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Temozolomide and Radiotherapy vs Radiotherapy Alone in Patients With IDH Wild-Type Glioblastoma
TAKE-HOME MESSAGE
- The CATNON clinical trial was a practice-changing, randomized, phase III trial that established a role for temozolomide in patients with IDH-mutant grade 3 astrocytoma. In this post hoc analysis of the CATNON trial, the authors evaluated patients with IDH1/2 wild-type astrocytoma grade 3 with molecular features of glioblastoma and found no benefit with the addition of temozolomide (concurrent, adjuvant, or both) to radiotherapy in either overall survival or progression-free survival. Patients with a methylated MGMT promoter also lacked clinical benefit from the addition of temozolomide.
- This post hoc analysis raises the question of whether temozolomide can be safely omitted in patients with IDH wild-type glioblastoma. The absence of clinical benefit should prompt further studies to evaluate the efficacy of temozolomide in this patient population, as the CATNON trial was not specifically powered to answer this question.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors].
PATIENTS AND METHODS
From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.
RESULTS
Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.
CONCLUSIONS
In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Additional Info
Disclosure statements are available on the authors' profiles:
Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial
Clin. Cancer Res 2022 Jun 13;28(12)2527-2535, CMS Tesileanu, M Sanson, W Wick, AA Brandes, PM Clement, SC Erridge, MA Vogelbaum, AK Nowak, JF Baurain, WP Mason, H Wheeler, OL Chinot, S Gill, M Griffin, L Rogers, W Taal, R Rudà, M Weller, C McBain, ME van Linde, K Aldape, RB Jenkins, JM Kros, P Wesseling, A von Deimling, Y Hoogstrate, I de Heer, PN Atmodimedjo, HJ Dubbink, RWW Brouwer, WFJ van IJcken, KJ Cheung, V Golfinopoulos, BG Baumert, T Gorlia, PJ French, MJ van den BentFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In 2021, my story of the year in the field of neuro-oncology focused on the outcomes of the randomized, open-label, phase III CANTON trial in adult patients with newly diagnosed 1p/19q non-codeleted anaplastic gliomas who were randomly assigned (1:1:1:1) to radiotherapy alone, radiotherapy with concurrent temozolomide, radiotherapy with adjuvant temozolomide, or radiotherapy with both concurrent and adjuvant temozolomide. I described CATNON as one of the last of the “classics”, and in true form, it is a “gift that keeps on giving”, as demonstrated by this recent post hoc analysis evaluating outcomes in IDH wild-type tumors.
The primary endpoint of this trial, which for all practical purposes included legacy “anaplastic astrocytoma” patients, stratified by MGMT methylation status, 1p status, and “oligodendroglial elements”, but crucially not by IDH status, was overall survival (OS). This large effort included 751 patients assigned to the four treatment arms, asking the following primary questions:
The current paper in Clinical Cancer Research evaluates whether the addition of temozolomide to radiotherapy improves survival in IDH wild-type (which would now be classified as glioblastoma according to WHO CNS5) legacy anaplastic astrocytoma in a post hoc analysis. Previously, the impact of IDH mutation as well as genome-wide methylation was also analyzed and reported in a companion paper in Neuro-Oncology, confirming the positive impact of IDH mutation, with a median OS of 19.9 months in patients with IDH1 and IDH2 wild-type tumors and 98.4 months in those with IDH1 or IDH2 mutant tumors (HR, 0.14; P < .0001). Furthermore, the paper in Neuro-Oncology demonstrated that in IDH1 or IDH2 mutant tumors (without any further molecular characterization), adjuvant temozolomide improved OS compared with no adjuvant temozolomide, but no OS benefit was seen with concurrent temozolomide compared with no concurrent temozolomide.
The current paper confirms that in IDH1/2 wild-type anaplastic astrocytomas with molecular features of glioblastoma, neither concurrent nor adjuvant temozolomide improved OS compared with radiotherapy alone. Specifically, the molecular selection involved IDH1/2 wild-type and H3F3A wild-type tumors with the presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Overall, 89% of the enrolled patients (670/751) were fully molecularly characterized, and of those, approximately 24% (159/670) met the WHO 2021 molecular criteria for glioblastoma, IDH wild-type. Of those patients, 47 received radiotherapy only and 112 received some combination of radiotherapy and temozolomide. Temozolomide did not enhance either OS or progression-free survival. MGMT promoter methylation remained prognostic for OS but, surprisingly, was not predictive of temozolomide treatment benefit.
How do we use these data? Legacy anaplastic astrocytoma, which would qualify as molecular glioblastoma, IDH wild-type, using the new WHO classification, reflexively would be treated with combination chemoradiotherapy based on a temozolomide platform, but the data from CATNON, limited as they are given the small patient numbers and post hoc analysis, do not support this reflexive approach, even in MGMT-methylated tumors. How then do we approach these patients, and what issues/problems now arise?
However, one needs to be cautious before over-interpreting the CATNON results as the study was designed and powered to ask the concurrent and adjuvant temozolomide question in a two-by-two factorial design trial and not adequately powered for further subgroup analysis. The authors’ conclusion was that “These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.”