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We investigated the role of Coefficient of Variation (CoV), a first-order texture parameter derived from ¹⁸F-FDG PET/CT, in the prognosis of Non-Small Cell Lung Cancer (NSCLC) patients. Eighty-four patients with advanced NSCLC who underwent ¹⁸F-FDG PET/CT before therapy were retrospectively studied. SUVmax, SUVmean, CoV, total Metabolic Tumor Volume (MTV_TOT) and whole-body Total Lesion Glycolysis (TLG_WB) were determined by an automated contouring program (SUV threshold at 2.5). We analyzed 194 lesions: primary tumors (<i>n</i> = 84), regional (<i>n</i> = 48) and non-regional (<i>n</i> = 17) lymph nodes and metastases in liver (<i>n</i> = 9), bone (<i>n</i> = 23) and other sites (<i>n</i> = 13); average CoVs were 0.36 ± 0.13, 0.36 ± 0.14, 0.42 ± 0.18, 0.30 ± 0.14, 0.37 ± 0.17, 0.34 ± 0.13, respectively. No significant differences were found between the CoV values among the different lesion categories. Survival analysis included age, gender, histology, stage, MTV_TOT, TLG_WB and imaging parameters derived from primary tumors. At univariate analysis, CoV (<i>p</i> = 0.0184), MTV_TOT (<i>p</i> = 0.0050), TLG_WB (<i>p</i> = 0.0108) and stage (<i>p</i> = 0.0041) predicted Overall Survival (OS). At multivariate analysis, age, CoV, MTV_TOT and stage were retained in the model (<i>p</i> = 0.0001). Patients with CoV > 0.38 had significantly better OS than those with CoV ≤ 0.38 (<i>p</i> = 0.0143). Patients with MTV_TOT ≤ 89.5 mL had higher OS than those with MTV_TOT > 89.5 mL (<i>p</i> = 0.0063). Combining CoV and MTV_TOT, patients with CoV ≤ 0.38 and MTV_TOT > 89.5 mL had the worst prognosis. CoV, by reflecting the heterogeneity of glycolytic phenotype, can predict clinical outcomes in NSCLC patients.