouf DJ, Lim HJ, Speers C, et al. Survival for metastatic colorectal cancer in the bevacizumab era: a population-based analysis. Clin Colorectal Cancer. 2011;10(2):97–101.

    Article  PubMed  CAS  Google Scholar 

  5. Mishima H, Oba K, Sakamoto J, et al. FOLFIRI plus bevacizumab 5 mg/kg versus 10 mg/kg as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: a randomized phase III study (EAGLE study). Jpn J Clin Oncol. 2012;42(2):134–8.

    Google Scholar 

  6. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.

    Article  PubMed  CAS  Google Scholar 

  7. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26(33):5326–34.

    Article  PubMed  CAS  Google Scholar 

  8. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20(11):1842–7.

    Article  PubMed  Google Scholar 

  9. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  PubMed  CAS  Google Scholar 

  10. National Cancer Institute (2006). Common terminology criteria for adverse events v3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 19 Dec 2011.

  11. Tebbutt NC, Murphy F, Zannino D, et al. Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab. Ann Oncol. 2011;22(8):1834–8.

    Article  PubMed  CAS  Google Scholar 

  12. Kabbinavar F, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23(16):3697–705.

    Article  PubMed  CAS  Google Scholar 

  13. Geiger-Gritsch S, Stollenwerk B, Miksad B, et al. Safety of bevacizumab in patients with advanced cancer: a meta-analysis of randomized controlled trials. Oncologist. 2010;15(11):1179–91.

    Google Scholar 

  14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.

    Article  PubMed  CAS  Google Scholar 

  15. Laird NM, Mosteller F. Some statistical methods for combining experimental results. Int J Technol Assess Health Care. 1990;6(1):5–30.

    Article  PubMed  CAS  Google Scholar 

  16. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  PubMed  Google Scholar 

  17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  PubMed  CAS  Google Scholar 

  18. Higgins J, Green S (2009) Cochrane handbook for systematic reviews of interventions, version 5.0.2 (updated September 2009)—the Cochrane Collaboration. http://www.cochrane-handbook.org. Accessed 18 Apr 2008.

  19. Review Manager (RevMan) [computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. http://ims.cochrane.org/revman/download. Accessed 22 Oct 2010.

  20. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300(19):2277–85.

    Article  PubMed  CAS  Google Scholar 

  21. Dohn LH, Jensen BV, Larsen FO. Short time infusion of bevacizumab in combination with 5fu-based chemotherapy as first-line therapy in a non-selective patient group with metastatic colorectal cancer. Acta Oncol. 2010;49(3):395–6.

    Article  PubMed  CAS  Google Scholar 

  22. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60–5.

    Article  PubMed  CAS  Google Scholar 

  23. Macedo LT, Lima A, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12:89.

    Article  PubMed  CAS  Google Scholar 

  24. Welch S, Spithoff K, Rumble RB, et al. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol. 2010;21(6):1152–62.

    Article  PubMed  CAS  Google Scholar 

  25. Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005;23(16):3706–12.

    Article  PubMed  CAS  Google Scholar 

  26. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91(3):173–80.

    Article  PubMed  CAS  Google Scholar 

  27. European Medicines Agency. Avastin (bevacizumab): European public assessment report (EPAR). http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000582/WC500029260.pdf. Accessed 22 Oct 2010.

  28. Jackson NA, Barrueco J, Soufi-Mahjoubi R, et al. Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelderly patients with metastatic colorectal cancer. Cancer. 2009;115(12):2617–29.

    Article  PubMed  CAS  Google Scholar 

  29. Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010;28(19):3191–8.

    Article  PubMed  CAS  Google Scholar 

  30. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23(15):3502–8.

    Article  PubMed  CAS  Google Scholar 

  31. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25(12):1539–44.

    Article  PubMed  CAS  Google Scholar 

  32. Kabbinavar FF, Hurwitz HI, Yi J, et al. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. 2009;27(2):199–205.

    Article  PubMed  CAS  Google Scholar 

  33. Hurwitz HI, Yi J, Ince W, et al. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist. 2009;14(1):22–8.

    Article  PubMed  CAS  Google Scholar 

  34. Okines A, Puerto OD, Cunningham D, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer: First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101(7):1033–8.

    Article  PubMed  CAS  Google Scholar 

  35. Moehler M, Sprinzl MF, Abdelfattah M, et al. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009;15(4):449–56.

    Article  PubMed  CAS  Google Scholar 

  36. Sharma S, Abhyankar V, Burgess RE, et al. A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol. 2010;21(2):297–304.

    Article  PubMed  CAS  Google Scholar 

  37. Kemeny NE, Jarnagin WR, Capanu M, et al. Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer. J Clin Oncol. 2011;29(7):884–9.

    Article  PubMed  CAS  Google Scholar 

  38. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol. 2013;14(1):29–37.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No sources of funding were used in the preparation of this manuscript. The authors have no potential conflicts of interest that are directly relevant to the content of this article. The data collection for this study was conducted by Fei Dai and Lixin Shu; the data analysis and manuscript writing were performed by Fei Dai, Yanfang Bian, Zhuo Wang and Zhangwei Yang; and the study was designed by Wengong Chu and Shen Gao.

Author information

Authors and Affiliations

  1. Pharmacy Department of Changhai Hospital, The First Affiliated Hospital of Second Military Medical University, Shanghai, China

    Fei Dai, Yangfang Bian, Zhuo Wang, Zhangwei Yang & Shen Gao

  2. Department of Pharmaceutical Administration, Second Military Medical University, Shanghai, China

    Fei Dai, Lixing Shu & Wengong Chu

Authors
  1. Fei Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lixing Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yangfang Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhuo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhangwei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wengong Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shen Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wengong Chu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dai, F., Shu, L., Bian, Y. et al. Safety of Bevacizumab in Treating Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis of All Randomized Clinical Trials. Clin Drug Investig 33, 779–788 (2013). https://doi.org/10.1007/s40261-013-0125-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-013-0125-6

Keywords

Search

Navigation