Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept

Gastroenterology Research and Practice

Volumn 2014, Issue , 2014, Pages

  Giordano, Guido ^a   Febbraro, Antonio ^a   Venditti, Michele ^a   Campidoglio, Serena ^a   Olivieri, Nunzio ^b   Raieta, Katia ^c   Parcesepe, Pietro ^d   Imbriani, Giusy Carmen ^e   Remo, Andrea ^f   Pancione, Massimo ^c  

^a UO of Dermatology   (Italy)

^b UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^c UNIVERSITY OF SANNIO   (Italy)

^d UNIVERSITY OF VERONA   (Italy)

^e SECOND UNIVERSITY OF NAPLES   (Italy)

^f Mater Salutis Hospital   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AFLIBERCEPT; BEVACIZUMAB; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; OXALIPLATIN; PANITUMUMAB; PLACEBO; PLACENTAL GROWTH FACTOR; REGORAFENIB; VASCULOTROPIN RECEPTOR 1;

ABDOMINAL PAIN; CANCER GROWTH; CARCINOGENESIS; DIARRHEA; DRUG TARGETING; GASTROINTESTINAL SYMPTOM; HUMAN; HYPERTENSION; INFECTION; INFLAMMATORY CELL; METASTATIC COLORECTAL CANCER; NEUTROPENIA; NONHUMAN; PROTEIN EXPRESSION; PROTEINURIA; REVIEW; STOMATITIS; TUMOR MICROENVIRONMENT; ULCER;

EID: 84921679225     PISSN: 16876121     EISSN: 1687630X     Source Type: Journal    
DOI: 10.1155/2014/526178     Document Type: Review

References (98)

1. R. Siegel, E. Ward, O. Brawley, and A. Jemal, "Cancer statistics," CA: Cancer Journal for Clinicians, vol. 61, no. 4, pp. 212-236, 2011.
2. A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, "Global cancer statistics," CA Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69-90, 2011.
3. J. Y. Douillard, D. Cunningham, A. D. Roth et al., "Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial," The Lancet, vol. 355, no. 9209, pp. 1041-1047, 2000.
4. L. B. Saltz, J. V. Cox, C. Blanke et al., "Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer," The New England Journal of Medicine, vol. 343, no. 13, pp. 905-914, 2000.
5. R. M. Goldberg, D. J. Sargent, R. F Morton et al., "A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer," Journal of Clinical Oncology, vol. 22, no. 1, pp. 23-30, 2004.
6. A. Grothey and D. Sargent, "Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line," Journal of Clinical Oncology, vol. 23, no. 36, pp. 9441-9442, 2005.
7. Y. S. R. Krishnaiah and M. A. Khan, "Strategies of targeting oral drug delivery systems to the colon and their potential use for the treatment of colorectal cancer," Pharmaceutical Development and Technology, vol. 17, no. 5, pp. 521-540, 2012.
8. C. Bokemeyer, E. Van Cutsem, P. Rougier et al., "Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials," European Journal of Cancer, vol. 48, no. 10, pp. 1466-1475, 2012.
9. G. Argiles, R. Dienstmann, E. Elez, and J. Tabernero, "Panitu-mumab: a summary of clinical development in colorectal cancer and future directions," Future Oncology, vol. 8, no. 4, pp. 373-389, 2012.
10. J. Y. Douillard, K. S. Oliner, and S. Siena, "Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer," The New England Journal of Medicine, vol. 369, no. 11, pp. 1023-1034, 2013.
11. J. Folkman, "Tumor angiogenesis: therapeutic implications.," The New England Journal of Medicine, vol. 285, no. 21, pp. 1182-1186, 1971.
12. H. Hurwitz, L. Fehrenbacher, W. Novotny et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer," The New England Journal of Medicine, vol. 350, no. 23, pp. 2335-2342, 2004.
13. E. van Cutsem, J. Tabernero, R. Lakomy et al., "Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen," Journal of Clinical Oncology, vol. 30, no. 28, pp. 3499-3506, 2012.
14. A. Grothey, E. Van Cutsem, A. Sobrero et al., "Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial," TheLancet, vol. 381, no. 9863, pp. 303-312, 2013.
15. J. A. Joyce and J. W. Pollard, "Microenvironmental regulation of metastasis," Nature Reviews Cancer, vol. 9, no. 4, pp. 239-252, 2009.
16. M. H. McLean, G. I. Murray, K. N. Stewart et al., "The inflammatory microenvironment in colorectal neoplasia," PLoS ONE, vol. 6, no. 1, Article ID e15366, 2011.
17. I. P. Witz, "The tumor microenvironment: the making of a paradigm," Cancer Microenvironment, vol. 2, supplement 1, pp. 9-17, 2009.
18. D. I. Gabrilovich and S. Nagaraj, "Myeloid-derived suppressor cells as regulators of the immune system," Nature Reviews Immunology, vol. 9, no. 3, pp. 162-174, 2009.
19. C. Fischer, M. Mazzone, B. Jonckx, and P. Carmeliet, "FLT1 and its ligands VEGFB and P1GF: drug targets for anti-angiogenic therapy?" Nature Reviews Cancer, vol. 8, no. 12, pp. 942-956, 2008.
20. J. D. Schwartz, E. K. Rowinsky, H. Youssoufian, B. Pytowski, and Y. Wu, "Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1)," Cancer, vol. 116, no. 4, pp. 1027-1032, 2010.
21. D. I. Gabrilovich, S. Ostrand-Rosenberg, and V. Bronte, "Coordinated regulation of myeloid cells by tumours," Nature Reviews Immunology, vol. 12, no. 4, pp. 253-268, 2012.
22. A. Mantovani, A. Sica, P. Allavena, C. Garlanda, and M. Locati, "Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation," Human Immunology, vol. 70, no. 5, pp. 325-330, 2009.
23. M. L. Squadrito and M. de Palma, "Macrophage regulation of tumor angiogenesis: implications for cancer therapy," Molecular Aspects of Medicine, vol. 32, no. 2, pp. 123-145, 2011.
24. J. Wels, R. N. Kaplan, S. Rafii, and D. Lyden, "Migratory neighbors and distant invaders: tumor-associated niche cells," Genes and Development, vol. 22, no. 5, pp. 559-574, 2008.
25. J. Folkman, E. Merler, C. Abernathy, and G. Williams, "Isolation of a tumor factor responsible or angiogenesis," The Journal of Experimental Medicine, vol. 133, no. 2, pp. 275-288, 1971.
26. J. Folkman, "Role of angiogenesis in tumor growth and metastasis," Seminars in Oncology, vol. 29, 6, supplement 6, pp. 15-18, 2002.
27. J. Folkman, "Fundamental concepts of the angiogenic process," Current Molecular Medicine, vol. 3, no. 7, pp. 643-651, 2003.
28. P. Carmeliet, "Angiogenesis in life, disease and medicine," Nature, vol. 438, no. 7070, pp. 932-936, 2005.
29. N. Ferrara, "Vascular endothelial growth factor: basic science and clinical progress," Endocrine Reviews, vol. 25, no. 4, pp. 581-611, 2004.
30. D. Shweiki, M. Neeman, A. Itin, and E. Keshet, "Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis," Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 3, pp. 768-772, 1995.
31. D. J. Hicklin and L. M. Ellis, "Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis," Journal of Clinical Oncology, vol. 23, no. 5, pp. 1011-1027, 2005.
32. G. Neufeld, T. Cohen, S. Gengrinovitch, and Z. Poltorak, "Vascular endothelial growth factor (VEGF) and its receptors," FASEB Journal, vol. 13, no. 1, pp. 9-22, 1999.
33. G. D. Yancopoulos, S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash, "Vascular-specific growth factors and blood vessel formation," Nature, vol. 407, no. 6801, pp. 242-248, 2000.
34. M. Shibuya, "Tyrosine kinase receptor Flt/VEGFR family: its characterization related to angiogenesis and cancer," Genes and Cancer, vol. 1, no. 11, pp. 1119-1123, 2011.
35. L. Claesson-Welsh and M. Welsh, "VEGFA and tumour angiogenesis," Journal of Internal Medicine, vol. 273, no. 2, pp. 114-127, 2013.
36. V. Joukov, K. Pajusola, A. Kaipainen et al., "A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases," The EMBO Journal, vol. 15, no. 2, pp. 290-298, 1996.
37. K. Holmqvist, M. J. Cross, C. Rolny et al., "The adaptor protein Shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration," The Journal of Biological Chemistry, vol. 279, no. 21, pp. 22267-22275, 2004.
38. F. Zhang, Z. Tang, and X. Hou, "VEGF-B is indispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, pp. 6152-6157, 2009.
39. L. Jussila and K. Alitalo, "Vascular growth factors and lymphan-giogenesis," Physiological Reviews, vol. 82, no. 3, pp. 673-700, 2002.
40. A. Khaliq, X. F. Li, M. Shams et al., "Localisation of placenta growth factor (PIGF) in human term placenta," Growth Factors, vol. 13, no. 3-4, pp. 243-250, 1996.
41. P. Vuorela, E. Hatva, A. Lymboussaki et al., "Expression of vascular endothelial growth factor and placenta growth factor in human placenta," Biology of Reproduction, vol. 56, no. 2, pp. 489-494, 1997
42. S. R. Brave, C. Eberlein, M. Shibuya, S. R. Wedge, and S. T. Barry, "Placental growth factor neutralising antibodies give limited anti-angiogenic effects in an in vitro organotypic angiogenesis model," Angiogenesis, vol. 13, no. 4, pp. 337-347, 2010.
43. J. E. Park, H. H. Chen, J. Winer, K. A. Houck, and N. Ferrara, "Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR," The Journal of Biological Chemistry, vol. 269, no. 41, pp. 25646-25654, 1994.
44. P. Carmeliet, L. Moons, A. Luttun et al., "Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions," Nature Medicine, vol. 7, no. 5, pp. 575-583, 2001.
45. S. F. Martins, E. A. Garcia, M. A. Luz, F. Pardal, M. Rodrigues, and A. L. Filho, "Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer," Cancer Genomics Proteomics, vol. 10, no. 2, pp. 55-67, 2013.
46. T. Wang, Z. Chen, X. Wei, B. Wei, and W. Dong, "Serum vascular endothelial growth factor-C and lymphoangiogenesis are associated with the lymph node metastasis and prognosis of patients with colorectal cancer," ANZ Journal of Surgery, vol. 81, no. 10, pp. 694-699, 2011.
47. A. A. Alabi, A. Suppiah, L. A. Madden, J. R. Monson, and J. Greenman, "Preoperative serum levels of serum is associated with distant metastasis in cancer," International Journal of Colorectal Disease, vol. 24, no. 3, pp. 269-274, 2009.
48. F. J. Gonzalez, A. R. Quesada, I. Sevilla et al., "Prognostic value of serum angiogenic activity in colorectal cancer patients," Journal of Cellular and Molecular Medicine, vol. 11, no. 1, pp. 120-128, 2007
49. D. Fukumura, D. G. Duda, L. L. Munn, and R. K. Jain, "Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models," Microcirculation, vol. 17, no. 3, pp. 206-225, 2010.
50. V. Barresi, C. Di Gregorio, L. Regiani-Bonetti, M. Ponz-De Leon, G. Barresi, and E. Vitarelli, "Stage i colorectal carcinoma: VEGF immunohistochemical expression, microvessel density, and their correlation with clinical outcome," Virchows Archiv, vol. 457, no. 1, pp. 11-19, 2010.
51. Y. Takahashi, S. L. Tucker, Y. Kitadai et al., "Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer," Archives of Surgery, vol. 132, no. 5, pp. 541-546, 1997
52. J. C. Lee, N. H. Chow, S. T. Wang, and S. M. Huang, "Prognostic of vascular endothelial growth factor expression in cancer," European Journal of Cancer, vol. 36, no. 6, pp. 748-753, 2000.
53. F. De Vita, M. Orditura, E. Lieto et al., "Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma," Cancer, vol. 100, no. 2, pp. 270-278, 2004.
54. S. Onogawa, Y. Kitadai, S. Tanaka, T. Kuwai, S. Kimura, and K. Chayama, "Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma," Cancer Science, vol. 95, no. 1, pp. 32-39, 2004.
55. A. Giatromanolaki, E. Sivridis, and M. I. Koukourakis, "Angiogenesis in colorectal cancer: prognostic and therapeutic implications," American Journal of Clinical Oncology: Cancer Clinical Trials, vol. 29, no. 4, pp. 408-417, 2006.
56. J. Cheng, R. E. Slavin, J. A. Gallagher et al., "Expression of vascular endothelial growth factor and receptor flk-1 in colon cancer liver metastases," Journal of Hepato-Biliary-Pancreatic Surgery, vol. 11, no. 3, pp. 164-170, 2004.
57. M. Eppenberger, I. Zlobec, D. Baumhoer, L. Terracciano, and A. Lugli, "Role of the VEGF ligand to receptor ratio in the progression of mismatch repair-proficient colorectal cancer," BMC Cancer, vol. 11, no. 1, p. 93, 2010.
58. Y. J. Lee, D. L. Karl, U. N. Maduekwe et al., "Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment," Cancer Research, vol. 70, no. 21, pp. 8357-8367, 2010.
59. T. Tokunaga, Y. Oshika, Y. Abe et al., "Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer," British Journal of Cancer, vol. 77, no. 6, pp. 998-1002, 1998.
60. S. E. Duff, M. Jeziorska, D. D. Rosa et al., "Vascular endothelial growth factors and receptors in colorectal cancer: implications for anti-angiogenic therapy," European Journal of Cancer, vol. 42, no. 1, pp. 112-117, 2006.
61. Y. Harada, Y. Ogata, and K. Shirouzu, "Expression of vascular endothelial growth factor and its receptor KDR (kinase domain-containing receptor)/Flk-1 (fetal liver kinase-1) as prognostic factors in human colorectal cancer," International Journal of Clinical Oncology, vol. 6, no. 5, pp. 221-228, 2001.
62. C. Eveno and M. Pocard, "VEGF levels and the angiogenic potential of the microenvironment can affect surgical strategy for colorectal liver metastasis," Cell Adhesion and Migration, vol. 6, no. 6, pp. 569-573, 2012.
63. N. Beauchemin, "The colorectal tumor microenvironment: the next decade," Cancer Microenvironment, vol. 4, no. 2, pp. 181-185, 2011.
64. V. W. M. van Hinsbergh, A. Collen, and P. Koolwijk, "Angiogenesis and anti-angiogenesis: perspectives for the treatment of solid tumors," Annals of Oncology, vol. 10, supplement 4, pp. S60-S63, 1999.
65. N. Ferrara and R. S. Kerbel, "Angiogenesis as a therapeutic target," Nature, vol. 438, no. 7070, pp. 967-974, 2005.
66. A. Grothey and E. Galanis, "Targeting angiogenesis: progress with anti-VEGF treatment with large molecules," Nature Reviews Clinical Oncology, vol. 6, no. 9, pp. 507-518, 2009.
67. H. Prenen, L. Vecchione, and E. van Cutsem, "Role of targeted agents in metastatic colorectal cancer," Targeted Oncology, vol. 8, no. 2, pp. 83-96, 2013.
68. D. J. Cohen and H. S. Hochster, "Update on clinical data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic colorectal cancer," Clinical Colorectal Cancer, vol. 7, no. 1, pp. S21-S27, 2007
69. http://www.ema.europa.eu/ema/.
70. J. Cassidy, S. Clarke, E. Diaz-Rubio et al., "XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: N016966 updated results," British Journal of Cancer, vol. 105, no. 1, pp. 58-64, 2011.
71. B. J. Giantonio, P. J. Catalano, N. J. Meropol et al., "Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200," Journal of Clinical Oncology, vol. 25, no. 12, pp. 1539-1544, 2007
72. L. T. Macedo, A. B. da Costa Lima, and A. D. Sasse, "Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups," BMC Cancer, vol. 12, article 89, 2012.
73. J. Bennouna, J. Sastre, D. Arnold et al., "Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial," The Lancet Oncology, vol. 14, no. 1, pp. 29-37, 2013.
74. S. L. Davis, S. G. Eckhardt, W. A. Messersmith, and A. Jimeno, "The development of regorafenib and its current and potential future role in cancer therapy," Drugs of Today, vol. 49, no. 2, pp. 105-115, 2013.
75. A. N. Economides, L. R. Carpenter, J. S. Rudge et al., "Cytokine traps: multi-component, high-affinity blockers of cytokine action," Nature Medicine, vol. 9, no. 1, pp. 47-52, 2003.
76. J. Holash, S. Davis, N. Papadopoulos et al., "VEGF-Trap: a VEGF blocker with potent antitumor effects," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11393-11398, 2002.
77. K. Jin, Y. Shen, K. He, Z. Xu, G. Li, and L. Teng, "Aflibercept (VEGF Trap): one more double-edged sword of anti-VEGF therapy for cancer?" Clinical and Translational Oncology, vol. 12, no. 8, pp. 526-532, 2010.
78. N. Papadopoulos, J. Martin, Q. Ruan et al., "Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab," Angiogenesis, vol. 15, no. 2, pp. 171-185, 2012.
79. A. T. Byrne, L. Ross, J. Holash et al., "Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model," Clinical Cancer Research, vol. 9, no. 15, pp. 5721-5728, 2003.
80. H. M. W. Verheul, H. Hammers, K. Van Erp et al., "Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model," Clinical Cancer Research, vol. 13, no. 14, pp. 4201-4208, 2007
81. M. Chiron, P. Lejeune, and F. Blandt, "Broad spectrum of antitumor activity of aflibercept (VEGF-Trap) in tumor-bearing mice, Proc Am Assoc Cancer Res," in Proceedings of the American Association for Cancer Research, Abstract 380, 2008.
82. M. Fukasawa and M. Korc, "Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines," Clinical Cancer Research, vol. 10, no. 10, pp. 3327-3332, 2004.
83. P. R. Wachsberger, R. Burd, C. Cardi et al, "VEGF Trap in combination with radiotherapy improves tumor control in U87 glioblastoma," International Journal of Radiation Oncology, Biology Physics, vol. 67, no. 5, pp. 1526-1537, 2007
84. M. V. P. Chiron, P. Lejeune, B. Demers, D. Leopold, and M. C. Bissery, "Synergistic activity of aflibercept (VEGF Trap) in combination with 5-fluorouracil and irinotecan in preclinical tumor models," in Proceeding from AACR-NCI-EORTC: Molecular Targets and Cancer Therapeutics, San Francisco, Calif, USA, Abstract A13, 2007
85. W. Lassoued, D. Murphy, J. Tsai, R. Oueslati, G. Thurston, and W. M. F. Lee, "Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors," Cancer Biology and Therapy, vol. 10, no. 12, pp. 1326-1333, 2010.
86. E. S. Kim, A. Serur, J. Huang et al., "Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11399-11404, 2002.
87. M. Chiron, P. Vrignaud, and P. Lejeune, "in vivo evaluation of the angiogenic agent VEGF Trap," in Proceedings of the American Association for Cancer Research, Abstract 547, 2005.
88. L. Hu, J. Hofmann, J. Holash, G. D. Yancopoulos, A. K. Sood, and R. B. Jaffe, "Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model," Clinical Cancer Research, vol. 11, no. 19, pp. 6966-6971, 2005.
89. P. Lejeune, M. Chiron, and R. Le Moigne, "Combination of the angiogenic agent aflibercept (VEGF-Trap) with docetaxel or gemcitabine results in greater antitumor activity in tumor bearing mice," in Proceedings of the American Association for Cancer Research, Abstract 1107, 2008.
90. P. R. Wachsberger, R. Burd, C. Cardi et al., "VEGF trap in combination with radiotherapy improves tumor control in U87 glioblastoma," International Journal of Radiation Oncology, Biology Physics, vol. 67, no. 5, pp. 1526-1537, 2007
91. E. van Cutsem, D. Khayat, C. Verslype et al., "Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours," European Journal of Cancer, vol. 49, no. 1, pp. 17-24, 2013.
92. T. Yoshino, K. Yamazaki, K. Yamaguchi et al., "Phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer," Investigational New Drugs, vol. 31, no. 4, pp. 910-917, 2013.
93. P. Tang, S. J. Cohen, G. A. Bjarnason et al., "Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial," Journal of Clinical Oncology, vol. 26, supplement, 2008, abstract 4027
94. P. A. Tang, S. J. Cohen, C. Kollmannsberger et al., "Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer," Clinical Cancer Research, vol. 18, no. 21, pp. 6023-6031, 2012.
95. C. Pericay, G. Folprecht, M. Saunders et al., "Phase 2 randomized, noncomparative, open-label study of aflibercept and modified Folfox6 in the first-line treatment of metastatic colorectal cancer (AFFIRM)," Annals of Oncology, supplement 4, no. 23, p. iv16, 2012.
96. Verslype et al., ASCO 2008 Abstract, 1450.
97. E. Van Cutsem, J. Tabernero, R. Lakomy et al., "Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen," Journal of Clinical Oncology, vol. 30, no. 28, pp. 3499-3506, 2012.
98. C. J. Allegra, R. Lakomy, J. Tabernero et al., "Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen," Journal of Clinical Oncology, no. 30, 2012, abstract 3505.