Abstract
Anti-angiogenic agents targeting brain tumor neovasculature may increase progression-free survival in patients with recurrent malignant gliomas. However, when these patients do recur it is not always apparent as an increase in enhancing tumor volume on MRI, which has been the standard of practice for following patients with brain tumors. Therefore alternative methods are needed to evaluate patients treated with these novel therapies. Furthermore, a method that can also provide useful information for the evaluation of conventional therapies would provide an important advantage for general applicability. Diffusion-weighted magnetic resonance imaging (DWI) has the potential to serve as a valuable biomarker for these purposes. In the current study, we explore the prognostic ability of functional diffusion maps (fDMs), which examine voxel-wise changes in the apparent diffusion coefficient (ADC) over time, applied to regions of fluid-attenuated inversion recovery (FLAIR) abnormalities in patients with malignant glioma, treated with either anti-angiogenic or cytotoxic therapies. Results indicate that the rate of change in fDMs is an early predictor of tumor progression, time to progression and overall survival for both treatments, suggesting the application of fDMs in FLAIR abnormal regions may be a significant advance in brain tumor biomarker technology.
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Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A, Green RM, Pope WB, Liau LM, Mischel PS, Nelson SF, Elashoff R, Cloughesy TF (2009) Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72:1217–1222
Vredenburgh JJ, Desjardins A, Herndon JE, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259
Iwamoto FM, Abrey LE, Beal K, Gutin PH, Rosenblum ML, Reuter VE, DeAngelis LM, Lassman AB (2009) Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73:1200–1206
Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787
Sugahara T, Korogi Y, Kochi M, Ikushima I, Shigematu Y, Hirai T, Okudo T, Liang L, Ge Y, Komohara Y, Ushio Y, Takahashi M (1999) Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 9:53–60
Lyng H, Haraldseth O, Rofstad EK (2000) Measurements of cell density and necrotic fraction in human melanoma xenografts by diffusion weighted magnetic resonance imaging. Magn Reson Med 43:828–836
Chenevert TL, Stegman LD, Taylor JM, Robertson PL, Greenberg HS, Rehemtulla A, Ross BD (2000) Diffusion magnetic resonance imaging: an early surrogate marker for therapeutic efficacy in brain tumors. J Natl Cancer Inst 92:2029–2036
Hayashida Y, Hirai T, Morishita S, Kitajima M, Murakami R, Korogi Y, Makino K, Nakamura H, Ikushima I, Yamura M, Kochi M, Kuratsu JI, Yamashita Y (2006) Diffusion-weighted imaging of metastatic brain tumors: comparison with histologic type and tumor cellularity. AJNR Am J Neuroradiol 27:1419–1425
Manenti G, Di Roma M, Mancino S, Bartolucci DA, Palmieri G, Mastrangeli R, Miano R, Squillaci E, Simonetti G (2008) Malignant renal neoplasms: correlation between ADC values and cellularity in diffusion weighted magnetic resonance imaging at 3 T. Radiol Med 113:199–213
Gauvain KM, McKinstry RC, Mukherjee P, Perry A, Neil JJ, Kaufman BA, Hayashi RJ (2001) Evaluating pediatric brain tumor cellularity with diffusion-tensor imaging. AJR Am J Roentgenol 177:449–454
Kinoshita M, Hashimoto N, Goto T, Kagawa N, Kishima H, Izumoto S, Tanaka H, Fujita N, Yoshimine T (2008) Fractional anisotropy and tumor cell density of the tumor core show positive correlation in diffusion tensor magnetic resonance imaging of malignant tumors. Neuroimage 43:29–35
Kono K, Inoue Y, Nakayama K, Shakudo M, Morino M, Ohata K, Wakasa K, Yamada R (2001) The role of diffusion-weighted imaging in patients with brain tumors. AJNR Am J Neuroradiol 22:1081–1088
Chenevert TL, McKeever PE, Ross BD (1997) Monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging. Clin Cancer Res 3:1457–1466
Moffat BA, Chenevert TL, Lawrence TS, Meyer CR, Johnson TD, Dong Q, Tsien CI, Mukherji S, Quint DJ, Gebarski SS, Robertson PL, Junck L, Rehemtulla A, Ross BD (2005) Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci USA 102:5524–5529
Moffat BA, Chenevert TL, Meyer CR, McKeever PE, Hall DE, Hoff BA, Johnson TD, Rehemtulla A, Ross BD (2006) The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome. Neoplasia 8:259–267
Hamstra DA, Chenevert TL, Moffat BA, Johnson TD, Meyer CR, Mukherji S, Quint DJ, Gebarski SS, Fan X, Tsien CI, Lawrence TS, Junck L, Rehemtulla A, Ross BD (2005) Evaluation of the functional diffusion map as an early biomarker of time-to-progression and overall survival in high-grade glioma. Proc Natl Acad Sci USA 102:16759–16764
Hamstra DA, Galbán CJ, Meyer CR, Johnson TD, Sundgren PC, Tsien CI, Lawrence TS, Junck L, Ross DJ, Rehemtulla A, Ross BD, Chenevert TL (2008) Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival. J Clin Oncol 26:3387–3394
Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA (2002) How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology 59:947–949
Barker FG II, Chang SM, Huhn SL, Davis RL, Gutin PH, McDDermott MW, Wilson CB, Prados MD (1997) Age and the risk of anaplasia in magnetic resonance-nonenhancing supratentorial cerebral tumors. Cancer 80:936–941
Ginsberg LE, Fuller GN, Hashmi M, Leeds NE, Schomer DF (1998) The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. Surg Neurol 49:436–440
Galloway RLJ, Maciunas RJ, Failinger AL (1993) Factors affecting perceived tumor volumes in magnetic resonance imaging. Ann Biomed Eng 21:367–375
Anderson C, Astrup J, Gyldensted C (1994) Quantification of peritumoural oedema and the effect of steroids using NMR-relaxation time imaging and blood-brain barrier analysis. Acta Neurochir Suppl (Wien) 60:413–415
Zaki HS, Jenkinson MD, Du Plessis DG, Smith T, Rainov NG (2004) Vanishing contrast enhancement in malignant glioma after corticosteroid treatment. Acta Neurochir (Wien) 146:841–845
Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, Schultz L, Mikkelsen T (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91:329–335
Brant-Zawadski M, Norman D, Newton TH (1984) Magnetic resonance imaging of the brain: the optimal screening technique. Radiology 152:71–77
Byrne TN (1994) Imaging of gliomas. Semin Oncol 21:162–171
Husstedt HW, Sickert M, Köstler H, Haubitz B, Becker H (2000) Diagnostic value of the fast-FLAIR sequence in MR imaging of intracranial tumors. Eur Radiol 10:745–752
Tsuchiya K, Mizutani Y, Hachiya J (1996) Preliminary evaluation of fluid-attenuated inversion-recovery MR in the diagnosis of intracranial tumors. AJNR Am J Neuroradiol 17:1081–1086
Essig M, Hawighorst H, Schoenberg SO, Engenhart-Cabillic R, Fuss M, Debus J, Zuna I, Knopp MV, van Kaick G (1998) Fast fluid-attenuated inversion-recovery (FLAIR) MRI in the assessment of intraaxial brain tumors. J Magn Reson Imaging 8:789–798
Ellingson BM, Malkin MG, Rand SD, Hoyt A, Connelly J, Bedekar DP, Kurpad SN, Schmainda KM (2009) Comparison of cytotoxic and anti-angiogenic treatment responses using functional diffusion maps in FLAIR abnormal regions. Proc Intl Soc Mag Reson Med 17:1010
Ellingson BM, Malkin MG, Rand SD, Bedekar DP, Schmainda KM (2009) Functional diffusion maps applied to FLAIR abnormal areas are valuable for the clinical monitoring of recurrent brain tumors. Proc Intl Soc Mag Reson Med 17:285
Ellingson BM, Rand SD, Malkin MG, Schmainda KM (2010) Utility of functional diffusion maps to monitor a patient diagnosed with gliomatosis cerebri. J Neurooncol 97:419–423
Cox RW, Jesmanowicz A (1999) Real-time 3D image registration for functional MRI. Magn Reson Med 42:1014–1018
Ellingson BM, Malkin MG, Rand SD, Connelly JM, Quinsey C, LaViolette PS, Bedekar DP, Schmainda KM (2010) Validation of functional diffusion maps (fDMs) as a biomarker for human glioma cellularity. J Magn Reson Imaging 31:538–548
Karnofsky DA, Burchenal JH (1949) The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM (ed) Evaluation of chemotherapeutic agents. Columbia University Press, New York, pp 191–205
Mor V, Laliberte L, Morris JN, Wiemann M (1984) The Karnofsky performance scale: an examination of its reliability and validity in a research setting. Cancer 53:2002–2007
Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280
Pope WB, Kim HJ, Huo J, Alger J, Brown MS, Gjertson D, Sai V, Young JR, Tekchandani L, Cloughesy TF, Mischel PS, Lai A, Nghiemphu PL, Rahmanuddin S, Goldin J (2009) Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 252:182–189
Ardekani BA, Guckemus S, Bachman A, Hoptman MJ, Wojtasek M, Nierenberg J (2005) Quantitative comparison of algorithms for inter-subject registration of 3D volumetric brain MRI scans. J Neurosci Methods 142:67–76
Padhani AR, Liu G, Mu-Koh D, Chenevert TL, Thoeny HC, Takahara T, Dzik-Jurasz A, Ross BD, Van Cauteren M, Collins D, Hammoud DA, Rustin GJS, Taouli B, Choyke PL (2009) Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 11:102–125
Acknowledgments
This work was financially supported by NIH/NCI R21-CA109820, NIH/NCI R01-CA082500, MCW Advancing Healthier Wisconsin/Translational Brain Tumor Research Program, and MCW Cancer Center Fellowship.
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Ellingson, B.M., Malkin, M.G., Rand, S.D. et al. Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas. J Neurooncol 102, 95–103 (2011). https://doi.org/10.1007/s11060-010-0293-7
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DOI: https://doi.org/10.1007/s11060-010-0293-7