Home Diffusion-weighted MR Imaging f or the Differentiation of True Progression from Pseudoprogression Following Concomitant Radiotherapy with Temozolomide in Patients with Newly Diagnosed High-grade Gliomas
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Diffusion-weighted MR Imaging f or the Differentiation of True Progression from Pseudoprogression Following Concomitant Radiotherapy with Temozolomide in Patients with Newly Diagnosed High-grade Gliomas

Posted Oct 31, 2012 Updated Apr 10, 2023
By Woong Jae Lee MD , Seung Hong Choi MD , Chul-Kee Park MD , Kyung Sik Yi MD , Tae Min Kim MD , Se-Hoon Lee MD PhD , Ji-Hoon Kim MD , Chul-Ho Sohn MD , Sung-Hye Park MD , Il Han Kim MD
11 min read

Rationale and Objectives

The assessment of the therapeutic response of high-grade gliomas treated with concomitant chemoradiotherapy (CCRT) using temozolomide is difficult because of the frequent occurrence of early imaging changes that are indistinguishable from tumor progression, termed pseudoprogression. The purpose of this study was to determine whether diffusion-weighted imaging could be used to differentiate true progression and pseudoprogression.

Materials and Methods

Magnetic resonance images and diffusion-weighted images obtained within 2 months of CCRT completion in patients with high-grade gliomas were retrospectively reviewed. A total of 22 patients with increases in measurable enhancing regions were identified and classified into true progression and pseudoprogression groups on the basis of contrast-enhanced magnetic resonance images obtained 12 weeks after CCRT. Qualitative and quantitative analysis of diffusion-weighted images and apparent diffusion coefficient maps, respectively, was performed to discriminate true progression and pseudoprogression. Statistical analyses were performed using Fisher’s exact test, unpaired t tests, and receiver-operating characteristic analysis.

Results

The true progression group showed a higher incidence of homogeneous or multifocal high signal intensity on diffusion-weighted images (seven of 10 patients [70%]), whereas rim high or no high signal intensity (10 of 12 [83%]) was observed in the pseudoprogression group ( P = .027). True progression was defined by newly appearing or enlarged enhancing lesions with mean apparent diffusion coefficient values of 1200 × 10 −6 mm 2 /s inside the radiation field after CCRT; the sensitivity, specificity, and accuracy were 80% (eight of 10), 83.3% (10 of 12), and 81.2% (18 of 22), respectively.

Conclusions

The assessment of diffusion-weighted images for patients with increases of measurable enhancing regions 2 months after CCRT completion is useful for differentiating true progression from pseudoprogression.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. The current standard care for newly diagnosed GBM includes postoperative concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) followed by maintenance TMZ, which significantly prolongs overall survival compared to radiation alone . Assessment of the response to treatment and disease progression, which includes variations in the contrast-enhancing tumor volume on radiologic imaging, neurologic function, and steroid dosage, is based on the criteria defined by Macdonald et al in 1990. However, this traditional method of measuring the enhancing tumor may not assess the true treatment response, particularly with pseudoprogression of high-grade gliomas after CCRT.

Pseudoprogression has been recognized and widely accepted to occur in the treatment of high-grade gliomas, as transient increases of the enhancing area usually <3 months after CCRT . This phenomenon was originally reported by Hoffman et al in 1979 and more fully described by de Wit et al in 2004 as the early tumor bed enhancement of high-grade gliomas treated with radiation therapy with or without carmustine. More recently, this was better defined in the era of the currently used TMZ regimen . Recent reports suggest that up to 30% of patients treated with this regimen may develop lesion changes that mimic early tumor progression on standard contrast-enhanced magnetic resonance (MR) imaging . This treatment-related change has implications for patient management and may result in premature discontinuation of effective adjuvant therapy. The absence of reliable and accepted imaging methods and biochemical markers to discriminate pseudoprogression from true progression further challenges its diagnosis.

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Materials and methods

Patients

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Figure 1, Flowchart of patient selection and inclusion and exclusion criteria for the study. AA, anaplastic astrocytoma; CCRT, concomitant chemoradiotherapy; DWI, diffusion-weighted imaging; GBM, glioblastoma multiforme; MR, magnetic resonance; MRI, magnetic resonance imaging; TMZ, temozolomide.

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Promoter Methylation Status of O6–Methylguanine–Deoxyribonucleic Acid–Methyltransferase

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MR Image Acquisition

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MR Image Analysis

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Qualitative analysis of diffusion-weighted images

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Figure 2, Four patterns of diffusion-weighted imaging (DWI) signal intensity on first follow-up magnetic resonance imaging: (a) homogenous high, (b) multifocal high, (c) rim high, and (d) no high signal intensity. High signal intensity was defined on DWI when the signal intensity of an enlarged or newly appeared enhancing lesion was higher than or equal to that of normal cerebral cortex.

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Quantitative analysis of ADC maps

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Statistical Analysis

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Results

Clinical and Histopathologic Analysis

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Table 1

Patient Characteristics

Characteristic Total True Progression Pseudoprogression_P_ ( n = 22) ( n = 10) ( n = 12) Age (y), mean ± standard deviation 48.5 ± 15.8 53 ± 12.8 44.8 ± 17.7 .329 ∗ Diagnosis .221 † Glioblastoma multiforme, grade IV 19 10 9 Anaplastic astrocytoma, grade III 3 0 3 Karnofsky performance status .455 † <70 1 1 0 ≥70 21 9 12 Surgery .412 † Biopsy 5 3 2 Subtotal resection 10 3 7 Gross total resection 7 4 3 Radiation dose (Gy), mean 59.54 59.1 59.9 .071 †

Numerical identifiers refer to individual comparisons.

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MR Image Analysis

Qualitative analysis of diffusion-weighted images

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Table 2

Signal Intensity Patterns of True Progression and Pseudoprogression on Diffusion-Weighted Imaging

Group Signal Intensity Pattern Homogenous High Multifocal High Rim High No High True progression ( n = 10) 50% (5/10) 20% (2/10) 0% (0/10) 30% (3/10) Pseudoprogression ( n = 12) 0% (0/10) 16.7% (2/12) 41.7% (5/12) 41.7% (5/12)

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Quantitative analysis of ADC maps

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Table 3

ADC Values of True Progression and Pseudoprogression

Variable True Progression Pseudoprogression_P_ ∗ ( n = 10) ( n = 12) Volume (mm 3 ) 884 ± 501 2822 ± 2021 .009 Mean ADC (10 −6 mm 2 /s) 1215 ± 385 1349 ± 169 .289 Kurtosis 3.73 ± 2.78 4.11 ± 1.70 .701 Skewness 0.48 ± 0.75 0.71 ± 0.56 .412

ADC, apparent diffusion coefficient.

Data are expressed as mean ± standard deviation.

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Figure 3, Box-and-whisker plot comparing the mean apparent diffusion coefficient (ADC) values between the progression and pseudoprogression groups. Brackets indicate the data range; boxes represent the distance between the first and third quartiles, with the mean between them marked with a red dot .

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Figure 4, True progression. A 67-year-old woman who underwent gross total resection and concomitant chemoradiotherapy (CCRT) with temozolomide for glioblastoma multiforme in the left parieto-occipital lobe. Contrast-enhanced T1-weighted magnetic resonance (MR) image obtained 21 days after CCRT completion (a) shows a newly developed measurable enhancing area ( arrow ) in the anterior portion of the surgical cavity. Follow-up MR image obtained 134 days after CCRT (b) shows an increase in the enhancement extent ( arrow ). Diffusion-weighted image obtained 21 days after CCRT completion (c) corresponding to the enhancing lesion shows homogenous high signal intensity pattern ( arrow ). The mean apparent diffusion coefficient (ADC) value of the enhancing lesion was 1157 × 10 −6 mm 2s ( arrow ), which was measured on the ADC map obtained 21 days after CCRT completion (d) .

Figure 5, Pseudoprogression. A 32-year-old woman who underwent gross total resection and concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) for glioblastoma multiforme in the left frontal lobe. Contrast-enhanced T1-weighted magnetic resonance (MR) image obtained 28 days after CCRT completion (a) demonstrates a new enhancing lesion ( arrow ) in the left frontal tumor resection site. Follow-up MR image obtained 92 days after CCRT (b) shows a near complete loss of enhancement ( arrow ) without a change or discontinuation of the maintenance TMZ regimen. Diffusion-weighted image obtained 28 days after CCRT completion (c) corresponding to the enhancing lesion shows no high signal intensity pattern ( arrow ). The mean apparent diffusion coefficient (ADC) value of the enhancing lesion was 1223 × 10 −6 mm 2s ( arrow ), which was measured on the ADC map obtained 28 days after CCRT completion (d) .

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Discussion

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Conclusions

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Acknowledgment

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Academic Radiology, Volume 19, Issue 11
Journals General Radiology
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