Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas

BackgroundThe nucleoside analog 3′-deoxy-3′-18F-fluorothymidine (FLT) has been investigated for evaluating tumor proliferating activity in brain tumors. We evaluated FLT uptake heterogeneity using textural features from the histogram analysis in patients with newly diagnosed gliomas and examined correlation of the results with proliferative activity and patient prognosis, in comparison with the conventional PET parameters.MethodsFLT PET was investigated in 37 patients with newly diagnosed gliomas. The conventional parameters [tumor-to-contralateral normal brain tissue (T/N) ratio and metabolic tumor volume (MTV)] and textural parameters (standard deviation, skewness, kurtosis, entropy, and uniformity) were derived from FLT PET images. Linear regression analysis was used to compare PET parameters and the proliferative activity as indicated by the Ki-67 index. The associations between parameters and overall survival (OS) were tested by Cox regression analysis.ResultsMedian OS was 662 days. For the conventional parameters, linear regression analysis indicated a significant correlation between T/N ratio and Ki-67 index (p = 0.02) and MTV and Ki-67 index (p = 0.02). Among textural parameters, linear regression analysis indicated a significant correlation for kurtosis (p = 0.003), entropy (p < 0.001), and uniformity (p < 0.001) as compared to Ki-67 index, exceeding those of the conventional parameters. The results of univariate analysis suggested that skewness and kurtosis were associated with OS (p = 0.03 and 0.02, respectively). Mean survival for patients with skewness values less than 0.65 was 1462 days, compared with 917 days for those with values greater than 0.65 (p = 0.02). Mean survival for patients with kurtosis values less than 6.16 was 1616 days, compared with 882 days for those with values greater than 6.16 (p = 0.006).ConclusionsBased on the results of this preliminary study in a small patient population, textural features reflecting heterogeneity on FLT PET images seem to be useful for the assessment of proliferation and for the potential prediction of survival in newly diagnosed gliomas.

[1]  Stefan Förster,et al.  Textural analysis of pre-therapeutic [18F]-FET-PET and its correlation with tumor grade and patient survival in high-grade gliomas , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[2]  F. Brooks,et al.  The Effect of Small Tumor Volumes on Studies of Intratumoral Heterogeneity of Tracer Uptake , 2014, The Journal of Nuclear Medicine.

[3]  Jinming Yu,et al.  Prognostic value of 3'-deoxy-3'-18F-fluorothymidine ([(18)F] FLT PET) in patients with recurrent malignant gliomas. , 2014, Nuclear medicine and biology.

[4]  J. R. Grierson,et al.  Simplified Labeling Approach for Synthesizing 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) , 2000 .

[5]  Laura H. Tang,et al.  Effect of Tumor Heterogeneity on the Assessment of Ki67 Labeling Index in Well-differentiated Neuroendocrine Tumors Metastatic to the Liver: Implications for Prognostic Stratification , 2011, The American journal of surgical pathology.

[6]  J. Mountz,et al.  Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation , 2009, Nuclear medicine communications.

[7]  M. Hatt,et al.  Intratumor Heterogeneity Characterized by Textural Features on Baseline 18F-FDG PET Images Predicts Response to Concomitant Radiochemotherapy in Esophageal Cancer , 2011, The Journal of Nuclear Medicine.

[8]  P Vaupel,et al.  Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[9]  Bal Sanghera,et al.  Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice? , 2012, Insights into Imaging.

[10]  畠山 哲宗.  11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma , 2010 .

[11]  P. Grigsby,et al.  Intratumoral Metabolic Heterogeneity of Cervical Cancer , 2008, Clinical Cancer Research.

[12]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[13]  Wei Chen,et al.  Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  B. Manaster.  Spatial Heterogeneity in Sarcoma 18F-FDG Uptake as a Predictor of Patient Outcome , 2010 .

[15]  Jae Seung Kim,et al.  [18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  Vicky Goh,et al.  Are Pretreatment 18F-FDG PET Tumor Textural Features in Non–Small Cell Lung Cancer Associated with Response and Survival After Chemoradiotherapy? , 2013, The Journal of Nuclear Medicine.

[17]  J. Hoffman,et al.  NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of FLT as a Marker of Proliferation in Patients with Recurrent Gliomas: Safety Studies , 2008, Molecular Imaging and Biology.

[18]  Marvin Bergsneider,et al.  Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[19]  Huan Yu,et al.  Coregistered FDG PET/CT-Based Textural Characterization of Head and Neck Cancer for Radiation Treatment Planning , 2009, IEEE Transactions on Medical Imaging.

[20]  V. Goh,et al.  Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. , 2011, Radiology.

[21]  Vicky Goh,et al.  Quantifying tumour heterogeneity in 18F-FDG PET/CT imaging by texture analysis , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[22]  J. Tonn,et al.  Molecular imaging of gliomas with PET: opportunities and limitations. , 2011, Neuro-oncology.

[23]  P Vaupel,et al.  Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. , 1996, Cancer research.

[24]  T. Cloughesy,et al.  3′-Deoxy-3′-18F-Fluorothymidine PET and MRI for Early Survival Predictions in Patients with Recurrent Malignant Glioma Treated with Bevacizumab , 2012, The Journal of Nuclear Medicine.

[25]  C Chatwin,et al.  Gray matter textural heterogeneity as a potential in-vivo biomarker of fine structural abnormalities in Asperger syndrome , 2012, The Pharmacogenomics Journal.

[26]  Sungeun Kim,et al.  11C-methionine PET as a prognostic marker in patients with glioma: comparison with 18F-FDG PET , 2004, European Journal of Nuclear Medicine and Molecular Imaging.

[27]  L. Wiens,et al.  Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  Florent Tixier,et al.  Visual Versus Quantitative Assessment of Intratumor 18F-FDG PET Uptake Heterogeneity: Prognostic Value in Non–Small Cell Lung Cancer , 2014, The Journal of Nuclear Medicine.

[29]  Peter Smeets,et al.  Predictive and prognostic value of metabolic tumour volume and total lesion glycolysis in solid tumours , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[30]  O. Chinot,et al.  Independent prognostic value of pre-treatment 18-FDG-PET in high-grade gliomas , 2012, Journal of Neuro-Oncology.

[31]  Robert King,et al.  Textural features corresponding to textural properties , 1989, IEEE Trans. Syst. Man Cybern..

[32]  K. Miles,et al.  Tumour heterogeneity in oesophageal cancer assessed by CT texture analysis: preliminary evidence of an association with tumour metabolism, stage, and survival. , 2012, Clinical radiology.