OBJECTIVE: To prospectively determine institutional cut-off values of apparent diffusion coefficients (ADCs) and concentration of tissue metabolites measured by MR spectroscopy (MRS) for early differentiation between glioblastoma (GBM) relapse and treatment-related changes after standard treatment. MATERIALS AND METHODS: Twenty-four GBM patients who received gross total resection and standard adjuvant therapy underwent MRI examination focusing on the enhancing region suspected of tumor recurrence. ADC maps, concentrations of N-acetylaspartate, choline, creatine, lipids, and lactate, and metabolite ratios were determined. Final diagnosis as determined by biopsy or follow-up imaging was correlated to the results of advanced MRI findings. RESULTS: Eighteen (75%) and 6 (25%) patients developed tumor recurrence and pseudoprogression, respectively. Mean time to radiographic progression from the end of chemoradiotherapy was 5.8 ± 5.6 months. Significant differences in ADC and MRS data were observed between those with progression and pseudoprogression. Recurrence was characterized by N-acetylaspartate ≤ 1.5 mM, choline/N-acetylaspartate ≥ 1.4 (sensitivity 100%, specificity 91.7%), N-acetylaspartate/creatine ≤ 0.7, and ADC ≤ 1300 × 10(-6) mm(2)/s (sensitivity 100%, specificity 100%). CONCLUSION: Institutional validation of cut-off values obtained from advanced MRI methods is warranted not only for diagnosis of GBM recurrence, but also as enrollment criteria in salvage clinical trials and for reporting of outcomes of initial treatment.

Department of Diagnostic Imaging Faculty of Medicine Masaryk University 625 00 Brno Czech Republic ; Department of Diagnostic Imaging St Anne's University Hospital Brno 656 91 Brno Czech Republic

Department of Radiation Oncology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic ; Department of Radiation Oncology Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno 656 91 Brno Czech Republic ; Department of Neurosurgery St Anne's University Hospital Brno Faculty of Medicine Masaryk University 625 00 Brno Czech Republic ; Department of Neurosurgery St Anne's University Hospital Brno 656 91 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno 656 91 Brno Czech Republic ; Department of Radiation Oncology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic ; Department of Radiation Oncology Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

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Stupp R., Mason W. P., van den Bent M. J., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005;352(10):987–996. doi: 10.1056/nejmoa043330. PubMed DOI

Brandsma D., Stalpers L., Taal W., Sminia P., van den Bent M. J. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. The Lancet Oncology. 2008;9(5):453–461. doi: 10.1016/s1470-2045(08)70125-6. PubMed DOI

Kumar A. J., Leeds N. E., Fuller G. N., et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology. 2000;217(2):377–384. doi: 10.1148/radiology.217.2.r00nv36377. PubMed DOI

Brandes A. A., Tosoni A., Spagnolli F., et al. Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro-Oncology. 2008;10(3):361–367. doi: 10.1215/15228517-2008-008. PubMed DOI PMC

Chakravarti A., Erkkinen M. G., Nestler U., et al. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clinical Cancer Research. 2006;12(15):4738–4746. doi: 10.1158/1078-0432.ccr-06-0596. PubMed DOI

Brandes A. A., Franceschi E., Tosoni A., et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. Journal of Clinical Oncology. 2008;26(13):2192–2197. doi: 10.1200/JCO.2007.14.8163. PubMed DOI

Lamborn K. R., Yung W. K. A., Chang S. M., et al. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-Oncology. 2008;10(2):162–170. doi: 10.1215/15228517-2007-062. PubMed DOI PMC

Radbruch A., Fladt J., Kickingereder P., et al. Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence. Neuro-Oncology. 2014;17(1):151–159. doi: 10.1093/neuonc/nou129. PubMed DOI PMC

Friedman H. S., Prados M. D., Wen P. Y., et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. 2009;27(28):4733–4740. doi: 10.1200/jco.2008.19.8721. PubMed DOI

Kao H.-W., Chiang S.-W., Chung H.-W., Tsai F. Y., Chen C.-Y. Advanced MR imaging of gliomas: an update. BioMed Research International. 2013;2013:14. doi: 10.1155/2013/970586.970586 PubMed DOI PMC

Bulik M., Jancalek R., Vanicek J., Skoch A., Mechl M. Potential of MR spectroscopy for assessment of glioma grading. Clinical Neurology and Neurosurgery. 2013;115(2):146–153. doi: 10.1016/j.clineuro.2012.11.002. PubMed DOI

Roy B., Gupta R. K., Maudsley A. A., et al. Utility of multiparametric 3-T MRI for glioma characterization. Neuroradiology. 2013;55(5):603–613. doi: 10.1007/s00234-013-1145-x. PubMed DOI PMC

Ahmed R., Oborski M. J., Hwang M., Lieberman F. S., Mountz J. M. Malignant gliomas: current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods. Cancer Management and Research. 2014;6(1):149–170. doi: 10.2147/cmar.s54726. PubMed DOI PMC

Ion-Margineanu A., van Cauter S., Sima D. M., et al. Tumour relapse prediction using multiparametric MR data recorded during follow-up of GBM patients. BioMed Research International. In press. PubMed PMC

Provencher S. W. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomedicine. 2001;14(4):260–264. doi: 10.1002/nbm.698. PubMed DOI

Jiru F., Skoch A., Wagnerova D., Dezortova M., Hajek M. jSIPRO—analysis tool for magnetic resonance spectroscopic imaging. Computer Methods and Programs in Biomedicine. 2013;112(1):173–188. doi: 10.1016/j.cmpb.2013.06.018. PubMed DOI

Wen P. Y., Macdonald D. R., Reardon D. A., et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. Journal of Clinical Oncology. 2010;28(11):1963–1972. doi: 10.1200/jco.2009.26.3541. PubMed DOI

Macdonald D. R., Cascino T. L., Schold S. C., Jr., Cairncross J. G. Response criteria for phase II studies of supratentorial malignant glioma. Journal of Clinical Oncology. 1990;8(7):1277–1280. PubMed

Gerstner E. R., McNamara M. B., Norden A. D., LaFrankie D., Wen P. Y. Effect of adding temozolomide to radiation therapy on the incidence of pseudo-progression. Journal of Neuro-Oncology. 2009;94(1):97–101. doi: 10.1007/s11060-009-9809-4. PubMed DOI

da Cruz L. C. H., Jr., Rodriguez I., Domingues R. C., Gasparetto E. L., Sorensen A. G. Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. American Journal of Neuroradiology. 2011;32(11):1978–1985. doi: 10.3174/ajnr.a2397. PubMed DOI PMC

Fabi A., Russillo M., Metro G., Vidiri A., Di Giovanni S., Cognetti F. Pseudoprogression and MGMT status in glioblastoma patients: implications in clinical practice. Anticancer Research. 2009;29(7):2607–2610. PubMed

Kong D.-S., Kim S. T., Kim E.-H., et al. Diagnostic dilemma of pseudoprogression in the treatment of newly diagnosed glioblastomas: the role of assessing relative cerebral blood flow volume and oxygen-6-methylguanine-DNA methyltransferase promoter methylation status. American Journal of Neuroradiology. 2011;32(2):382–387. doi: 10.3174/ajnr.A2286. PubMed DOI PMC

Wagnerova D., Herynek V., Malucelli A., et al. Quantitative MR imaging and spectroscopy of brain tumours: a step forward? European Radiology. 2012;22(11):2307–2318. doi: 10.1007/s00330-012-2502-6. PubMed DOI

D’Souza M. M., Sharma R., Jaimini A., et al. 11C-MET PET/CT and advanced MRI in the evaluation of tumor recurrence in high-grade gliomas. Clinical Nuclear Medicine. 2014;39(9):791–798. doi: 10.1097/rlu.0000000000000532. PubMed DOI

Wiebenga O. T., Klauser A. M., Nagtegaal G. J., et al. Longitudinal absolute metabolite quantification of white and gray matter regions in healthy controls using proton MR spectroscopic imaging. NMR in Biomedicine. 2014;27(3):304–311. doi: 10.1002/nbm.3063. PubMed DOI

Minati L., Aquino D., Bruzzone M. G., Erbetta A. Quantitation of normal metabolite concentrations in six brain regions by in-vivoH-MR spectroscopy. Journal of Medical Physics. 2010;35(3):154–163. doi: 10.4103/0971-6203.62128. PubMed DOI PMC

Chawla S., Zhang Y., Wang S., et al. Proton magnetic resonance spectroscopy in differentiating glioblastomas from primary cerebral lymphomas and brain metastases. Journal of Computer Assisted Tomography. 2010;34(6):836–841. doi: 10.1097/RCT.0b013e3181ec554e. PubMed DOI

Polley M.-Y. C., Lamborn K. R., Chang S. M., Butowski N., Clarke J. L., Prados M. Six-month progression-free survival as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma patients receiving temozolomide. Neuro-Oncology. 2010;12(3):274–282. doi: 10.1093/neuonc/nop034. PubMed DOI PMC

Trippa L., Wen P. Y., Parmigiani G., Berry D. A., Alexander B. M. Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials. Neuro-Oncology. 2015 doi: 10.1093/neuonc/nou345. PubMed DOI PMC

Hein P. A., Eskey C. J., Dunn J. F., Hug E. B. Diffusion-weighted imaging in the follow-up of treated high-grade gliomas: tumor recurrence versus radiation injury. The American Journal of Neuroradiology. 2004;25(2):201–209. PubMed PMC

Weybright P., Sundgren P. C., Maly P., et al. Differentiation between brain tumor recurrence and radiation injury using MR spectroscopy. American Journal of Roentgenology. 2005;185(6):1471–1476. doi: 10.2214/ajr.04.0933. PubMed DOI

Zeng Q.-S., Li C.-F., Liu H., Zhen J.-H., Feng D.-C. Distinction between recurrent glioma and radiation injury using magnetic resonance spectroscopy in combination with diffusion-weighted imaging. International Journal of Radiation, Oncology, Biology, Physics. 2007;68(1):151–158. doi: 10.1016/j.ijrobp.2006.12.001. PubMed DOI

Nakajima T., Kumabe T., Kanamori M., et al. Differential diagnosis between radiation necrosis and glioma progression using sequential proton magnetic resonance spectroscopy and methionine positron emission tomography. Neurologia Medico-Chirurgica. 2009;49(9):394–401. doi: 10.2176/nmc.49.394. PubMed DOI

Bobek-Billewicz B., Stasik-Pres G., Majchrzak H., Zarudzki Ł. Differentiation between brain tumor recurrence and radiation injury using perfusion, diffusion-weighted imaging and MR spectroscopy. Folia Neuropathologica. 2010;48(2):81–92. PubMed

Amin A., Moustafa H., Ahmed E., El-Toukhy M. Glioma residual or recurrence versus radiation necrosis: accuracy of pentavalent technetium-99m-dimercaptosuccinic acid [Tc-99m (V) DMSA] brain SPECT compared to proton magnetic resonance spectroscopy (1H-MRS): initial results. Journal of Neuro-Oncology. 2012;106(3):579–587. doi: 10.1007/s11060-011-0694-2. PubMed DOI

Advanced MRI increases the diagnostic accuracy of recurrent glioblastoma: Single institution thresholds and validation of MR spectroscopy and diffusion weighted MR imaging