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Tumor Biology

, Volume 37, Issue 5, pp 6297–6306 | Cite as

Does the addition of drugs targeting the vascular endothelial growth factor pathway to first-line chemotherapy increase complete response? A meta-analysis of randomized clinical trials

  • Yan Li
  • Xin-Yue Liang
  • Yi-Qi Yue
  • Lei Sheng
  • Ji-Kai Liu
  • Zhan-Yu Wang
  • Gang Chen
Original Article
  • 295 Downloads

Abstract

Drugs targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling (anti-VEGF/VEGFR drugs) are the most validated anti-angiogenic strategies for cancer treatment. Complete response (CR) is a rare event in cancer patients receiving chemotherapy. A meta-analysis was conducted to determine whether adding anti-VEGF/VEGFR drugs to chemotherapy can further increase the chance of CR in the first-line therapy. Relevant databases were systematically searched for the period 2000–2015. Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 12,453 patients from 28 randomized controlled trials were included. The overall incidence of CR in patients treated with anti-VEGF/VEGFR drugs plus chemotherapy was 1.5 % (95 % CI, 1.0–2.0 %) compared to 1.1 % (95 % CI, 0.7–1.4 %) in the chemotherapy-alone arm. Adding anti-VEGF/VEGFR drugs was associated with significant improvement of CR (RR, 1.52, 95 % CI, 1.18–1.95, P = 0.001). When stratified by drug type, adding VEGFR tyrosin kinase inhibitors (TKIs) did not increase the chance of CR (RR, 0.87, 95 % CI, 0.51–1.49; P = 0.614). The addition of bevacizumab with 7.5 mg/kg every 3 weeks, but not 15 mg/kg every 3 weeks, significantly improves the CR (7.5 mg, RR, 2.43, 95 % CI, 1.64–3.60, P = 0.000; 15 mg, RR, 1.07, 95 % CI, 0.63–1.81, P = 0.799). In subgroup analysis, a significant improvement of CR by the addition of anti-VEGF/VEGFR drugs was observed in patients with colorectal cancer (RR, 2.10, 95 % CI 1.21–3.63, P = 0.008), ovarian cancer (RR, 3.07; 95 % CI, 1.68–5.62, P = 0.000), and patients who are treated with platinum-based regimens (RR, 1.78, 95 % CI, 1.23–2.59, P = 0.002). Low-dose bevacizumab, rather than VEGFR TKIs or high-dose bevacizumab, can increase the chance of CR in patients receiving chemotherapy.

Keywords

Anti-VEGF/VEGFR drugs Complete response Chemotherapy Meta-analysis 

Notes

Author contributions

Study concept and design: Yan Li and Gang Chen; acquisition of data: Yan Li, Yi-Qi Yue, and Lei Sheng; analysis and interpretation of data: Yan Li and Xin-Yue Liang; statistical analysis: Xin-Yue Liang and Yan Li; drafting of the manuscript: Yan Li, Lei Sheng, Xin-Yue Liang, Ji-Kai Liu, and Zhan-Yu Wang; and study supervision: Gang Chen and Yan Li.

Compliance with ethical standard

Conflicts of interest

None

References

  1. 1.
    Delbaldo C, Michiels S, Syz N, et al. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. JAMA. 2004;292:470–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Javle M, Smyth EC, Chau I. Ramucirumab: successfully targeting angiogenesis in gastric cancer. Clin Cancer Res 2014Google Scholar
  5. 5.
    Chau NG, Haddad RI. Vandetanib for the treatment of medullary thyroid cancer. Clin Cancer Res. 2013;19:524–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.CrossRefPubMedGoogle Scholar
  7. 7.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Park SR, Davis M, Doroshow JH, Kummar S. Safety and feasibility of targeted agent combinations in solid tumours. Nat Rev Clin Oncol. 2013;10:154–68.CrossRefPubMedGoogle Scholar
  9. 9.
    Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24:20–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Miles DW, Dieras V, Cortes J, et al. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol. 2013;24:2773–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Herbst RS, Sun Y, Eberhardt WE, et al. 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. 2010;11:619–26.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Mackey JR, Ramos-Vazquez M, Lipatov O et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol 2014Google Scholar
  15. 15.
    Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Ocana A, Amir E, Vera F, et al. Addition of bevacizumab to chemotherapy for treatment of solid tumors: similar results but different conclusions. J Clin Oncol. 2011;29:254–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Rugo HS, Stopeck AT, Joy AA, et al. Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol. 2011;29:2459–65.CrossRefPubMedGoogle Scholar
  18. 18.
    Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013;31:373–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013;31:1341–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012;30:3084–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Bedikian AY, Johnson MM, Warneke CL, et al. Does complete response to systemic therapy in patients with stage IV melanoma translate into long-term survival? Melanoma Res. 2011;21:84–90.CrossRefPubMedGoogle Scholar
  22. 22.
    Darnton SJ, Archer VR, Stocken DD, et al. Preoperative mitomycin, ifosfamide, and cisplatin followed by esophagectomy in squamous cell carcinoma of the esophagus: pathologic complete response induced by chemotherapy leads to long-term survival. J Clin Oncol. 2003;21:4009–15.CrossRefPubMedGoogle Scholar
  23. 23.
    van de Velde HJ, Liu X, Chen G, et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica. 2007;92:1399–406.CrossRefPubMedGoogle Scholar
  24. 24.
    Buyse M, Thirion P, Carlson RW, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356:373–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.CrossRefGoogle Scholar
  27. 27.
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Shen L, Li J, Xu J et al. 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 2014.Google Scholar
  30. 30.
    Gianni L, Romieu GH, Lichinitser M, et al. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013;31:1719–25.CrossRefPubMedGoogle Scholar
  31. 31.
    Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85.CrossRefPubMedGoogle Scholar
  32. 32.
    Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer. 2012;76:362–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol. 2012;30:2509–15.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol. 2012;30:34–41.CrossRefPubMedGoogle Scholar
  35. 35.
    Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011;29:2215–22.CrossRefPubMedGoogle Scholar
  36. 36.
    Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252–60.CrossRefPubMedGoogle Scholar
  37. 37.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.CrossRefPubMedGoogle Scholar
  38. 38.
    Ohtsu A, Shah MA, Van Cutsem E, 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.CrossRefPubMedGoogle Scholar
  39. 39.
    Guan ZZ, Xu JM, Luo RC, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011;30:682–9.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010;28:3191–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26:3523–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Kabbinavar FF, Schulz J, McCleod M, 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.CrossRefPubMedGoogle Scholar
  44. 44.
    Krege S, Rexer H, Vom Dorp F, et al. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05). BJU Int. 2014;113:429–36.CrossRefPubMedGoogle Scholar
  45. 45.
    Tabernero J, Garcia-Carbonero R, Cassidy J, et al. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Clin Cancer Res. 2013;19:2541–50.CrossRefPubMedGoogle Scholar
  46. 46.
    Gradishar WJ, Kaklamani V, Sahoo TP, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49:312–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:1835–42.CrossRefPubMedGoogle Scholar
  48. 48.
    McDermott DF, Sosman JA, Gonzalez R, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol. 2008;26:2178–85.CrossRefPubMedGoogle Scholar
  49. 49.
    Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12:256–62.CrossRefPubMedGoogle Scholar
  50. 50.
    Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol. 2006;24:3939–45.CrossRefPubMedGoogle Scholar
  51. 51.
    Ling S, Hu Z, Yang Z et al. Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A 2015.Google Scholar
  52. 52.
    Mirone G, Shukla A, Marfe G. Signaling mechanisms of resistance to EGFR- and anti-angiogenic inhibitors cancer. Crit Rev Oncol Hematol 2015.Google Scholar
  53. 53.
    Funakoshi T, Latif A, Galsky MD. Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials. Cancer Treat Rev. 2014;40:636–47.CrossRefPubMedGoogle Scholar
  54. 54.
    Jayson GC, Hicklin DJ, Ellis LM. Antiangiogenic therapy—evolving view based on clinical trial results. Nat Rev Clin Oncol. 2012;9:297–303.CrossRefPubMedGoogle Scholar
  55. 55.
    Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205–18.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhou Q, Guo P, Gallo JM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res. 2008;14:1540–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071–121.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Cesca M, Bizzaro F, Zucchetti M, Giavazzi R. Tumor delivery of chemotherapy combined with inhibitors of angiogenesis and vascular targeting agents. Front Oncol. 2013;3:259.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fan F, Gray MJ, Dallas NA, et al. Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells. Mol Cancer Ther. 2008;7:3064–70.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hanrahan EO, Lin HY, Kim ES, et al. Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol. 2010;28:193–201.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yan Li
    • 1
  • Xin-Yue Liang
    • 2
  • Yi-Qi Yue
    • 3
  • Lei Sheng
    • 4
  • Ji-Kai Liu
    • 1
  • Zhan-Yu Wang
    • 1
  • Gang Chen
    • 1
  1. 1.Department of Urology, Jinshan HospitalFudan UniversityShanghaiChina
  2. 2.Institute of Clinical Pharmacology, Qilu HospitalShandong UniversityShandongChina
  3. 3.Department of GynecologyXuhui District Central HospitalShanghaiChina
  4. 4.Centre for Personalised Cancer Medicine, School of MedicineThe University of AdelaideAdelaideAustralia

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