Skip to main content

Advertisement

SpringerLink
Log in

High circulating VEGF level predicts poor overall survival in lung cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Vascular endothelial growth factor (VEGF) is considered as the best-validated key regulator of angiogenesis, while the prognostic role of circulating VEGF in lung cancer remains controversial. We conducted a meta-analysis to evaluate the prognostic role of circulating VEGF.

Methods

Nineteen studies with a total number of 2,890 patients were analyzed in our meta-analysis. Hazard ratios (HRs) and their 95 % confidence intervals (CIs) were used to quantify the predictive ability of circulating VEGF on survival.

Results

The pooled HR of all 17 studies evaluating overall survival (OS) was 1.29 (95 % CI 1.19–1.40, p < 0.001), indicating high circulating VEGF predicted poor OS. When grouped by disease stages, the pooled HRs were 0.97 (95 % CI 0.47–1.47, p < 0.001) for operable stage and 1.34 (95 % CI 1.18–1.49, p < 0.001) for inoperable stage. The pooled HRs were 1.28 (95 % CI 1.15–1.42, p < 0.001) for serum and 1.31 (95 % CI 1.13–1.49, p < 0.001) for plasma, when categorized by blood sample. Meta-analysis of circulating VEGF related to progression-free survival (PFS) was performed in 7 studies, and the pooled HR was 1.03 (95 % CI 0.96–1.09).

Conclusions

Our results indicate that high level of circulating VEGF predicts poor OS in lung cancer, yet it does not predict poor PFS.

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

Abbreviations

PS:

Performance status

ERCC1:

Excision repair cross-complementing 1

VEGF:

Vascular endothelial growth factor

VPF:

Vascular permeability factor

OS:

Overall survival

PFS:

Progression-free survival

ELISA:

Enzyme-linked immunosorbent assays

HR:

Hazard ratio

CI:

Confidence interval

NSCLC:

Non-small-cell lung cancer

SCLC:

Small cell lung cancer

IHC:

Immunohistochemistry

RT-PCR:

Reverse transcription-polymerase chain reaction

References

  • Altman DG (2001) Systematic reviews of evaluations of prognostic variables. BMJ 323(7306):224–228

    Article  PubMed  CAS  Google Scholar 

  • An SJ, Huang YS, Chen ZH, Su J, Yang Y, Chen JG, Yan HH, Lin QX, Yang JJ, Yang XN, Zhou Q, Zhang XC, Wu YL (2012) Posttreatment plasma VEGF levels may be associated with the overall survival of patients with advanced non-small cell lung cancer treated with bevacizumab plus chemotherapy. Med Oncol 29(2):627–632. doi:10.1007/s12032-011-9924-x

    Article  PubMed  CAS  Google Scholar 

  • Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  PubMed  CAS  Google Scholar 

  • Brattstrom D, Bergqvist M, Larsson A, Holmertz J, Hesselius P, Rosenberg L, Brodin O, Wagenius G (1998) Basic fibroblast growth factor and vascular endothelial growth factor in sera from non-small cell lung cancer patients. Anticancer Res 18(2A):1123–1127

    PubMed  CAS  Google Scholar 

  • Brattstrom D, Bergqvist M, Hesselius P, Larsson A, Lamberg K, Wernlund J, Brodin O, Wagenius G (2002) Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients. Lung Cancer 37(1):57–63

    Article  PubMed  Google Scholar 

  • Carrillo-de Santa Pau E, Carrillo Arias F, Caso Pelaez E, Muguruza Trueba I, Sanchez Hernandez I, Munoz Molina GM, Moreno Balsalobre R, Sacristan Lopez S, Gomez-Pinillos A, Toledo Lobo Mdel V (2010) Vascular endothelial growth factor (VEGF) serum levels are associated with survival in early stages of lung cancer patients. Cancer Invest 28(4):393–398. doi:10.3109/07357900903405900

    PubMed  CAS  Google Scholar 

  • Chakra M, Pujol JL, Lamy PJ, Bozonnat MC, Quantin X, Jacot W, Daures JP (2008) Circulating serum vascular endothelial growth factor is not a prognostic factor of non-small cell lung cancer. J Thorac Oncol 3(10):1119–1126. doi:10.1097/JTO.0b013e318187464e

    Article  PubMed  Google Scholar 

  • Choi JH, Kim HC, Lim HY, Nam DK, Kim HS, Yi JW, Chun M, Oh YT, Kang S, Park KJ, Hwang SC, Lee YH, Hahn MH (2001) Vascular endothelial growth factor in the serum of patients with non-small cell lung cancer: correlation with platelet and leukocyte counts. Lung Cancer 33(2–3):171–179

    Article  PubMed  CAS  Google Scholar 

  • Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere J, Benamouzig R, Breau J, Perret G (2006) Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer 94(12):1823–1832

    Article  PubMed  CAS  Google Scholar 

  • Donovan L, Sankaridurg P, Ho A, Naduvilath T, Smith EL III, Holden BA (2012) Myopia progression rates in urban children wearing single-vision spectacles. Optom Vis Sci 89(1):27–32. doi:10.1097/OPX.0b013e3182357f79

    Article  PubMed  Google Scholar 

  • Dudek AZ, Mahaseth H (2005) Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Cancer Invest 23(3):193–200

    Article  PubMed  CAS  Google Scholar 

  • Edelman MJ, Hodgson L, Wang XF, Christenson R, Jewell S, Vokes E, Kratzke R (2011) Serum vascular endothelial growth factor and COX-2/5-LOX inhibition in advanced non-small cell lung cancer: cancer and leukemia group B 150304. J Thorac Oncol 6(11):1902–1906. doi:10.1097/JTO.0b013e31822a7383

    Article  PubMed  Google Scholar 

  • Egger M, Zellweger-Zähner T, Schneider M, Junker C, Lengeler C, Antes G (1997) Language bias in randomised controlled trials published in English and German. Lancet 350(9074):326

    Article  PubMed  CAS  Google Scholar 

  • Farhat FS, Tfayli A, Fakhruddin N, Mahfouz R, Otrock ZK, Alameddine RS, Awada AH, Shamseddine A (2012) Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer. Crit Rev Oncol Hematol 84(2):149–160. doi:10.1016/j.critrevonc.2012.02.012

    Article  PubMed  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  PubMed  CAS  Google Scholar 

  • Firat S, Bousamra M, Gore E, Byhardt RW (2002) Comorbidity and KPS are independent prognostic factors in stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 52(4):1047

    Article  PubMed  Google Scholar 

  • Folkman J, Kalluri R (2004) Cancer without disease. Nature 427(6977):787

    Article  PubMed  CAS  Google Scholar 

  • Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BE, Heymach JV (2009) Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res 15(10):3600–3609. doi:10.1158/1078-0432.CCR-08-2568

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa Y, Takanashi S, Okudera K, Kumagai M, Hayashi A, Morimoto T, Okumura K (2005) Vascular endothelial growth factor level as a prognostic determinant of small cell lung cancer in Japanese patients. Intern Med 44(1):26–34

    Article  PubMed  CAS  Google Scholar 

  • Hegde PS, Jubb AM, Chen D, Li NF, Meng G, Bernaards C, Elliott R, Scherer S, Chen DS (2012) Predictive impact of circulating vascular endothelial growth factor in 4 phase III trials evaluating bevacizumab. Clin Cancer Res. doi:10.1158/1078-0432.ccr-12-2535

    Google Scholar 

  • Imoto H, Osaki T, Taga S, Ohgami A, Ichiyoshi Y, Yasumoto K (1998) Vascular endothelial growth factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc Surg 115(5):1007–1014

    Article  PubMed  CAS  Google Scholar 

  • Jantus-Lewintre E, Sanmartin E, Sirera R, Blasco A, Sanchez JJ, Taron M, Rosell R, Camps C (2011) Combined VEGF-A and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC. Lung Cancer 74(2):326–331. doi:10.1016/j.lungcan.2011.02.016

    Article  PubMed  Google Scholar 

  • Jelkmann W (2001) Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem 47(4):617–623

    PubMed  CAS  Google Scholar 

  • Jiang J, Liang X, Zhou X, Huang R, Chu Z, Zhan Q (2012) ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis. Mol Biol Rep 39(6):6933–6942. doi:10.1007/s11033-012-1520-4

    Article  PubMed  CAS  Google Scholar 

  • Kaya A, Ciledag A, Gulbay BE, Poyraz BM, Celik G, Sen E, Savas H, Savas I (2004) The prognostic significance of vascular endothelial growth factor levees in sera of non-small cell lung cancer patients. Respir Med 98(7):632–636. doi:10.1016/j.rmed.2003.12.017

    Article  PubMed  Google Scholar 

  • Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H (1994) Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta 1221(2):211–214

    Article  PubMed  CAS  Google Scholar 

  • Kut C, Mac Gabhann F, Popel AS (2007) Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer. Br J Cancer 97(7):978–985. doi:10.1038/sj.bjc.6603923

    Article  PubMed  CAS  Google Scholar 

  • Kyzas PA, Cunha IW, Ioannidis JPA (2005) Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 11(4):1434–1440

    Article  PubMed  CAS  Google Scholar 

  • Laack E, Scheffler A, Burkholder I, Boeters I, Andritzky B, Schuch G, Gorn M, Vohwinkel G, Edler L, Fiedler W, Hossfeld DK (2005) Pretreatment vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) serum levels in patients with metastatic non-small cell lung cancer (NSCLC). Lung Cancer 50(1):51–58. doi:10.1016/j.lungcan.2005.05.011

    Article  PubMed  Google Scholar 

  • Lakatos E (1988) Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 44(1):229–241

    Article  PubMed  CAS  Google Scholar 

  • Lakatos E (2002) Designing complex group sequential survival trials. Stat Med 21(14):1969–1989

    Article  PubMed  Google Scholar 

  • Leal YA, Cedillo-Rivera R, Simon JA, Velazquez JR, Flores LL, Torres J (2011) Utility of stool sample-based tests for the diagnosis of Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 52(6):718–728. doi:10.1097/MPG.0b013e3182077d33

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Hong Y, Han C, Hwang D, Hong S (2000) Clinical usefulness of serum and plasma vascular endothelial growth factor in cancer patients: which is the optimal specimen? Int J Oncol 17(1):149–152

    PubMed  CAS  Google Scholar 

  • Mack PC, Redman MW, Chansky K, Williamson SK, Farneth NC, Lara PN Jr, Franklin WA, Le QT, Crowley JJ, Gandara DR (2008) Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26(29):4771–4776. doi:10.1200/JCO.2008.17.0662

    Article  PubMed  CAS  Google Scholar 

  • Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S, Lafitte JJ, Sculier JP (2005) The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 92(1):131–139. doi:10.1038/sj.bjc.6602258

    Article  PubMed  CAS  Google Scholar 

  • Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, Michel J, Van Cutsem O, Sergysels R, Mommen P et al (1995) Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. The European Lung Cancer Working Party. J Clin Oncol 13(5):1221–1230

    PubMed  CAS  Google Scholar 

  • Qin L, Bromberg-White J, Qian C (2012) Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. Adv Cancer Res 113:191

    Article  PubMed  CAS  Google Scholar 

  • Qu JT, Wang M, He HL, Tang Y, Ye XJ (2012) The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: a meta-analysis and systemic review. J Can Res Clin Oncol 138(5):819–825

    Article  CAS  Google Scholar 

  • Sakurai T, Kudo M (2011) Signaling pathways governing tumor angiogenesis. Oncology 81(Suppl 1):24–29. doi:10.1159/000333256

    Article  PubMed  CAS  Google Scholar 

  • Salven P, Ruotsalainen T, Mattson K, Joensuu H (1998) High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 79(2):144–146

    Article  PubMed  CAS  Google Scholar 

  • Schoenleber S, Kurtz D, Talwalkar J, Roberts L, Gores G (2009) Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 100(9):1385–1392

    Article  PubMed  CAS  Google Scholar 

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587):983–985

    Article  PubMed  CAS  Google Scholar 

  • Shimanuki Y, Takahashi K, Cui R, Hori S, Takahashi F, Miyamoto H, Fukurchi Y (2005) Role of serum vascular endothelial growth factor in the prediction of angiogenesis and prognosis for non-small cell lung cancer. Lung 183(1):29–42. doi:10.1007/s00408-004-2521-4

    Article  PubMed  CAS  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62(1):10–29. doi:10.3322/caac.20138

    Article  PubMed  Google Scholar 

  • Smith R, Tang J, Tudur-Smith C, Neoptolemos J, Ghaneh P (2011) Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer 104(9):1440–1451

    Article  PubMed  CAS  Google Scholar 

  • Sorenson S, Fohlin H, Lindgren A, Lindskog M, Bergman B, Sederholm C, Ek L, Lamberg K, Clinchy B (2012) Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy. Eur J Cancer. doi:10.1016/j.ejca.2012.07.032

    PubMed  Google Scholar 

  • Stewart L, Parmar M (1993) Meta-analysis of the literature or of individual patient data: is there a difference? Lancet 341(8842):418–422

    Article  PubMed  CAS  Google Scholar 

  • Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E (2006) Serum vascular endothelial growth factor (VEGF) and bcl-2 levels in advanced stage non-small cell lung cancer. Cancer Invest 24(6):576–580. doi:10.1080/07357900600894781

    Article  PubMed  CAS  Google Scholar 

  • Thurston G, Kitajewski J (2008) VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 99(8):1204–1209

    Article  PubMed  CAS  Google Scholar 

  • Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8(1):16

    Article  PubMed  Google Scholar 

  • Tonini C, Beghi E, Berg AT, Bogliun G, Giordano L, Newton RW, Tetto A, Vitelli E, Vitezic D, Wiebe S (2004) Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res 62(1):75

    Article  PubMed  CAS  Google Scholar 

  • Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G (2011) Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum 41(1):1–11. doi:10.1016/j.semarthrit.2010.08.001

    Article  PubMed  Google Scholar 

  • Young RJ, Tin AW, Brown NJ, Jitlal M, Lee SM, Woll PJ (2012) Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide. Br J Cancer 106(6):1153–1159. doi:10.1038/bjc.2012.50

    Article  PubMed  CAS  Google Scholar 

  • Zhan P, Wang J, Lv X, Wang Q, Qiu L, Lin X, Yu L, Song Y (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4(9):1094

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by Provincial Science and Technology Development Planning of Shandong (2011GGH21819) and Provincial Science and Technology Development Planning of Shandong (2012G0021836). The authors thank all the investigators of the primary studies and all the members of our team.

Conflict of interest

The authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University, 324 Jingwu Road, Jinan, 250021, People’s Republic of China

    Pingping Hu, Liguang Wang, Miaomiao Yang & Jiajun Du

  2. Shandong Medical Imaging Research Institute, 324 Jingwu Road, Jinan, 250021, People’s Republic of China

    Weidong Liu

  3. Department of Thoracic Surgery and Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University, 324 Jingwu Road, Jinan, 250021, People’s Republic of China

    Jiajun Du

Authors
  1. Pingping Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weidong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liguang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miaomiao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiajun Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiajun Du.

Additional information

Pingping Hu and Weidong Liu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, P., Liu, W., Wang, L. et al. High circulating VEGF level predicts poor overall survival in lung cancer. J Cancer Res Clin Oncol 139, 1157–1167 (2013). https://doi.org/10.1007/s00432-013-1425-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-013-1425-1

Keywords

Search

Navigation