Seminars in Oncology
Volume 33 , Pages S41-S49 , October 2006

Future Directions in Vascular Endothelial Growth Factor–Targeted Therapy for Metastatic Colorectal Cancer

  • Axel Grothey

      Affiliations

    • Dr Grothey has served as a consultant to Pfizer, Genentech, and AstraZeneca.
    • Corresponding Author InformationAddress reprint requests to Axel Grothey, MD, Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA

References 

  1. Avastin (bevacizumab) prescribing information. South San Francisco, CA: Genentech, Inc; 2006;
  2. Nexavar (sorafenib) prescribing information. Emeryville, CA: Onyx Pharmaceuticals; 2005;
  3. Sutent (sunitinib malate) prescribing information. New York, NY: Pfizer; 2006;
  4. Goldman E. The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet. 1907;2:1236–1240
  5. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: Final analysis of the TREE study. J Clin Oncol. 2006;24(suppl):148s;(abstr 3510)
  6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX-4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol. 2005;23(suppl):1s;(abstr 2)
  7. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non–small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) trial – E4599. J Clin Oncol. 2005;23(suppl):2s;(abstr 4)
  8. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005;23:792–799
  9. Burger RA, Sill M, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study. J Clin Oncol. 2005;23(suppl):457s;(abstr 5009)
  10. Garcia AA, Oza AM, Hirte H, et al. Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: A California Cancer Consortium trial. J Clin Oncol. 2005;23(suppl):455s;(abstr 5000)
  11. Clinicaltrials.gov. 2006. Available at http://www.clinicaltrials.gov/ct/show/NCT00091026?order=2; (accessed July 19, 2006)
  12. Ko AH, Dito E, Schillinger B, et al. A phase II study of gemcitabine given at fixed-dose rate infusion, low-dose cisplatin, and bevacizumab in metastatic pancreatic cancer. J Clin Oncol. 2006;24(suppl):188s;(abstr 4041)
  13. Stopeck AT, Bellamy W, Unger J, et al. Phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin’s lymphoma (NHL): Southwest Oncology Group study S0108. J Clin Oncol. 2005;23(suppl):583s;(abstr 6592)
  14. Zhu AX, Sahani D, Norden-Zfoni A, et al. A phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOX-B) in patients with hepatocellular carcinoma. J Clin Oncol. 2005;23(suppl):337s;(abstr 4120)
  15. Hainsworth JD, Sosman JA, Spigel DR, et al. Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): A Minnie Pearl Cancer Research Network phase I/II trial. J Clin Oncol. 2005;23(suppl):388s;(abstr 4542)
  16. Spigel DR, Hainsworth JD, Sosman JA, et al. Bevacizumab and erlotinib in the treatment of patients with metastatic renal cell carcinoma (RCC): Update of a phase II multicenter trial. J Clin Oncol. 2005;23(suppl):583s;(abstr 4540)
  17. National Institutes of Health: Study of SU011248 plus Iressa in patients with advanced renal cell carcinoma. Available at: http://www.clinicaltrials.gov (accessed July 19, 2006)
  18. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–819
  19. Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–1206
  20. Dupont J, Schwartz L, Koutcher D, et al. Phase I and pharmacokinetic study of VEGF Trap administered subcutaneously (sc) to patients (pts) with advanced solid malignancies. J Clin Oncol. 2005;22:197;(abstr 3009)
  21. Levine AM, Quinn DI, Gorospe G, et al. Phase I trial of anti-sense oligonucleotide vascular endothelial growth factor (VEGF-AS, Veglin) in patients with relapsed and refractory malignancies. J Clin Oncol. 2004;22:197;(abstr 3008)
  22. Schleucher N, Trarbach T, Junker U, et al. Phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer. J Clin Oncol. 2004;22:260;(abstr 3558)
  23. Heymach JV, Johnson BE, Rowbottom JA, et al. A randomized, placebo-controlled phase II trial of ZD6474 plus docetaxel, in patients with NSCLC. J Clin Oncol. 2005;23(suppl):197s;(abstr 3023)
  24. Rini B, Rixe O, Bukowski R, et al. AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). J Clin Oncol. 2005;23(suppl):381s;(abstr 4509)
  25. Lorusso PM, Heath E, Valdivieso M, et al. Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors. J Clin Oncol. 2006;24(suppl):129s;(abstr 3034)
  26. Crawford J, Burris H, Stein M, et al. Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies. J Clin Oncol. 2006;24(suppl):602s;(abstr 3005)
  27. Huang CH, Langer CJ, Millenson MM, et al. Phase II trial evaluating combination, weekly gemcitabine and docetaxel in progressive, chemotherapy-exposed NSCLC: Preliminary results of OPN 003. J Clin Oncol. 2005;23(suppl):694s;(abstr 7295)
  28. Camidge DR, Eckhardt SG, Diab S, et al. A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer. J Clin Oncol. 2006;24(suppl):129s;(abstr 3032)
  29. Hurwitz H, Carducci MA, Robertson P, et al. A phase I study of the pan-VEGFR tyrosine kinase inhibitor, CEP-7055, in patients with advanced malignancy. Proc Am Soc Clin Oncol. 2003;22:207;(abstr 831)
  30. Hecht JR, Trarbach T, Jaeger E, et al. A randomized, double-blind, placebo-controlled phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1). J Clin Oncol. 2005;23(suppl):2s;(abstr 3)
  31. Koehne C, Bajetta E, Lin E, et al. Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients with previously treated metastatic colorectal cancer receiving FOLFOX4 and PTK787/ZK 222584 or placebo (CONFIRM 2). J Clin Oncol. 2006;24(suppl):148s;(abstr 3508)
  32. Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 2005;307:58–62
  33. Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–969
  34. Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23:939–952
  35. Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999;103:159–165
  36. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998;125:1591–1598
  37. Sundberg C, Kowanetz M, Brown LF, et al. Stable expression of angiopoietin-1 and other markers by cultured pericytes: Phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab Invest. 2002;82:387–401
  38. Gerhardt H, Wolburg H, Redies C. N-cadherin mediates pericyte-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn. 2000;218:472–479
  39. Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287–1295
  40. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338–340
  41. Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52
  42. Izumi Y, Xu L, di Tomaso E, et al. Tumor biology: Herceptin acts as an anti-angiogenic cocktail. Nature. 2002;416:279–280
  43. Tarceva (erlotinib) prescribing information. Melville, NY: OSI Pharmaceuticals; 2005;
  44. Iressa (gefitinib) prescribing information. Wilmington, DE: AstraZeneca; 2005;
  45. Gleevec (imatinib mesylate) prescribing information. East Hanover, NJ: Novartis; 2005;
  46. van Cruijsen H, Voest EE, van Herpen CML, et al. Phase I clinical evaluation of AZD2171 in combination with gefitinib, in patients with advanced tumors. J Clin Oncol. 2005;23(suppl):199s;(abstr 3030)
  47. Saltz LB, Lenz HJ, Hochster H, et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol. 2005;23(suppl):248s;(abstr 3508)
  48. Wainberg Z, Hecht JR. A phase III randomized, open-label, controlled trial of chemotherapy and bevacizumab with or without panitumumab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2006;5:363–367
  49. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–H576
  50. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev. 2004;4:423–436
  51. Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–1886
  52. Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood. 2005;106:3058–3061
  53. Colleoni M, Orlando L, Sanna G, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: Antitumor activity and biological effects. Ann Oncol. 2006;17:232–238
  54. Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(suppl 16):117–124
  55. 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;21:60–65
  56. Bendell J, Fernando N, Morse M, et al. A phase II study of oxaliplatin, capecitabine, and bevacizumab in the treatment of metastatic colorectal cancer. J Clin Oncol. 2006;24(suppl):156s;(abstr 3541)
  57. Yang JC. Bevacizumab for patients with metastatic renal cancer: An update. Clin Cancer Res. 2004;10:6367S–6370S
  58. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345
  59. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer [erratum in: Nat Med 10:649, 2004]. Nat Med. 2004;10:145–147
  60. Willett CG, Boucher Y, Duda DG, et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol. 2005;23:8136–8139
  61. McDonald DM, Choyke PL. Imaging of angiogenesis: From microscope to clinic. Nat Med. 2003;9:713–725
  62. Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: A pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys. 1996;36:417–428
  63. Gross S, Gilead A, Scherz A, et al. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat Med. 2003;9:1327–1331
  64. Jain RK. Understanding barriers to drug delivery: High resolution in vivo imaging is key. Clin Cancer Res. 1999;5:1605–1606

PII: S0093-7754(06)00315-0

doi: 10.1053/j.seminoncol.2006.08.004

Seminars in Oncology
Volume 33 , Pages S41-S49 , October 2006