Pseudo-progression (PsP) has been documented with increasing frequency in glioblastoma (GBM) after adjuvant chemoradiotherapy (CRT). Radiographic features are often not adequate to distinguish PsP from early true progression (eTP); therefore, current response criteria include both clinical and imaging findings in progression assessments. We hypothesize that clinical changes are key to the diagnosis of PsP and delineate the time points in the clinical trajectory that radiographic and clinical changes occur. Materials/Methods: Sixty-seven patients who received curative intent CRT for GBM at our institute between 2003 and 2015 had pre-treatment and post-treatment imaging suitable for retrospective evaluation using RANO criteria. Patients with signs of progression within the first 12-wks post-radiation (post-RT) were selected. Lesions that subsequently improved or stabilized were denoted as PsP and lesions that continued to progress were considered eTP. Survival was estimated using Kaplan-Meier method, Cox regression was used for multivariate analysis, and Fisher's exact test was used to compare groups. Results: Median follow-up was 17.6 mo. Outcomes revealed a median PFS of 8.0 mo (95% CI: 7.4 e 10.4), and median OS of 20.7 mo (95% CI: 17.3 e 27). Signs of progression developed in 35/67 (52.2%) within 12-wks post-RT. Of these, 20/35 (57.1%) fulfilled criteria for eTP and 15/35 (42.9%) fulfilled criteria for PsP. Time to radiologist-documented radiographic signs of progression were similar between groups at a median of 3.4 weeks for eTP and 3.8 weeks for PsP. At that time, 19 eTP and 15 PsP patients had evaluable MRI. MRI demonstrated similar rates of increased contrast enhancement in 16/19 (84.2%) eTP and 15/15 (100%) PsP. FLAIR was increased, decreased, and stable in 7/15 (46.7%), 4/15 (26.7%), and 4/ 15 (26.7%) PsP patients, respectively. FLAIR was increased in 14/19 (73.7%) and stable in 5/19 (26.3%) of eTP, with none having decreased FLAIR. A significant difference was seen between PsP and eTP in their need for increased steroid or clinical decline (OR 4.89, 95% CI: 1.003 e 19.27; P Z 0.046). 9/20 (45%) ePD and 3/15 (20%) PsP required increased steroid. Importantly, KPS declined in 5/20 (25%) eTP and none of the PsP patients. Unmethylated MGMT was an independent risk factor for survival and predictive of eTP (P Z 0.005). As expected, OS was significantly worse in eTP (P Z 0.032) with a median OS of 13.2 mo (95% CI: 11.1 e 20.1) versus 23.6 mo (95% CI: 16.5 e 65.3+) for eTP and PsP, respectively. Conclusion: Change in KPS or the need for increased steroids within the first 12-weeks was significantly increased in eTP versus PsP. This was often preceded by clinical neurologic worsening. These findings require prospective validation, and the implementation of standardized assessment of neurologic function would greatly facilitate the widespread use of this metric as an aid in decision making regarding PsP.

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