• 1
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307: 58-62.
  • 2
    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001; 7: 987-989.
  • 3
    Wachsberger P, Burd R, Dicker AP. Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin Cancer Res. 2003; 9: 1957-1971.
  • 4
    Wachsberger P, Burd R, Dicker AP. Improving tumor response to radiotherapy by targeting angiogenesis signaling pathways. Hematol Oncol Clin North Am. 2004; 18: 1039-1057, viii.
  • 5
    Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000; 60: 5565-5570.
  • 6
    Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008; 8: 425-437.
  • 7
    Shinohara ET, Cao C, Niermann K, et al. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene. 2005; 24: 5414-5422.
  • 8
    Li B, Sharpe EE, Maupin AB, et al. VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J. 2006; 20: 1495-1497.
  • 9
    Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006; 313: 1785-1787.
  • 10
    Su Y, Zheng L, Wang Q, Bao J, Cai Z, Liu A. The PI3K/Akt pathway up-regulates Id1 and integrin alpha4 to enhance recruitment of human ovarian cancer endothelial progenitor cells [serial online]. BMC Cancer. 2010; 10: 459.
  • 11
    de Bouard S, Herlin P, Christensen JG, et al. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol. 2007; 9: 412-423.
  • 12
    Milker-Zabel S, Bois AZ, Ranai G, et al. SU11657 enhances radiosensitivity of human meningioma cells. Int J Radiat Oncol Biol Phys. 2008; 70: 1213-1218.
  • 13
    Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003; 2: 471-478.
  • 14
    Abrams TJ, Murray LJ, Pesenti E, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003; 2: 1011-1021.
  • 15
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003; 111: 1287-1295.
  • 16
    Carter TA, Wodicka LM, Shah NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A. 2005; 102: 11011-11016.
  • 17
    Laird AD, Cherrington JM. Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs. 2003; 12: 51-64.
  • 18
    Marzola P, Degrassi A, Calderan L, et al. Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrast-enhanced magnetic resonance imaging in an experimental model of colon carcinoma. Clin Cancer Res. 2005; 11: 5827-5832.
  • 19
    Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003; 9: 327-337.
  • 20
    O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003; 101: 3597-3605.
  • 21
    Sun L, Liang C, Shirazian S, et al. Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003; 46: 1116-1119.
  • 22
    Yee KW, Schittenhelm M, O'Farrell AM, et al. Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood. 2004; 104: 4202-4209.
  • 23
    Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 2001; 61: 2413-2419.
  • 24
    Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999; 59: 3374-3378.
  • 25
    Griffin RJ, Williams BW, Wild R, Cherrington JM, Park H, Song CW. Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response. Cancer Res. 2002; 62: 1702-1706.
  • 26
    Hess C, Vuong V, Hegyi I, et al. Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer. 2001; 85: 2010-2016.
  • 27
    Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK, Suit HD. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res. 2001; 61: 39-44.
  • 28
    Schueneman AJ, Himmelfarb E, Geng L, et al. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003; 63: 4009-4016.
  • 29
    Cuneo KC, Geng L, Fu A, Orton D, Hallahan DE, Chakravarthy AB. SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation. Int J Radiat Oncol Biol Phys. 2008; 71: 873-879.
  • 30
    Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5: 649-655.
  • 31
    National Cancer Institute, Cancer Therapy Evaluation Program (CTEP). Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3), vol. 2008; 2006. http://ctep. Accessed December 1, 2010.
  • 32
    Escudier B, Roigas J, Gillessen S, et al. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009; 27: 4068-4075.
  • 33
    Srinivas S, Roigas J, Gillessen S, et al. Continuous daily administration of sunitinib in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC): updated results [abstract]. J Clin Oncol. 2007; 25( 18S). Abstract 5040.
  • 34
    George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009; 45: 1959-1968.
  • 35
    George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009; 27: 3154-3160.
  • 36
    Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997; 89: 1138-1147.
  • 37
    Macdonald DR, Cascino TL, Schold SC, Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990; 8: 1277-1280.
  • 38
    Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res. 2008; 14: 2378-2386.
  • 39
    Chan LW, Moses MA, Goley E, et al. Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: a longitudinal study of protein kinetics throughout tumor progression and therapy. J Clin Oncol. 2004; 22: 499-506.
  • 40
    Athauda G, Giubellino A, Coleman JA, et al. c-Met ectodomain shedding rate correlates with malignant potential. Clin Cancer Res. 2006; 12( 14 pt 1): 4154-4162.
  • 41
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 53: 457-481.
  • 42
    Deprimo SE, Bello CL, Smeraglia J, et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins [serial online]. J Transl Med. 2007; 5: 32.
  • 43
    Knisely JP, Berkey B, Chakravarti A, et al. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008; 71: 79-86.
  • 44
    Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol. 2006; 24: 106-114.
  • 45
    Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with 1 to 3 brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004; 363: 1665-1672.
  • 46
    Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003; 21: 2529-2536.
  • 47
    Kao J, Packer S, Vu HL, et al. Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response. Cancer. 2009; 115: 3571-3580.
  • 48
    Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004; 6: 553-563.
  • 49
    Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007; 11: 83-95.
  • 50
    Pouessel D, Culine S. High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol. 2008; 53: 376-381.
  • 51
    Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009; 75: 156-163.
  • 52
    Heymach JV, Desai J, Manola J, et al. Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res. 2004; 10: 5732-5740.
  • 53
    Norden-Zfoni A, Desai J, Manola J, et al. Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res. 2007; 13: 2643-2650.
  • 54
    Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in 3 Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997; 37: 745-751.
  • 55
    Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol. 2006; 24: 1295-1304.
  • 56
    Sundstrom JT, Minn H, Lertola KK, Nordman E. Prognosis of patients treated for intracranial metastases with whole-brain irradiation. Ann Med. 1998; 30: 296-299.