Skip to main content
SpringerLink
Log in

Addition of bevacizumab to chemotherapy in patients with ovarian cancer: a systematic review and meta-analysis of randomized trials

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

This systematic review and meta-analysis analyzed randomized controlled trials (RCTs) assessing the efficacy and tolerance of incorporating bevacizumab into chemotherapy in patients with advanced ovarian cancer.

Methods

MEDLINE, Web of Science, EMBASE and the Cochrane Central Register of Controlled Trials were reviewed for RCTs evaluating add-on bevacizumab in advanced ovarian cancer. Progression-free survival (PFS), overall survival (OS), objective response rate and adverse events were obtained from RCTs comparing first- and second-line bevacizumab plus chemotherapy with chemotherapy alone for advanced ovarian cancer. Meta-analyses were performed to determine hazard ratios for time-to-event variables and odds ratios for dichotomous outcomes using random-effects or fixed-effects model based on the heterogeneity of included studies.

Results

Four RCTs, including 4246 patients, were identified and analyzed. Two trials, GOG218 and ICON7, assessing bevacizumab in first-line chemotherapy, found that bevacizumab significantly extended PFS (HR 0.82; 95 % CI 0.75–0.89) and OS (HR 0.86; 95 % CI 0.75–0.99). The other two trials, OCEANS and AURELIA, analyzing second-line bevacizumab, found that this agent extended PFS (HR 0.48; 95 % CI 0.41–0.57), but did not enhance OS (HR 0.93; 95 % CI 0.78–1.12). The most common adverse events associated with bevacizumab included hypertension, proteinuria and gastrointestinal perforation.

Conclusion

The addition of bevacizumab to chemotherapy followed by bevacizumab significantly improved PFS and OS in frontline setting and PFS in recurrent settings compared with that of chemotherapy alone in patients with advanced ovarian cancer.

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

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.

    Article  PubMed  Google Scholar 

  2. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194–200.

    Article  CAS  PubMed  Google Scholar 

  3. McGuire WP 3rd, Markman M. Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer. 2003;89(Suppl 3):S3–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S161–92.

    Article  PubMed  Google Scholar 

  5. Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol. 2012;120(3):612–8.

    Article  PubMed  Google Scholar 

  6. Bookman MA. The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2010;21(7):211–7.

    Google Scholar 

  7. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972;175(3):409–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999;56(3):794–814.

    Article  CAS  PubMed  Google Scholar 

  9. Hefler LA, Zeillinger R, Grimm C, Sood AK, Cheng WF, Gadducci A, et al. Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecol Oncol. 2006;103(2):512–7.

    Article  CAS  PubMed  Google Scholar 

  10. Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, et al. Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997;76(9):1221–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Xu L, Yoneda J, Herrera C, Wood J, Killion JJ, Fidler IJ. Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Int J Oncol. 2000;16(3):445–54.

    CAS  PubMed  Google Scholar 

  12. Sher I, Adham SA, Petrik J, Coomber BL. Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis. Int J Cancer. 2009;124(3):553–61.

    Article  CAS  PubMed  Google Scholar 

  13. Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9(15):5721–8.

    CAS  PubMed  Google Scholar 

  14. Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB. Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 2002;161(5):1917–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.

    Article  CAS  PubMed  Google Scholar 

  16. Bethesda M. Common terminology criteria for adverse events (CTCAE), v3.0 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_30. 2006. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_30.

  17. Byrt T, Bishop J, Carlin JB. Bias, prevalence and kappa. J Clin Epidemiol. 1993;46(5):423–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484–96.

    Article  CAS  PubMed  Google Scholar 

  21. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer. N Engl J Med. 2011;365(26):2473–83.

    Article  CAS  PubMed  Google Scholar 

  22. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. Oceans: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the auRELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.

    Article  CAS  PubMed  Google Scholar 

  24. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12.

    Article  PubMed  Google Scholar 

  25. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  CAS  PubMed  Google Scholar 

  26. Rustin GJS, Bast RC, Kelloff GJ, Barrett JC, Carter SK, Nisen PD, et al. Use of CA-125 in clinical trial evaluation of new therapeutic drugs for ovarian cancer. Clin Cancer Res. 2004;10(11):3919–26.

    Article  CAS  PubMed  Google Scholar 

  27. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593–9.

    CAS  PubMed  Google Scholar 

  28. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25(33):5165–71.

    Article  CAS  PubMed  Google Scholar 

  29. Stuart GC, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J, et al. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2011;21(4):750–5.

    Article  Google Scholar 

  30. Korn EL, Freidlin B, Abrams JS. Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. J Clin Oncol. 2011;29(17):2439–42.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(33):5180–6.

    Article  CAS  Google Scholar 

  32. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol. 2009;10(6):559–68.

    Article  CAS  PubMed  Google Scholar 

  33. Ye Q, Chen HL. Bevacizumab in the treatment of ovarian cancer: a meta-analysis from four phase III randomized controlled trials. Arch Gynecol Obstet. 2013;288(3):655–66.

    Article  CAS  PubMed  Google Scholar 

  34. Zhou M, Yu P, Qu X, Liu Y, Zhang J. Phase III trials of standard chemotherapy with or without bevacizumab for ovarian cancer: a meta-analysis. PLoS One. 2013;8(12):e81858.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43.

    Article  CAS  PubMed  Google Scholar 

  36. Alberts DS. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950–5.

    Article  CAS  PubMed  Google Scholar 

  37. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(4):1001–7.

    CAS  Google Scholar 

  38. Jaaback K, Johnson N, Lawrie TA. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2011;11:CD005340.

    PubMed  Google Scholar 

  39. Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–53.

    Article  CAS  PubMed  Google Scholar 

  40. Rauh-Hain JA, Rodriguez N, Growdon WB, Goodman AK, Boruta DM 2nd, Horowitz NS, et al. Primary debulking surgery versus neoadjuvant chemotherapy in stage IV ovarian cancer. Ann Surg Oncol. 2012;19(3):959–65.

    Article  PubMed  Google Scholar 

  41. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374(9698):1331–8.

    Article  CAS  PubMed  Google Scholar 

  42. Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21(13):2460–5.

    Article  CAS  PubMed  Google Scholar 

  43. Markman M, Liu PY, Moon J, Monk BJ, Copeland L, Wilczynski S, et al. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Gynecol Oncol. 2009;114(2):195–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Lesnock JL, Farris C, Krivak TC, Smith KJ, Markman M. Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced epithelial ovarian cancer. Gynecol Oncol. 2011;122(3):473–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(4):372–9.

    Article  CAS  Google Scholar 

  46. Karlan BY, Oza AM, Richardson GE, Provencher DM, Hansen VL, Buck M, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(4):362–71.

    Article  CAS  Google Scholar 

  47. Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(33):5601–6.

    Article  CAS  Google Scholar 

  48. Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119(1):32–7.

    Article  CAS  PubMed  Google Scholar 

  49. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2015;16(1):87–97.

    Article  CAS  PubMed  Google Scholar 

  50. Hensley ML. Big costs for little gain in ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1230–2.

    Article  Google Scholar 

  51. Cohn DE, Kim KH, Resnick KE, O’Malley DM, Straughn JM Jr. At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1247–51.

    Article  Google Scholar 

Download references

Acknowledgments

Li Jialu, Zhou Likun, and Ba Yi contributed equally to this work.

Conflict of interest

Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of interest form.

Author information

Author notes

    Authors and Affiliations

    1. Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Rd., Tiyuanbei, Tianjin, 300060, China

      J. Li, L. Zhou & Y. Ba

    2. Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China

      X. Chen

    Authors
    1. J. Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. L. Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. X. Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Y. Ba
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Y. Ba.

    Additional information

    J. Li, L. Zhou, and Y. Ba contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, J., Zhou, L., Chen, X. et al. Addition of bevacizumab to chemotherapy in patients with ovarian cancer: a systematic review and meta-analysis of randomized trials. Clin Transl Oncol 17, 673–683 (2015). https://doi.org/10.1007/s12094-015-1293-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12094-015-1293-z

    Keywords

    Search

    Navigation