Glioblastoma Pseudoprogression

Pseudoprogression (PsP) is a transient magnetic resonance imaging (MRI) pattern mimicking tumor progression but not necessarily accompanied by clinical deterioration. It occurs most frequently during the first 3 months after radiation therapy and improvement will usually occur within a few weeks or months. PsP is more frequent in patients treated with concomitant temozolomide than in those receiving radiation therapy alone 1) 2).

The incidence of tumor pseudoprogression ranges from 28% to 66% in all glioblastoma patients undergoing chemoradiation and typically occurs within 3 months after the completion of concurrent radiation and temozolomide 3).

Glioblastoma patients with promoter methylation of the repair enzyme 06-methyl guanine DNA methyltransferase (MGMT) may be at a higher risk of tumor pseudoprogression, with 91% (21 of 23 patients) of such patients developing early radiographic changes in one study 4).

Approximately one-third of patients are symptomatic from tumor pseudoprogression and may require treatment with corticosteroids. Bevacizumab (Avastin), a humanized, monoclonal antibody against the vascular endothelial growth factor (VEGF)-A ligand might be efficacious in the treatment of radiation-related brain necrosis but has not been adequately studied or established as an effective therapy for symptomatic tumor pseudoprogression 5).

Although preliminary evidence suggests that concurrent treatment of newly diagnosed glioblastoma patients with chemoradiation and an inhibitor of VEGF may reduce the incidence of pseudoprogression, no VEGF inhibitor is yet approved for newly diagnosed glioblastoma, and follow-up studies are required 6).

Diagnosis of progression is complex given the possibility of pseudoprogression in glioblastoma. The Response Assessment in Neurooncology criteria increase the sensitivity for detecting progression.

Radiation necrosis and other normal responses associated with surgical treatment may lead to mimicking recurrent glioblastoma.

Kim et al. from the University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, therefore developed and validated a radiomics model using multiparametric MRI to differentiate pseudoprogression from early tumor progression in patients with glioblastoma.

The model was developed from the enlarging contrast-enhancing portions of 61 glioblastomas within 3 months after standard treatment with 6472 radiomic features being obtained from contrast-enhanced T1-weighted imaging, fluid attenuated inversion recovery imaging, and apparent diffusion coefficient (ADC), and cerebral blood volume (CBV) maps. Imaging features were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression model with 10-fold cross-validation. Diagnostic performance for pseudoprogression was compared with that for single parameters (mean and minimum ADC and mean and maximum CBV) and single imaging radiomics models using the area under the receiver-operating-characteristics curve (AUC). The model was validated with an external cohort (n = 34) imaged on a different scanner and an internal prospective registry data (n = 23).

Twelve significant radiomic features (3 from conventional, 2 from diffusion and 7 from perfusion MRI) were selected for model construction. The multiparametric radiomics model (AUC 0.90) showed significantly better performance than any single ADC or CBV parameter (AUC 0.57-0.79, P<.05), and better than single radiomics model using conventional MRI (AUC 0.76, P =.012), ADC (AUC 0.78, P =.014), or CBV (AUC 0.80, P=.43). The multiparametric radiomics showed higher performance in the external validation (AUC 0.85) and internal validation (AUC 0.96) than any single approach, thus demonstrating robustness.

Incorporating diffusion- and perfusion weighted imaging into a radiomics model improved diagnostic performance for identifying pseudoprogression and showed robustness in a multicenter setting 7).

Taal, W. , Brandsma D., de Bruin H. G., Bromberg J. E., Swaak‐Kragten A. T., Smitt P. A., et al. 2008. Incidence of early pseudo‐progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113:405–410.
Brandsma, D. , Stalpers L., Taal W., Sminia P., and van den Bent M. J.. 2008. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 9:453–461.
Fink J, Born D, Chamberlain MC: Pseudoprogression: Relevance with respect to treatment of high-grade gliomas. Curr Treat Options Oncol 12:240-252, 2011.
Brandes AA, 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. J Clin Oncol 26:2192-2197, 2008.
Levin VA, Bidaut L, Hou P, et al: Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79:1487-1495, 2011.
Pinho MC, Polaskova P, Jennings D, et al: Impact of adjuvant anti-VEGF therapy on treatment-related pseudoprogression in patients with newly diagnosed glioblastoma receiving chemoradiation with or without anti-VEGF therapy. 2012 ASCO Annual Meeting. Abstract 2025. Presented June 1, 2012.
Kim JY, Park JE, Jo Y, Shim WH, Nam SJ, Kim JH, Yoo RE, Choi SH, Kim HS. Incorporating diffusion- and perfusion-weighted MRI into a radiomics model improves diagnostic performance for pseudoprogression in glioblastoma patients. Neuro Oncol. 2018 Aug 11. doi: 10.1093/neuonc/noy133. [Epub ahead of print] PubMed PMID: 30107606.
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