Development and validation of a clinical risk score for postoperative outcome in newly diagnosed glioblastoma: A report of the RANO Resect group.

Abstract

2060 Background: Following resection or biopsy, patients with newly diagnosed glioblastoma frequently enter clinical trials. To standardize terminology for extent of resection, we proposed the RANO classification acknowledging four prognostic resection classes reflecting different amounts of residual tumor. Here, we aim to make use of our classification to (I) analyze the interactive effects of residual tumor with clinical and molecular factors on outcome (II) to define a prognostic postoperative risk score. Methods: The RANO resect group retrospectively compiled an international, seven-center training cohort of newly diagnosed glioblastoma. Predictors of outcome were identified by uni- and multivariate Cox’s proportional hazard regression. The combined effects of residual tumor with prognostic molecular and clinical factors on survival were assessed by recursive partitioning analysis (significance level: p≤ 0.05). Terminal regression tree nodes were combined into risk classes guided by Kaplan-Meier survival analyses and log-rank tests. The risk classes were converted into a numerical score which was prognostically verified in an external validation cohort. Results: Our training cohort compromised 1003 patients with newly diagnosed IDH-wildtype glioblastoma, including 744 patients who underwent adjuvant radiochemotherapy per EORTC-NCIC (TMZ/RT→TMZ). Residual tumor per RANO classification, MGMT promotor methylation status, age (as continuous variable; optimal cutoff: ≤65 years), and KPS (as continuous variable; optimal cutoff: ≥80) were prognostic of overall survival and forwarded into regression tree analysis. By combining eleven terminal nodes and individually weighting the prognostic factors, an additive scale (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for poor postoperative outcome (median overall survival: 24 vs. 16 vs. 6 months; p < 0.01). Adjustment of the regression tree for adjuvant therapy was applied, and the presence of the three risk groups was confirmed in the subgroups of patients treated with or without RT/TMZ→TMZ. The prognostic value of the risk score was verified in a external single-center validation cohort of newly diagnosed glioblastoma ( n = 231, p < 0.01). When we compared our risk score to previously postulated risk models, our score was superior in concordance between predicted with observed survival (c-index; development cohort: 0.7, validation cohorts: 0.6). Conclusions: The novel RANO risk score integrates molecular and clinical factors to serve as an easy-to-use, yet highly prognostic tool to stratify patients after resection or biopsy of newly diagnosed glioblastoma. The score may serve to guide patient management and reduce imbalances between study arms in prospective interventional trials.