Pseudoprogression and Pseudoresponse: Imaging Challenges in the Assessment of Posttreatment Glioma

Abstract

SUMMARY:The current standard of care for newly diagnosed cases of high-grade glioma is surgical resection followed by RT with concurrent chemotherapy. The most widely used criteria for assessing treatment response are based on a 2D measurement of the enhancing area on MR imaging known as the Macdonald Criteria. Recently, nontumoral increases (pseudoprogression) and decreases (pseudoresponse) in enhancement have been found, and these can confuse outcome evaluation. Here we review pseudoprogression and pseudoresponse and describe how better understanding of these phenomena can aid interpretation.ABBREVIATIONS: ADC ϭ apparent diffusion coefficient; BBB ϭ blood-brain barrier; Cho ϭ choline; DSC ϭ dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging; DTI ϭ diffusion tensor imaging; DWI ϭ diffusion-weighted imaging; FDG ϭ fluorodeoxyglucose; FLAIR ϭ fluidattenuated inversion recovery; GBM ϭ glioblastoma multiforme; MGMT ϭ methyltransferase; NAA ϭ N-acetylaspartate; PET ϭ positron-emission tomography; PSR ϭ percentage of signalintensity recovery; RANO ϭ Response Assessment in Neuro-Oncology; rCBV ϭ relative cerebral blood volume; RECIST ϭ Response Evaluation Criteria in Solid Tumors; ROC ϭ receiver operating characteristic analysis; RT ϭ radiation therapy; TMZ ϭ temozolomide; VEGF ϭ vascular endothelial growth factor G BM is the most common primary malignant type of brain neoplasm in adults and is associated with a dismal prognosis. The current standard of care is surgical resection followed by RT and concomitant and adjuvant TMZ chemotherapy. This is a relatively recent standard, with pivotal data published in 2005, and it represents a milestone, because this approach has been shown to prolong the overall survival of these patients.1 With the standardization of treatment around surgery/RT/TMZ, certain patterns are beginning to emerge that were not previously noticed. In addition, in May 2009, the US Food and Drug Administration approved bevacizumab for recurrent glioblastoma. This anti-VEGF agent also can have a marked pattern of change on MR imaging. In addition to impacting individual patient care, these changes have also had an impact on clinical trials of new therapies. Macdonald CriteriaThe Macdonald Criteria 2 are currently the most widely used guideline for assessing response to therapy in patients with highgrade gliomas. These are based on 2D tumor measurements made in MR imaging scans, in conjunction with clinical assessment and corticosteroid dose. According to the Macdonald Criteria, tumor progression is considered to have occurred when an increase of Ͼ25% in the size of the contrast-enhancing lesion is observed. There are important limitations to these criteria, which only address the contrast-enhancing component of the tumor, and various updated guidelines for RANO have been published.3,4 As radiologists learn early in their training, contrast enhancement in posttreatment brain tumors is nonspecific and may not always be considered a true surrogate of tumor response.The limitations of th...

Late Pseudoprogression in Glioblastoma: Diagnostic Value of Dynamic O-(2-[18F]fluoroethyl)-L-Tyrosine PET

“…We believe it is more important not to overlook the diagnosis of late PsP as it reflects an ongoing benefit from previous/current treatment. Hence, in the event of a TBR max value in between 1.0 and 2.4 it might be safest (when trying to avoid missing PsP) to defer the initiation of a salvage treatment until a follow-up MRI has been performed or to obtain a tumor specimen via biopsy to confirm Patients with MGMT-methylated glioma are more likely to develop PsP, amounting to an incidence of up to 31% as compared with 5% in patients with non-methylated tumors (8,16,21). Accordingly, our study found that almost all patients with late PsP had a methylated MGMT promoter.…”

Single dose bevacizumab as treatment for symptomatic, corticosteroid-refractory pseudoprogression after chemoradiation therapy for newly diagnosed glioblastoma: A case report

“…Contrast enhancement in brain tumors post-treatment is nonspecific and may not always be indicative of tumor response. Both pseudoprogression, an increase in the non-tumoral enhancing area, and pseudoresponse, a decrease in the enhancing area, show that enhancement alone is not a reliable measure of tumor activity but rather reflects a disturbed bloodbrain barrier [4,9].…”

“…Pseudoprogression is an early-to-subacute post-treatment effect observed on the imaging of high-grade gliomas usually occurring within the initial three months following the start of chemoradiation therapy [2][3][4][5][6]. The increased gadolinium contrast enhancement on magnetic resonance imaging (MRI) can be misinterpreted as tumor recurrence or radiation necrosis (RN).…”

Advanced neuroimaging in the clinic: critical appraisal of the evidence base

“…We thus may underestimate the strength of the evidence. Reviews with such partial responses included: "was the search strategy comprehensive", (DTI-mTBI, n 5 [45][46][47][48]52,53,55,57,63,64,66 ), "are all of the results presented with confidence intervals", (DTI-mTBI n 5 1; 34 DSCglioma n 5 4 50-52,65 ), "does it state the study design of all included articles" (DTI-mTBI, n 5 3; 25,39,44 DSC-glioma, n 5 3 62,64 ) and "does it specify the number of subjects for all included studies" (DTI-mTBI, n 5 11; 8,25,27,28,31,34,37,38,40,42,44 DSC-glioma, n 5 8 47,50,51,57,60,61,63,64 ).…”

“…Regarding critical appraisal worksheet grades for DTI-mTBI detection reviews, 1 review achieved Grade A, 29 8 reviews achieved Grade B 8,24,25,36,39,41,42,44 and 14 reviews achieved Grade C. 6,[26][27][28][30][31][32][33][34][35]37,38,40,43 Of the reviews of DTI-mTBI outcome prediction, three reviews achieved Grade B 25,39,41 and the remaining reviews were Grade C. 6,[26][27][28][30][31][32]37,40 Of the reviews of DSC-glioma detection, 1 review achieved Grade A, 7 1 review achieved Grade B 62 and 24 reviews achieved Grade C. 9,12,[45][46][47][48][49][50][51][52][53][54]…”