The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wild type and -mutant lower grade gliomas

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 26; no. 10; pp. 1839 - 1849
• Main Authors: Kinslow, Connor J, Roy, Soumyajit, Iwamoto, Fabio M, Brown, Paul D, DeStephano, David M, Canoll, Peter D, Qureshi, Summer S, Gallito, Matthew, Sisti, Michael B, Bruce, Jeffrey N, Horowitz, David P, Kachnic, Lisa A, Neugut, Alfred I, Yu, James B, Mehta, Minesh P, Cheng, Simon K, Wang, Tony J C
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 03.10.2024
• Subjects: meta-analysis; radiotherapy; glioma; isocitrate-dehydrogenase; alkylating chemotherapy
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/noae102

Abstract Background IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear. Methods We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2–3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. Results We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62–0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64–1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42–0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39–0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. Conclusions Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy. Graphical Abstract Graphical Abstract