A pilot study to determine the timing and effect of bevacizumab on vascular normalization of metastatic brain tumors in breast cancer

Bang-Bin Chen, Yen-Shen Lu, Ching-Hung Lin, Wei-Wu Chen, Pei-Fang Wu, Chao-Yu Hsu, Chih-Wei Yu, Shwu-Yuan Wei, Ann-Lii Cheng, Tiffany Ting-Fang Shih, Bang-Bin Chen, Yen-Shen Lu, Ching-Hung Lin, Wei-Wu Chen, Pei-Fang Wu, Chao-Yu Hsu, Chih-Wei Yu, Shwu-Yuan Wei, Ann-Lii Cheng, Tiffany Ting-Fang Shih

Abstract

Background: To determine the appropriate time of concomitant chemotherapy administration after antiangiogenic treatment, we investigated the timing and effect of bevacizumab administration on vascular normalization of metastatic brain tumors in breast cancer patients.

Methods: Eight patients who participated in a phase II trial for breast cancer-induced refractory brain metastases were enrolled and subjected to 4 dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations that evaluated Peak, Slope, iAUC 60 , and Ktrans before and after treatment. The treatment comprised bevacizumab on Day 1, etoposide on Days 2-4, and cisplatin on Day 2 in a 21-day cycle for a maximum of 6 cycles. DCE-MRI was performed before treatment and at 1 h, 24 h, and 21 days after bevacizumab administration.

Results: Values of the 4 DCE-MRI parameters reduced after bevacizumab administration. Compared with baseline values, the mean reductions at 1 and 24 h were -12.8 and -24.7 % for Peak, -46.6 and -65.8 % for Slope, -27.9 and -55.5 % for iAUC 60 , and -46.6 and -63.9 % for Ktrans, respectively (all P < .05). The differences in the 1 and 24 h mean reductions were significant (all P < .05) for all the parameters. The generalized estimating equation linear regression analyses of the 4 DCE-MRI parameters revealed that vascular normalization peaked 24 h after bevacizumab administration.

Conclusion: Bevacizumab induced vascular normalization of brain metastases in humans at 1 and 24 h after administration, and the effect was significantly higher at 24 h than at 1 h.

Trial registration: ClinicalTrials.gov, identifier NCT01281696 , registered prospectively on December 24, 2010.

Keywords: Bevacizumab; Breast cancer; Chemotherapy; DCE-MRI.

Figures

Fig. 1
Fig. 1
A 75-year-old patient with breast cancer with a single brain metastasis had a partial response after 3 BEEP regimen cycles. T1-weighted image (T1WI) and DCE-MRI parameter maps (Peak, Slope, iAUC60, and Ktrans) of the metastatic tumor in the right frontal lobe at baseline, 1 h, 24 h, and 21 days after the first cycle of BEEP regimen, respectively
Fig. 2
Fig. 2
Mean percentage changes of DCE-MRI parameters at 1 h, 24 h, and 21 days compared with baseline values

References

    1. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–5. doi: 10.1126/science.6823562.
    1. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9. doi: 10.1126/science.2479986.
    1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6. doi: 10.1056/NEJM197108122850711.
    1. Kim KJ, Li B, Winer J, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–4. doi: 10.1038/362841a0.
    1. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, 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. doi: 10.1016/S0002-9440(10)63273-7.
    1. Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res. 2012;72:1909–14. doi: 10.1158/0008-5472.CAN-11-3406.
    1. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9. doi: 10.1038/nm0901-987.
    1. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62. doi: 10.1126/science.1104819.
    1. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther. 2008;7:3670–84. doi: 10.1158/1535-7163.MCT-08-0715.
    1. Chan A, Miles DW, Pivot X. Bevacizumab in combination with taxanes for the first-line treatment of metastatic breast cancer. Ann Oncol. 2010;21:2305–15. doi: 10.1093/annonc/mdq122.
    1. Reddy S, Raffin M, Kaklamani V. Targeting angiogenesis in metastatic breast cancer. Oncologist. 2012;17:1014–26. doi: 10.1634/theoncologist.2012-0043.
    1. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007;13:3942–50. doi: 10.1158/1078-0432.CCR-07-0278.
    1. Lu YS, Chen TW, Lin CH, Yeh DC, Tseng LM, Wu PF, et al. Bevacizumab preconditioning followed by etoposide and cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy. Clin Cancer Res. 2015;21(8):1851–8. doi: 10.1158/1078-0432.CCR-14-2075.
    1. Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol. 2006;24:3293–8. doi: 10.1200/JCO.2006.06.8080.
    1. O’Connor JP, Jackson A, Parker GJ, Roberts C, Jayson GC. Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies. Nat Rev Clin Oncol. 2012;9:167–77. doi: 10.1038/nrclinonc.2012.2.
    1. Sorensen AG, Patel S, Harmath C, Bridges S, Synnott J, Sievers A, et al. Comparison of diameter and perimeter methods for tumor volume calculation. J Clin Oncol. 2001;19:551–7.
    1. Chen BB, Hsu CY, Yu CW, Wei SY, Kao JH, Lee HS, et al. Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients. Eur Radiol. 2012;22(1):171–80. doi: 10.1007/s00330-011-2249-5.
    1. Chung WJ, Kim HS, Kim N, Choi CG, Kim SJ. Recurrent glioblastoma: optimum area under the curve method derived from dynamic contrast-enhanced T1-weighted perfusion MR imaging. Radiology. 2013;269:561–8. doi: 10.1148/radiol.13130016.
    1. Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging. 1999;10:223–32. doi: 10.1002/(SICI)1522-2586(199909)10:3<223::AID-JMRI2>;2-S.
    1. Liang KYZS. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13–22. doi: 10.1093/biomet/73.1.13.
    1. Lambrechts D, Lenz H-J, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31:1219–30. doi: 10.1200/JCO.2012.46.2762.
    1. Narang J, Jain R, Arbab AS, Mikkelsen T, Scarpace L, Rosenblum ML, et al. Differentiating treatment-induced necrosis from recurrent/progressive brain tumor using nonmodel-based semiquantitative indices derived from dynamic contrast-enhanced T1-weighted MR perfusion. Neuro Oncol. 2011;13:1037–46. doi: 10.1093/neuonc/nor075.
    1. Chen BB, Hsu CY, Yu CW, Hou HA, Liu CY, Wei SY, et al. Dynamic contrast-enhanced MR imaging measurement of vertebral bone marrow perfusion may be indicator of outcome of acute myeloid leukemia patients in remission. Radiology. 2011;258:821–31. doi: 10.1148/radiol.10100995.
    1. Verstraete KL, Van der Woude HJ, Hogendoorn PC, De-Deene Y, Kunnen M, Bloem JL. Dynamic contrast-enhanced MR imaging of musculoskeletal tumors: basic principles and clinical applications. J Magn Reson Imaging. 1996;6:311–21. doi: 10.1002/jmri.1880060210.
    1. Evelhoch JL. Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imaging. 1999;10:254–9. doi: 10.1002/(SICI)1522-2586(199909)10:3<254::AID-JMRI5>;2-9.
    1. Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer. 2005;92:1599–610. doi: 10.1038/sj.bjc.6602550.
    1. Jain R. Measurements of tumor vascular leakiness using DCE in brain tumors: clinical applications. NMR Biomed. 2013;26:1042–9. doi: 10.1002/nbm.2994.
    1. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, 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. doi: 10.1016/j.ccr.2006.11.021.
    1. Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, et al. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 2009;69:5296–300. doi: 10.1158/0008-5472.CAN-09-0814.
    1. Miller JC, Pien HH, Sahani D, Sorensen AG, Thrall JH. Imaging angiogenesis: applications and potential for drug development. J Natl Cancer Inst. 2005;97:172–87. doi: 10.1093/jnci/dji023.
    1. Lin NU, Gelman RS, Younger WJ, Sohl J, Freedman RA, Sorensen AG, et al. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). J Clin Oncol. 2013;31(suppl; abstr 513). .
    1. Wu PF, Lin CH, Kuo CH, Chen WW, Yeh DC, Liao HW, et al. A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis. BMC Cancer. 2015;15:299. doi: 10.1186/s12885-015-1290-1.
    1. Kamiie J, Ohtsuki S, Iwase R, Ohmine K, Katsukura Y, Yanai K, et al. Quantitative atlas of membrane transporter proteins: development and application of a highly sensitive simultaneous LC/MS/MS method combined with novel in-silico peptide selection criteria. Pharm Res. 2008;25:1469–83. doi: 10.1007/s11095-008-9532-4.
    1. Kusuhara H, Sugiyama Y. Efflux transport systems for organic anions and cations at the blood-CSF barrier. Adv Drug Deliv Rev. 2004;56:1741–63. doi: 10.1016/j.addr.2004.07.007.
    1. Jensen MM, Kjaer A. Monitoring of anti-cancer treatment with (18)F-FDG and (18)F-FLT PET: a comprehensive review of pre-clinical studies. Am J Nucl Med Mol Imaging. 2015;5:431–56.
    1. Kristian A, Revheim ME, Qu H, Mælandsmo GM, Engebråten O, Seierstad T, et al. Dynamic (18)F-FDG-PET for monitoring treatment effect following anti-angiogenic therapy in triple-negative breast cancer xenografts. Acta Oncol. 2013;52:1566–72. doi: 10.3109/0284186X.2013.813634.
    1. Colavolpe C, Chinot O, Metellus P, Mancini J, Barrie M, Bequet-Boucard C, et al. FDG-PET predicts survival in recurrent high-grade gliomas treated with bevacizumab and irinotecan. Neuro Oncol. 2012;14(5):649–57. doi: 10.1093/neuonc/nos012.
    1. Henriksen OM, Larsen VA, Muhic A, Hansen AE, Larsson HB, Poulsen HS, et al. Simultaneous evaluation of brain tumour metabolism, structure and blood volume using [(18)F]-fluoroethyltyrosine (FET) PET/MRI: feasibility, agreement and initial experience. Eur J Nucl Med Mol Imaging. 2016;43:103–12. doi: 10.1007/s00259-015-3183-6.
    1. Gerber B, Loibl S, Eidtmann H, Rezai M, Fasching PA, Tesch H, et al. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44) Ann Oncol. 2013;24:2978–84. doi: 10.1093/annonc/mdt361.
    1. Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, 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;23:8136–9. doi: 10.1200/JCO.2005.02.5635.
    1. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020–6. doi: 10.1200/JCO.2008.21.1771.
    1. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–7. doi: 10.1038/nm988.
    1. Gross S, Gilead A, Scherz A, Neeman M, Salomon Y. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat Med. 2003;9:1327–31. doi: 10.1038/nm940.
    1. Duda DG, Willett CG, Ancukiewicz M, di Tomaso E, Shah M, Czito BG, et al. Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer. Oncologist. 2010;15:577–83. doi: 10.1634/theoncologist.2010-0029.

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