Tumor Biology

, Volume 35, Issue 8, pp 7675–7683 | Cite as

The role of anti-VEGF agents in the treatment of advanced gastric cancer: a meta-analysis of randomized controlled trials

  • Wei-Xiang Qi
  • Zan Shen
  • Li-Na Tang
  • Yang Yao
Research Article


Inhibition of vascular epithelial growth factor (VEGF) signaling pathways has proven to be an effective strategy for the treatment of several common solid tumors, but its role in the management of advanced gastric cancer (AGC) is yet to be defined. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of anti-VEGF agents in the treatment of AGC. Several databases were searched, including PubMed, Embase, and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). The pooled hazard ratio (HR) or relative risk (RR) and 95 % confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Seven RCTs which involved 2,340 patients were ultimately identified. The pooled analysis demonstrated that anti-VEGF therapy significantly improved OS (HR 0.74, 95 % CI 0.61–0.91, p = 0.003), PFS (HR 0.59, 95 % CI 0.44–0.78, p < 0.001), and ORR (RR 1.43, 95 % CI 1.14–1.79, p = 0.002) when compared to non-anti-VEGF therapy. Sensitivity analysis further confirmed this association. Additionally, more incidences of grade 3 or 4 thrombocytopenia, diarrhea, and hypertension were observed in anti-VEGF therapy. The anti-VEGF therapy offers a significant survival benefit in patients with AGC, especially for those previously treated patients, when compared to non-anti-VEGF therapy. With the present available data from randomized clinical trials, we could not clearly set the role of specific anti-VEGF agents in the treatment of AGC. Further studies are recommended to identify patients who could derive greater benefits from specific anti-VEGF agents.


Advanced gastric cancer VEGF inhibitors Meta-analysis 


Conflicts of interest

All authors declare that they have no potential conflicts of interests.


  1. 1.
    Lambert R, Guilloux A, Oshima A, Pompe-Kirn V, Bray F, Parkin M, et al. Incidence and mortality from stomach cancer in Japan, Slovenia and the USA. Int J Cancer. 2002;97:811–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United K: capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006;24:2903–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Qi WX, Shen Z, Lin F, Sun YJ, Min DL, Tang LN, et al. Overall survival benefits for irinotecan-containing regimens as first-line treatment for advanced gastric cancer: an updated meta-analysis of ten randomized controlled trials. Int J Cancer. 2013;132:E66–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972;175:409–16.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23:3502–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, 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;23:3697–705.PubMedCrossRefGoogle Scholar
  12. 12.
    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (correct): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Amit L, Ben-Aharon I, Vidal L, Leibovici L, Stemmer S. The impact of bevacizumab (avastin) on survival in metastatic solid tumors—a meta-analysis and systematic review. PLoS One. 2013;8:e51780.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Macedo LT, da Costa Lima AB, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.PubMedCrossRefGoogle Scholar
  16. 16.
    Qi WX, Tang LN, He AN, Shen Z, Yao Y. 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. 2011;189:437–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Qi WX, Wang Q, Jiang YL, Sun YJ, Tang LN, He AN, et al. Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data. PLoS One. 2013;8:e55637.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Melichar B, Koralewski P, Ravaud A, Pluzanska A, Bracarda S, Szczylik C, et al. First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol. 2008;19:1470–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Calgb 90206. J Clin Oncol. 2008;26:5422–8.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287–94.PubMedCrossRefGoogle Scholar
  22. 22.
    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;365:2473–83.PubMedCrossRefGoogle Scholar
  23. 23.
    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;365:2484–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Wells Jr SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–41.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Moher DLA, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–37.PubMedCrossRefGoogle Scholar
  30. 30.
    Vandenbroucke JP. Bias in meta-analysis detected by a simple, graphical test. Experts’ views are still needed. BMJ. 1998;316:469–70. author reply 470–461.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase ii trial. J Clin Oncol. 2013;31:3219–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Investigators RT: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (regard): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase iii study. J Clin Oncol. 2011;29:3968–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y: Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2014Google Scholar
  35. 35.
    Koizumi W, Yamaguchi K, Hosaka H, Takinishi Y, Nakayama N, Hara T, et al. Randomised phase ii study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer. Br J Cancer. 2013;109:2079–86.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Yi JH, Lee J, Park SH, Park JO, Yim DS, Park YS, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer. 2012;106:1469–74.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Wilke H, Van Cutsem E, Cheul Oh S, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Ohtsu A, Rougie P, Emig M, Carlesi R, Chandrawansa K, K. M: RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol 2014;32:abstr LBA7.Google Scholar
  38. 38.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.PubMedCrossRefGoogle Scholar
  39. 39.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Ellis LM. Angiogenesis and its role in colorectal tumor and metastasis formation. Semin Oncol. 2004;31:3–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–55.PubMedCrossRefGoogle Scholar
  42. 42.

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of OncologyShanghai Jiao Tong University affiliated Sixth People’s HospitalShanghaiChina

Personalised recommendations