Ducray, François

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients &gt;40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction &lt;.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.