Prognostic validation and refinement of a classification system for extent of resection in glioblastoma: A report of the RANO resect group.
Authors: Karschnia Philipp , Young Jacob S , Dono Antonio , Häni Levin , Sciortino Tommaso , Bruno Francesco , Jünger Stefanie T. , Teske Nico , Weller Michael , Ruda Roberta , Bello Lorenzo , Schnell Oliver , Esquenazi Yoshua , Grau Stefan , Molinaro Annette M. , Berger Mitchel S. , Chang Susan Marina , Van Den Bent Martin J. , Tonn Joerg ,   RANO Resect Investigators
Published: June 2022

2003 Background: Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system for glioblastoma was previously proposed based upon the absolute residual contrast-enhancing (CE) tumor (in cm3) and the relative reduction of CE tumor (in percentage) on postoperative MRI. Class 0 was defined as ‘supramaximal CE resection’ (also including removal of non-CE tumor), class 1 as ‘maximal CE resection’, class 2 as ‘submaximal CE resection’, and class 3 as ‘biopsy’. We aimed to (I) explore the prognostic utility of the proposed classification system and (II) define how much non-CE tumor needs to be removed to translate into a survival benefit. Methods: An international Response Assessment in Neuro-Oncology (RANO) group was formed, entitled RANO resect. The members of the RANO resect group retrospectively searched the databases from seven neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma. Clinical characteristics, volumetric information from pre- and postoperative MRI, and outcome were collected. Kaplan-Meier survival analysis and log-rank test were applied to calculate survival, and Cox’s proportional hazard regression model to adjust for multiple variables. Significance level was set at p ≤ 0.05. Results: We encountered 1021 patients with newly diagnosed glioblastoma, including 1008 IDHwt patients. 744 IDHwt patients were treated with radiochemotherapy per EORTC 26981/22981 following surgery. Among such homogenously treated patients, higher extent of resection was favorably associated with outcome: patients with ‘maximal CE resection’ (class 1) had superior outcome compared to patients with ‘submaximal CE resection’ (class 2) or ‘biopsy’ (class 3) (median OS: 20 versus 16 versus 10 months; p = 0.001). Similar findings were made when assessing progression (median PFS: 9 versus 8 versus 5 months; p = 0.001). Extensive resection of non-CE tumor (≥60% of non-CE tumor removed and ≤5 cm3 residual non-CE tumor) provided an additional survival benefit in patients with complete CE resection (class 1), thus defining class 0 (‘supramaximal CE resection’) (median OS: 29 versus 20 months; p = 0.003). Smaller pre-operative tumor volumes were associated with larger extent of resection. The favorable prognostic effect of CE resection was conserved in a multivariate analysis when stratifying for molecular and clinical markers including pre-operative tumor volume and MGMT promotor status ( p = 0.001). Conclusions: The proposed classification system for extent of surgery in glioblastoma is highly prognostic and may serve for stratification and design of clinical trials. Removal of non-CE tumor beyond the CE tumor borders translates into additional survival benefit in glioblastomas, providing a rationale to explicitly denominate such a 'supramaximal CE resection.'