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Background A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. Methods In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. Results The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). Conclusions Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Diffuse midline glioma (DMG), H3 K27-altered is a newly defined diagnosis in the 2021 WHO Classification of Tumors of the Central Nervous System. H3 K27 alterations are associated with a uniformly poor prognosis in children with DMG, but they have been linked to improved survival in adults. Clinical experience in adults with DMG, H3 K27M-altered remains limited. Consequently, there exists a knowledge gap regarding the optimal management and responsiveness to chemoradiation therapy, which translates into the current absence of standard treatment. Here we present the case of an 18-year-old female patient treated for a thalamic DMG, H3 K27-altered at a Canadian tertiary center. The patient first presented with headache, dysarthria, and signs of increased intracranial pressure. Her initial brain magnetic resonance imaging demonstrated a right thalamo-mesencephalic lesion with central nodular enhancement and secondary hydrocephalus. She underwent an endoscopic third ventriculostomy followed by a subtotal resection, and pathology confirmed the presence of a DMG, H3 K27-altered, WHO grade 4. She was treated with combined radiotherapy and concomitant plus adjuvant (12 cycles) temozolomide. The Stupp regimen induced a spectacular response with a reduction in tumor dimensions on T2/FLAIR (20 x 18 mm versus 60 x 51 mm), > 50% decrease in size of the enhancing component, complete resolution of mass effect, and return to functional independence (KPS = 100%). Unfortunately, her disease progressed 16 months after diagnosis and she passed away 8 months later, despite having received 3 cycles of ONC201 through a clinical trial. Her progression-free survival (16 months) was superior to that reported in the literature, which could be related to her young age, subtotal resection status, and thalamic location. Although the addition of chemotherapy to adjuvant radiotherapy has not been shown to improve survival in children with DMG, the Stupp regimen may provide a survival benefit in adults.

Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.

BACKGROUND PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival. METHODS CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients. RESULTS 42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models. CONCLUSIONS PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.

PURPOSE We investigated the long term impact of SRS and WBRT in two large prospective phase III trials. METHODS Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed. RESULTS 88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p< 0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p< 0.001). CONCLUSIONS We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.

BACKGROUND In glioblastomas (GBM) patients the first post-radiation MRI is usually difficult to interpret given the post-radiotherapy enhancement and possible pseudo-progression which is present in almost 50% of the patients. METHODS We retrospectively analyzed all patients with GBM treated between 2006 and 2017 at the CHUM (SARDO database). If the first brain MRI done within 3 months after the systemic treatment showed progression of contrast, these patients were considered pseudoprogressors (PsP) while the patients who had stable or response to treatment were the non-progressors (nP). If progression persisted in subsequent MRI with a change of treatment within 6 months, they were considered early progressors (eP). If subsequent MRI improved or was stable, they were classified as nP (or true pseudo-progression). RESULTS In our cohort of 470 patients with GBM, 57.7% were nP and 42.3% were PsP after the first post-treatment imagery. The median follow-up was 10 months. The nP had a longer mOS 15.3m vs 11.3m, p < 0.001, regardless of subsequent evolution. After the second assessment, 67.8% of PsP patients were then considered as eP and 36.4% of nP patients also progressed within 6 months. The nP either after the first or second evaluation had the same mOS (19.9m vs 18.3m), just like the eP (9.3m vs 8.6m), independently of the subsequent treatment. No demographic, molecular or clinical factor predicted PsP, except for tumor size (> 5cm, p=0.024). PsP incidence was similar between 2006–2011 (PsP 57.8%) and 2012–2017 (42.2%). The 1y OS with pseudo progression at the first MRI was 39.7% vs 54.8% with no progression (p=0.001) which has a meaningful impact for the patient. CONCLUSION Pseudo-progression is frequent (42%) in glioblastoma and predicts a poorer prognosis with 1y OS of 39,7%. In fact, PsP patients have more than two-thirds chance to progress precociously.

BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

BACKGROUND Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated. METHODS We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016. RESULTS A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148. CONCLUSION As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.

BACKGROUND: Recent results of R9802 (Buckner et al; J Clin Oncol 32:5s, 2014 (suppl; abstr 2000)) demonstrated that PCV given with RT at the time of initial diagnosis prolongs both progression-free survival (PFS) and overall survival (OS) for all patients enrolled in the trial. Herein, we report the impact of treatment on PFS and OS based upon specific histologic type. METHODS: Eligibility criteria included age 40 with any extent of resection, and supratentorial grade ll oligodendroglioma (O), oligo-astrocytoma (OA), or astrocytoma (A). Patients were stratified by age, histology, Karnofsky Performance Status, and presence versus absence of contrast enhancement on the preoperative imaging study and randomized to RT alone (54 Gy in 30 fractions) or RT followed by 6 cycles of PCV chemotherapy. In an exploratory analysis, we used the log rank test to compare survival and progression free survival (PFS) distributions for each histologic type. RESULTS: 251 eligible patients were accrued from 1998 to 2002: 107 had O, 79 had OA, and 65 had A. In total, 67% have progressed and 55% have died. Median PFS (RT vs. RT + PCV) overall, O, OA, and A, respectively, are 4.0 vs 10.4 (p < 0.001); 6.0 vs not reached (NR) (p < 0.001); 3.0 vs 8.9 (p = 0.01); and 1.8 vs 3.7 (p = 0.06) years. Median survival times (RT vs. RT + PCV) overall, O, OA, and A, respectively, are 7.8 vs 13.3 (p = 0.002); 10.8 vs NR (p = 0.008); 5.9 vs 11.4 (p = 0.05); and 4.4 vs 7.7 (p = 0.31) years. CONCLUSIONS: For grade 2 glioma patients with less than gross total tumor resection or >40 years of age, PCV + RT prolongs both OS and PFS compared with RT alone. The observed benefit is most definitive for O and OA patients.