Skip to main content

Advertisement

SpringerLink
Log in

Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated meta-analysis

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor. The aim of this study was to gain a better understanding of the overall incidence and risk of significantly raised blood pressure in cancer patients who receive bevacizumab therapy.

Methods

We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, Embase, and American Society of Clinical Oncology conferences. Overall incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. The primary clinical endpoint was significantly raised blood pressure (grade 3 or above).

Results

A total of 12,949 cancer patients with a variety of solid tumors from 19 RCTs were included in our meta-analysis. The overall incidence of significantly raised blood pressure was 8% (95% CI 6–10%) among patients receiving bevacizumab. Bevacizumab treatment was associated with a statistically significant increased risk of developing significantly raised blood pressure (RR 5.38, 95% CI 3.63–7.97). The RRs of significantly raised blood pressure in patients receiving bevacizumab at 5 and 2.5 mg/kg per week were 7.17 (95% CI, 3.91–13.13) and 4.11 (95% CI 2.49–6.78), respectively. Among cancer patients, those with renal cell carcinoma (RR 13.77, 95% CI 2.28–83.15) and breast cancer (RR 18.83, 95% CI 1.23–292.29) who received bevacizumab at 5 mg/kg per week had a higher risk of developing significantly raised blood pressure.

Conclusions

Among the patients included in the trials analyzed in this meta-analysis, the addition of bevacizumab to cancer therapy treatments significantly increased the risk of significantly raised blood pressure. The risk may be dose-dependent and vary with tumor type.

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
Fig. 5

Similar content being viewed by others

References

  1. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29[6 Suppl 16]:15–18

    CAS  PubMed  Google Scholar 

  3. Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65:671–680

    CAS  PubMed  Google Scholar 

  4. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) 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 25:1539–1544

    Article  CAS  PubMed  Google Scholar 

  5. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  6. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508

    Article  CAS  PubMed  Google Scholar 

  7. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65

    Article  CAS  PubMed  Google Scholar 

  8. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019

    Article  CAS  PubMed  Google Scholar 

  9. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF (2005) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23:3697–3705

    Article  CAS  PubMed  Google Scholar 

  10. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  CAS  PubMed  Google Scholar 

  11. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  CAS  PubMed  Google Scholar 

  12. Miles D, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, Tomczak P, Taran T, Harbeck N, Steger GG (2008) Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC):AVADO (abstract). Proc Am Soc Clin Oncol 26[15 Suppl]:LBA1011

    Google Scholar 

  13. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799

    Article  CAS  PubMed  Google Scholar 

  14. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428

    Article  CAS  PubMed  Google Scholar 

  15. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a odifyzed, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  16. Genentech. Bevacizumab prescribing information. Available at: http://www.Gene.com/gene/products/information/oncology/avastin/. Accessed 27 Oct 2008

  17. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27:1227–1234

    Article  CAS  PubMed  Google Scholar 

  18. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184–2191

    Article  CAS  PubMed  Google Scholar 

  19. Herbst RS, O’Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, Melnyk O, Ramies D, Lin M, Sandler A (2007) Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 25:4743–4750

    Article  CAS  PubMed  Google Scholar 

  20. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Wolmark N (2008) Initial safety report of NSABP C-08, a randomized phase III study of odify ed 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer (abstract). Proc Am Soc Clin Oncol 26[15 Suppl]:4006

    Google Scholar 

  21. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27:2231–2237

    Article  PubMed  CAS  Google Scholar 

  22. Kindler HL, Niedzwiecki D, Hollis D, Oraefo E, Schrag D, Hurwitz H, McLeod HL, Mulcahy MF, Schilsky RL, Goldberg RM (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB) (abstract). Proc Am Soc Clin Oncol 25[18 Suppl]:4508

    Google Scholar 

  23. Karrison T, Kindler HL, Gandara DR, Lu C, Guterz TL, Nichols K, Chen H, Stadler WM, Vokes E (2007) Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo (P) in patients (pts) with malignant mesothelioma (MM). J Clin Oncol (Meeting Abstracts) 25:7526

    Google Scholar 

  24. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434

    Google Scholar 

  25. Zhu X, Wu S, Dahut WL, Parikh CR (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49:186–193

    Article  CAS  PubMed  Google Scholar 

  26. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    Article  CAS  PubMed  Google Scholar 

  27. Khan KS, Daya S, Jadad A (1996) The importance of quality of primary studies in producing unbiased systematic reviews. Arch Intern Med 156:661–666

    Article  CAS  PubMed  Google Scholar 

  28. Moher D, Jadad AR, Tugwell P (1996) Assessing the quality of randomized controlled trials. Current issues and future directions. Int J Technol Assess Health Care 12:195–208

    Article  CAS  PubMed  Google Scholar 

  29. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  30. Wu S, Chen JJ, Kudelka A, Lu J, Zhu X (2008) Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 9:117–123

    Article  CAS  PubMed  Google Scholar 

  31. Zhu X, Stergiopoulos K, Wu S (2009) Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 48:9–17

    Article  CAS  PubMed  Google Scholar 

  32. Choueiri TK, Vaziri SA, Jaeger E, Elson P, Wood L, Bhalla IP, Small EJ, Weinberg V, Sein N, Simko J, Golshayan AR, Sercia L, Zhou M, Waldman FM, Rini BI, Bukowski RM, Ganapathi R (2008) von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol 180:860–866

    Article  CAS  PubMed  Google Scholar 

  33. Lau J, Ioannidis JPA, Schmid CH (1997) summing up the evidence: one answer is not always enough. Lancet 351:123–127

    Article  Google Scholar 

  34. Thompson SG (1994) Why sources of heterogeneity in meta-analysis should be investigated. Br Med J 309:1351–1355

    CAS  Google Scholar 

Download references

Acknowledgments

We are indebted to the authors of the primary studies; without their contributions, this work would have been impossible. We thank Yu GZ and Xue LJ for consulting on eligible studies.

Conflict of interest

The authors state that they have no conflict of interest.

Funding

None

Author information

Authors and Affiliations

  1. R&D Center of New Drug, School of Pharmacy, Second Military Medical University, 325 Guo He Road, Shanghai, 200433, People’s Republic of China

    Mao Mao An, Yong Bing Cao & Yuan Ying Jiang

  2. Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Zui Zou

  3. Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Science–Peking Union Medical Collage, 167 Beilishi Road, Beijing, 100037, People’s Republic of China

    Hui Shen

  4. Department of Clinical Pharmacology, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing, 100853, People’s Republic of China

    Ping Liu & Meng Li Chen

Authors
  1. Mao Mao An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zui Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meng Li Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Bing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuan Ying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yong Bing Cao or Yuan Ying Jiang.

Additional information

Mao Mao An and Zui Zou contributed equally to this article and can be considered to be co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

An, M.M., Zou, Z., Shen, H. et al. Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated meta-analysis. Eur J Clin Pharmacol 66, 813–821 (2010). https://doi.org/10.1007/s00228-010-0815-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-010-0815-4

Keywords

Search

Navigation