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

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Tumor Biology

Abstract

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.

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References

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  7. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Moher DLA, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  29. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–37.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Li J, Qin S, Xu J, Guo W, **ong 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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 2014

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  39. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–30.

    Article  CAS  PubMed  Google Scholar 

  40. Ellis LM. Angiogenesis and its role in colorectal tumor and metastasis formation. Semin Oncol. 2004;31:3–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  42. http://www.Accessdata.Fda.Gov/drugsatfda_docs/label/2014/125477lbl.Pdf. assess April 24, 2014

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Qi, WX., Shen, Z., Tang, LN. et al. The role of anti-VEGF agents in the treatment of advanced gastric cancer: a meta-analysis of randomized controlled trials. Tumor Biol. 35, 7675–7683 (2014). https://doi.org/10.1007/s13277-014-2037-3

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