Pseudoprogression refers to the transient worsening of radiographic features on anatomical MRI after glioblastoma treatment, especially following radiotherapy combined with alkylating agents. This phenomenon mimics tumor progression, leading to misinterpretation and potentially premature adjustments to the ongoing treatment. Importantly, consequences of misinterpreting pseudoprogression may be profound. Patients may be subjected to unnecessary changes in treatment, including premature discontinuation of therapies that could potentially be beneficial or to overestimation of the efficacy of the subsequent therapy. Moreover, the emotional burden on patients and their families cannot be overstated.
Distinguishing between actual tumor progression and pseudoprogression remains clinically challenging. More accurate diagnostic tools, such as positron emission tomography using radiolabeled amino acids1–3 and advanced MRI such as perfusion-weighted imaging,4 may add valuable additional diagnostic information in a considerable fraction of patients.
In the study by Blakstad and colleagues recently published in Neuro-Oncology Practice,5 284 glioblastoma patients who underwent radiotherapy (100%) with concomitant (95%) and adjuvant temozolomide chemotherapy over ≤6 cycles (92%) and subsequent MRI follow-up scans were evaluated regarding the incidence and clinical significance of pseudoprogression using the Response Assessment in Neuro-Oncology Working Group criteria.6 Confirmation MRI scans during follow-up were used to verify the initial MRI findings post-radiation allowing, for example, the reclassification from progressive disease to pseudoprogression when follow-up MRI changes stabilized or regressed without change in treatment.
Despite the retrospective nature of study by Blakstad et al., the study population is fairly homogenous, the number of evaluated patients is considerably high, and the neuropathological characterization of glioblastomas including the determination of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is in line with current standards.
In that study, pseudoprogression incidence at 3- and 6-month post-radiation was 19% and 7%, respectively. Of note, in the AVAglio trial, the overall pseudoprogression rate was comparatively low (9%) in the control arm including glioblastoma patients treated with temozolomide chemoradiation and placebo (in this arm, 26% of patients had a methylated MGMT promoter, and in 23% of patients the methylation status was undetermined).7 In contrast, in the study by Blakstad, the overall pseudoprogression rate was considerably higher (21.5%). The fraction of patients with a methylated MGMT promoter was 36%, and the MGMT status was unknown in 15% of the patients.
Of note, study results suggested that the occurrence of pseudoprogression in glioblastoma patients is not only related to a methylated MGMT promoter. In addition to the previously described association between MGMT promoter methylation and pseudoprogression,8–11 they strengthened the present evidence that the absence of a neurological deterioration significantly correlated with pseudoprogression. The observed lacking association between pseudoprogression and neurological deterioration reported in earlier studies8,10 is most probably related to differences in neuropathological and radiological diagnostics, treatment protocol variations, and, at least partially, smaller study populations.
Furthermore, patients with pseudoprogression at both 3- and 6-months post-radiation had a significantly longer median overall survival than patients with progressive disease (24.5 vs. 11.4 months, and 31.8 vs. 13.0 months (both P < .001), respectively), indicating that not only a methylated MGMT promoter but also a stable neurological status are prognostic.
Thus, accurate diagnosis with additional emphasis especially on a neurological deterioration and management of pseudoprogression are crucial to avoid unnecessary treatment and improve patient outcomes.
Funding
None declared.
Conflict of interest statement
N.G. received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals.
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