True progression versus pseudoprogression in the treatment of glioblastomas: a comparison study of normalized cerebral blood volume and apparent diffusion coefficient by histogram analysis

Abstract

Objective: The purpose of this study was to differentiate true progression from pseudoprogression of glioblastomas treated with concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ) by using histogram analysis of apparent diffusion coefficient (ADC) and normalized cerebral blood volume (nCBV) maps.

Materials and methods: Twenty patients with histopathologically proven glioblastoma who had received CCRT with TMZ underwent perfusion-weighted imaging and diffusion-weighted imaging (b = 0, 1000 sec/mm(2)). The corresponding nCBV and ADC maps for the newly visible, entirely enhancing lesions were calculated after the completion of CCRT with TMZ. Two observers independently measured the histogram parameters of the nCBV and ADC maps. The histogram parameters between the true progression group (n = 10) and the pseudoprogression group (n = 10) were compared by use of an unpaired Student's t test and subsequent multivariable stepwise logistic regression analysis to determine the best predictors for the differential diagnosis between the two groups. Receiver operating characteristic analysis was employed to determine the best cutoff values for the histogram parameters that proved to be significant predictors for differentiating true progression from pseudoprogression. Intraclass correlation coefficient was used to determine the level of inter-observer reliability for the histogram parameters.

Results: The 5th percentile value (C5) of the cumulative ADC histograms was a significant predictor for the differential diagnosis between true progression and pseudoprogression (p = 0.044 for observer 1; p = 0.011 for observer 2). Optimal cutoff values of 892 × 10(-6) mm(2)/sec for observer 1 and 907 × 10(-6) mm(2)/sec for observer 2 could help differentiate between the two groups with a sensitivity of 90% and 80%, respectively, a specificity of 90% and 80%, respectively, and an area under the curve of 0.880 and 0.840, respectively. There was no other significant differentiating parameter on the nCBV histograms. Inter-observer reliability was excellent or good for all histogram parameters (intraclass correlation coefficient range: 0.70-0.99).

Conclusion: The C5 of the cumulative ADC histogram can be a promising parameter for the differentiation of true progression from pseudoprogression of newly visible, entirely enhancing lesions after CCRT with TMZ for glioblastomas.

Keywords: Apparent diffusion coefficient; Cerebral blood volume; Glioblastoma multiforme; Histogram analysis; Pseudoprogression.

Fig. 1

Flow chart for patient selection and inclusion and exclusion criteria for study. CCRT = concurrent chemoradiotherapy, DWI = diffusion-weighted imaging, GBM = Glioblastoma multiforme, PWI = perfusion-weighted imaging, TMZ = temozolomide

Fig. 2

MR images, nCBV histograms and ADC histograms in 59-year-old man with glioblastoma. A. Axial CE T1W image taken immediately after gross total resection shows no definite enhancing lesion. B. Three weeks after CCRT with TMZ, new enhancing lesions are visible in left periventricular white matter and in left occipital lobe. C. nCBV map, which is displayed as color overlay on CE T1W image taken 3 weeks after CCRT with TMZ, shows slightly increased nCBV in lesion (polygonal ROIs #1 and #2) compared with contralateral white matter (round ROI #3). D. Normalized CBV histograms and (E) cumulative histograms of enhancing lesions. F. ADC map, which is displayed as color overlay (in hot scale) on CE T1W image, shows slightly decreased ADC value for lesion (polygonal ROIs #1 and #2). G. ADC histograms and (H) cumulative histograms of enhancing lesion. I. After continuing TMZ for 1 month, patient visited emergency room due to involuntary movement. On second follow-up MR imaging that was performed during visit to emergency room, there was increase in enhancement of lesions without further treatment. After 3 months, patient passed away in spite of continuation of adjuvant TMZ, which is compatible with true progression. ADC = apparent diffusion coefficient, CBV = cerebral blood volume, CCRT = concurrent chemoradiotherapy, CE = contrast-enhanced, nCBV = normalized CBV, ROIs = regions of interest, TMZ = temozolomide, T1W = T1-weighted

Fig. 3

MR images, nCBV histograms and ADC histograms in 23-year-old man with glioblastoma. A. Axial CE T1W image taken immediately after gross total resection shows subtle enhancing lesion at right splenium of corpus callosum and (B) enlargement of enhancing lesion, 1 month after CCRT with TMZ. C. nCBV map, which is displayed as color overlay on CE T1W image taken one month after CCRT with TMZ, shows slightly increased nCBV in lesion (polygonal ROI #1) compared with contralateral white matter (round ROI #2). D. Normalized CBV histograms and (E) cumulative histograms of enhancing lesion. F. ADC map, which is displayed as color overlay (in hot scale) on CE T1W image, shows increased ADC value for lesion (polygonal ROI #1). G. ADC histograms and (H) cumulative histograms of enhancing lesion. I. On second follow-up MR imaging that was performed during outpatient visit after continuing TMZ for 3 months, enhancement of lesion was decreased without further treatment, which confirms pseudoprogression. ADC = apparent diffusion coefficient, CBV = cerebral blood volume, CCRT = concurrent chemoradiotherapy, CE = contrast-enhanced, nCBV = normalized CBV, ROI = region of interest, TMZ = temozolomide, T1W = T1-weighted