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. 2025 Feb 10;27(2):557-566.
doi: 10.1093/neuonc/noae205.

Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with lomustine/temozolomide

Thomas Zeyen  1   2 , Laura Böhm  1   2 , Daniel Paech  2   3 , Niklas Schäfer  1   2 , Theophilos Tzaridis  1   2 , Cathrina Duffy  1   2 , Louisa Nitsch  4 , Matthias Schneider  2   5 , Anna-Laura Potthoff  2   5 , Javen Lennard Schneider-Rothhaar  2   5 , Joachim Peter Steinbach  6 , Peter Hau  7 , Thomas Kowalski  8 , Clemens Seidel  9 , Dietmar Krex  10 , Oliver Grauer  11 , Roland Goldbrunner  12   2 , Pia Susan Zeiner  6 , Ghazaleh Tabatabai  13   14 , Norbert Galldiks  15   2   16 , Walter Stummer  17 , Elke Hattingen  18 , Martin Glas  19   20 , Eleni Gkika  2   21 , Hartmut Vatter  2   5 , Alexander Radbruch  2   3 , Ulrich Herrlinger  2   1 , Johannes Weller  2   4   1 , Christina Schaub  2   1
Affiliations

Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with lomustine/temozolomide

Thomas Zeyen et al. Neuro Oncol. .

Abstract

Background: Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The response assessment in neuro-oncology (RANO) resects group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyze the prognostic performance of binary EOR assessment compared to volumetric assessment.

Methods: Seventy-eight patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and progression-free survival was analyzed using uni- and multivariable Cox regression analysis as well as two-sided log-rank test. Patients were divided into residual tumor volume (RTV) ≤1 cm³, >1-≤5 cm³, and >5 cm³ following the proposed criteria of the RANO resect group.

Results: Prolonged OS was associated with age <60 years, low RTV, and gross total resection. RTV had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤ 1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI: 46.94-not reached), with a 5-year survival rate of 49%.

Conclusions: Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients.

Keywords: MGMT-promotor; extend of resection; glioblastoma; residual tumor volume.

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Conflict of interest statement

C.Sei. reports Grants from Seagen and Amgen (provided for a Lab project in brain metastases), Consulting fees from Seagen, honoraria from Seagen, Novocure, Oncovis, Mitteldeutsche Studiengruppe and Zuckschwerdt-Verlag. D.P. reports Grants from Bonfor (UNTWIST), Deutsche Forschungsgemeinschaft (DFG) (project number: 445704496) and EKFS (EKES.33), Consulting fees from Guerbet and honoraria from Siemens Healthcare.

E.G. reports honoraria and support for attending meetings from Astra Zeneca, Novocure, and IntraOp. E.H. reports honoraria from Ely Lilly. G.T. reports the following support for the present manuscript: Adolf-Leuze-Stiftung, Medical Faculty Tübingen, Else Kröner Forschungskolleg 2019_Kolleg_14, DFG Germany´s Excellence Strategy, EXC2180. G.T. further reports consulting fees from Bayer, Boehringer Ingelheim, and Curevac, honoraria from Novocure and Servier, travel grants from Novocure and Servier, participation on an advisory board for Bayer, Boehringer Ingelheim, CureVac, Miltenyi Biomedicine, and Novocure. G.T. further reports a fiduciary role in Steering Committee ONTRK, Bayer, and Steering Committee TIGER, Novocure. J.St. reports consulting fees from Glaxo-Smith Kline, Boehringer, Servier, Novocure, Seagen, and Roche, and honoraria from Med-Update. L.N. reports honoraria for talks from Merck, Novartis GmbH, and Alexion and travel grants from CSL Behring. M.G. reports consulting fees from Roche, Novartis, Daiichi Sankyo, Novocure, Bayer, Janssen-Cilag, Servier, and Oncomagnetix, honoraria from Novartis, Merck, Novocure, Medac, and Kyowa Kirin, travel grants from Novocure. M.G. further reports participation on an advisory board from Zeiss. N.G. reports honoraria from Blue Earth Diagnostics for lectures, participation on advisory boards for Telix, and the following memberships: Head of the PET/RANO group, Co-Chair Publishing Activity Committee. P.H. reports Grants from Deutsche Krebshilfe, DFG, Wilhelm Sander-Stiftung and Bayrisches Zentrum für Krebsforschung, consulting fees from Novocure, Glaxo Smith Kline and Seagen, honoraria from Novocure and Seagen. PH further reports participation on an advisory board for Glaxo Smith Kline and the following memberships: Neuroonkologische Arbeitsgemenschaft in der deutschen Krebsgesellschaft, Kommission Neuroonkologie in der Deutschen Gesellschaft für Neurologie, Steering Board Brain tumor group of EORTC. R.G. reports participation on an advisory board for CAR T-cell study on glioblastoma and the following memberships: President of the German Society of Neurosurgery, Vice President of the German Society of Surgery. U.H. reports consulting fees from Medac, Oncomagnetics, Servier, and Bayer and honoraria from Medac and Bayer. All other authors report no conflicts of interest.

Figures

Figure 1.
Figure 1.
The selection of patients according to the given inclusion and exclusion criteria, as described in the main text. Abbreviations: NA, not available; GBM-O, Glioblastoma with oligodendroglial component.
Figure 2.
Figure 2.
Volumetric assessment of residual contrast-enhancing (CE) tumor. As described in the main text, ROI1 (resection cavity and precontrast hyperintensities) and ROI2 (also including CE residual tumor on postcontrast T1) were determined. Residual tumor volume was calculated using the following formula: ROI(2)-ROI(1).
Figure 3.
Figure 3.
Association of stepwise defined residual tumor volume cutoffs from 1 to 10 cm³ with overall survival. For each cutoff value, the significance level (P-value of log-rank test) for dichotomous survival prediction is shown. The straight line (above and parallel to the X-axis) line indicates a significance level of P = .05. All cutoffs, except one (2 cm²), have a P-value of <.05, and the difference of all P-values is marginal (range 0.001–0.055) indicating that defining a single binary cutoff for survival prediction is not useful.
Figure 4.
Figure 4.
(A) shows OS in Kaplan–Meier plots with stratification according to residual tumor volume as proposed by the response assessment in the neuro-oncology resect group. (B) shows median OS in groups and 12 months, as well as 5-year survival rates, respectively. aLog-rank test over all three groups.
See this image and copyright information in PMC

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