Skip to main content

Advertisement

SpringerLink
Log in

Meta-analysis of the risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer who were receiving vandetanib

  • Review Article
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

A meta-analysis of published data was conducted to investigate the overall risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer (NSCLC) who were receiving vandetanib.

Methods

A computerized search through electronic databases, including PubMed and Embase (until Dec 2014), was performed to obtain eligible randomized controlled trials (RCTs) that compared hypertension and/or QTc prolongation profile of vandetanib alone or plus chemotherapy with control groups (placebo, single targeted therapy, chemotherapy, or a combination of them) in patients with advanced NSCLC. The outcome measures were the overall risks of hypertension and QTc prolongation. Relative risk (RR) and 95 % confidence interval (CI) were calculated and pooled using a random effects model.

Results

A total of nine RCTs, which involved 4813 patients, were enrolled in the present study. A significant increase in risk was observed for all-grade hypertension (RR 5.58; 95 % CI 4.16 to 7.48; P < 0.00001) and grade ≥3 hypertension (RR 4.79; 95 % CI 2.31 to 9.93; P < 0.0001) in advanced NSCLC patients who were receiving vandetanib compared with the controls. Moreover, vandetanib significantly prolonged all-grade QTc interval (RR 7.90; 95 % CI 4.03 to 15.50; P < 0.00001) and grade ≥3 QTc interval (RR 3.12; 95 % CI 1.01 to 9.63; P = 0.05).

Conclusions

Current evidence showed that significant risks in developing hypertension and QTc prolongation exist in advanced NSCLC patients who were receiving vandetanib. Thus, appropriate monitoring and management of these events are recommended.

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

Similar content being viewed by others

References

  1. Boyle P, Dresler C (2005) Preventing the lung cancer epidemic. Ann Oncol 16:1565–1566

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  3. Chong CR, Wirth LJ, Nishino M et al (2014) Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer 86:241–246

    Article  PubMed Central  PubMed  Google Scholar 

  4. Martinez P, Martinez-Marti A, Navarro A et al (2014) Molecular targeted therapy for early-stage non-small-cell lung cancer: will it increase the cure rate? Lung Cancer 84:97–100

    Article  PubMed  Google Scholar 

  5. Wedge SR, Ogilvie DJ, Dukes M et al (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655

    CAS  PubMed  Google Scholar 

  6. Carlomagno F, Vitagliano D, Guida T et al (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290

    CAS  PubMed  Google Scholar 

  7. Ma W, Xu M, Liu Y et al (2014) Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small-cell lung cancer: a meta-analysis of 15 phase II/III randomized trials. Int J Cancer. doi:10.1002/ijc.29377

    PubMed Central  Google Scholar 

  8. Tian W, Ding W, Kim S et al (2013) Efficacy and safety profile of combining vandetanib with chemotherapy in patients with advanced non-small cell lung cancer: a meta-analysis. PLoS One 8:e67929

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Qi WX, Tang LN, He AN et al (2011) The role of vandetanib in the second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of four randomized controlled trials. Lung 189:437–443

    Article  CAS  PubMed  Google Scholar 

  10. Xiao YY, Zhan P, Yuan DM et al (2013) Chemotherapy plus vandetanib or chemotherapy alone in advanced non-small cell lung cancer: a meta-analysis of four randomised controlled trials. Clin Oncol (R Coll Radiol) 25:e7–e15

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Kjaergard LL, Villumsen J, Gluud C (2001) Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 135:982–989

    Article  CAS  PubMed  Google Scholar 

  13. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed Central  PubMed  Google Scholar 

  16. Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Herbst RS, Sun Y, Eberhardt WE et al (2010) Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 11:619–626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. de Boer RH, Arrieta O, Yang CH et al (2011) Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 29:1067–1074

    Article  PubMed  Google Scholar 

  19. Heymach JV, Johnson BE, Prager D et al (2007) Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 25:4270–4277

    Article  CAS  PubMed  Google Scholar 

  20. Heymach JV, Paz-Ares L, De Braud F et al (2008) Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 26:5407–5415

    Article  CAS  PubMed  Google Scholar 

  21. Natale RB, Thongprasert S, Greco FA et al (2011) Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 29:1059–1066

    Article  CAS  PubMed  Google Scholar 

  22. Natale RB, Bodkin D, Govindan R et al (2009) Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase II study. J Clin Oncol 27:2523–2529

    Article  CAS  PubMed  Google Scholar 

  23. Ahn JS, Lee KH, Sun JM et al (2013) A randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy. Lung Cancer 82:455–460

    Article  PubMed  Google Scholar 

  24. Lee JS, Hirsh V, Park K et al (2012) Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 30:1114–1121

    Article  CAS  PubMed  Google Scholar 

  25. Gridelli C, Novello S, Zilembo N et al (2014) Phase II randomized study of vandetanib plus gemcitabine or gemcitabine plus placebo as first-line treatment of advanced non-small-cell lung cancer in elderly patients. J Thorac Oncol 9:733–773

    Article  CAS  PubMed  Google Scholar 

  26. Qi WX, Shen Z, Lin F et al (2013) Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol 75:919–930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Zang J, Wu S, Tang L et al (2012) Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS One 7:e30353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Ghatalia P, Je Y, Kaymakcalan MD et al (2015) QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer 112:296–305

    Article  CAS  PubMed  Google Scholar 

  29. Shah DR, Shah RR, Morganroth J (2013) Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy. Drug Saf 36:413–426

    Article  CAS  PubMed  Google Scholar 

  30. Izzedine H, Ederhy S, J F et al (2009) Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 20:807–815

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have no competing interests to declare.

Grant support

The study received support from National Natural Science Foundation of China (General Program, no. 81170007; 81370104) and Fok Ying-Tong Education Foundation, China (no. 131039).

Location of the study

The study was performed at Chinese PLA General Hospital and Chinese PLA Air Force General Hospital, Beijing, China.

Author contributions

Ying Liu and Yi Liu were responsible for article search, acquisition of data, data analysis, and first drafting. Zai-Wen Fan and Jian Li were responsible for acquisition of data, data analysis, and revision of the article. Guo-Gang Xu was responsible for the study design, interpretation of data, critical appraisal, and revision of the article. All the authors were responsible for the final approval of the version to be published.

Ethical standards

Ethics approval was not necessary as this is a meta-analysis.

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine, Chinese PLA Air Force General Hospital, Beijing, 100142, China

    Ying Liu, Yi Liu, Zai-Wen Fan & Jian Li

  2. Nanlou Respiratory Diseases Department, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China

    Guo-Gang Xu

Authors
  1. Ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zai-Wen Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guo-Gang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guo-Gang Xu.

Additional information

Ying Liu and Yi Liu contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

Description of the grades of hypertension and QTc prolongation according to CTC v2.0 and CTCAE v3.0 (DOC 32 kb)

Table S2

Risks of all-grade hypertension and QTc prolongation in each of the previous meta-analyses (DOC 39 kb)

Table S3

Subgroup analyses based on various exclusion criteria for the risk of hypertension (DOC 50 kb)

Table S4

Subgroup analyses based on various exclusion criteria for the risk of QTc interval (DOC 51 kb)

Figure S1

Meta-analysis of the risks of high-grade hypertension and QTc prolongation among all RCTs (GIF 137 kb)

(TIFF 458 kb)

Figure S2

Publication bias for hypertension (A) and QTc prolongation (B) (GIF 30 kb)

(TIFF 222 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Liu, Y., Fan, ZW. et al. Meta-analysis of the risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer who were receiving vandetanib. Eur J Clin Pharmacol 71, 541–547 (2015). https://doi.org/10.1007/s00228-015-1831-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-015-1831-1

Keywords

Search

Navigation