Highlight
- Adjuvant temozolomide (12 cycles) demonstrated a transformative impact on survival for patients with IDH-mutated 1p/19q non-co-deleted anaplastic glioma, with a median overall survival of 12.5 years compared to 6.0 years without it.
- The addition of concurrent temozolomide to radiotherapy failed to show a statistically significant survival benefit in this population, suggesting that the timing of chemotherapy is critical.
- IDH wild-type anaplastic gliomas derived no benefit from either concurrent or adjuvant temozolomide, reinforcing their clinical classification as molecular glioblastomas requiring different therapeutic approaches.
Background and Clinical Context
For decades, the management of anaplastic gliomas (World Health Organization [WHO] grade 3) was guided primarily by histological features. However, the discovery of molecular markers—specifically the co-deletion of chromosome arms 1p and 19q and mutations in the isocitrate dehydrogenase (IDH) gene—has fundamentally restructured our understanding of these tumors. The 1p/19q non-co-deleted anaplastic gliomas, primarily anaplastic astrocytomas, represent a heterogeneous group with widely varying prognoses based on IDH status.
While the Stupp protocol established the efficacy of concurrent and adjuvant temozolomide for glioblastoma (WHO grade 4), the specific benefit of this regimen in grade 3 tumors remained a subject of intense debate. The CATNON trial (EORTC 26053-22054) was designed to address this uncertainty by evaluating the individual and combined contributions of concurrent and adjuvant temozolomide to radiotherapy in patients with 1p/19q non-co-deleted anaplastic gliomas. This final analysis provides long-term follow-up data that is essential for defining the standard of care in the era of molecularly defined CNS tumors.
The CATNON Trial: Study Design and Methodology
CATNON was a randomized, open-label, phase 3 trial conducted across 137 institutions worldwide. The study enrolled 751 participants aged 18 or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. Participants were randomly assigned in a 1:1:1:1 ratio to one of four treatment arms:
- Radiotherapy alone (59.4 Gy in 33 fractions).
- Radiotherapy with concurrent oral temozolomide (75 mg/m2 daily).
- Radiotherapy followed by 12 cycles of adjuvant oral temozolomide (150-200 mg/m2 on days 1-5 of a 28-day cycle).
- Radiotherapy with both concurrent and adjuvant temozolomide.
Stratification factors included institution, WHO performance status, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status. In 2011, the protocol was amended to incorporate IDH mutational status, which proved to be the most critical prognostic and potentially predictive factor. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population.
Key Findings: Long-Term Survival Data
With a median follow-up of 10.9 years, the CATNON trial offers a robust look at the long-term trajectory of these patients. The results underscore a profound survival advantage conferred by adjuvant chemotherapy, but only in specific molecular subsets.
The Impact of Adjuvant and Concurrent Temozolomide
In the ITT population, adjuvant temozolomide significantly improved overall survival with a hazard ratio (HR) of 0.65 (95% CI 0.54-0.77). Conversely, concurrent temozolomide did not provide a statistically significant improvement in OS (HR 0.91 [95% CI 0.76-1.08]). This finding challenges the assumption that the concurrent phase, so vital in glioblastoma treatment, is universally necessary in lower-grade astrocytic tumors.
The Decisive Role of IDH Mutation
The exploratory analysis of the 444 participants with IDH-mutated (IDHmt) tumors provided the most compelling data. In these patients, the median OS reached a remarkable 12.5 years (95% CI 9.4-15.0) when adjuvant temozolomide was administered, compared to only 6.0 years (95% CI 5.1-7.2) in the radiotherapy-only or concurrent-only groups. This corresponds to an HR of 0.54 (95% CI 0.42-0.69), representing a 46% reduction in the risk of death.
In contrast, the concurrent use of temozolomide in the IDHmt subgroup showed a median OS of 9.7 years versus 7.2 years without concurrent treatment, a difference that did not reach statistical significance (HR 0.81 [95% CI 0.63-1.04]).
The IDH Wild-Type Subset
For patients with IDH wild-type (IDHwt) tumors, the outcomes were starkly different. No survival benefit was observed for either concurrent or adjuvant temozolomide. These tumors behaved similarly to glioblastomas, characterized by much shorter survival times and a lack of responsiveness to the CATNON treatment intensification. This confirms that IDHwt anaplastic gliomas should be managed according to glioblastoma protocols or enrolled in clinical trials specifically targeting their unique molecular drivers.
Molecular Subtyping and Secondary Alterations
The researchers also investigated secondary DNA alterations. Factors such as homozygous deletion of CDKN2A, amplification of PDGFRA and CDK4, and high total copy number variation were associated with a worse prognosis. However, none of these markers were found to be predictive of the benefit of temozolomide, suggesting that IDH status remains the primary guide for utilizing this alkylating agent.
Expert Commentary: Interpreting the Data
The final CATNON results represent a landmark in neuro-oncology. The observation that adjuvant, but not concurrent, temozolomide is the driver of survival in IDHmt grade 3 astrocytomas is clinically significant. It suggests a biological difference in how these tumors respond to DNA damage compared to glioblastomas. In glioblastomas, the radiosensitizing effect of concurrent temozolomide is vital; in IDHmt anaplastic astrocytomas, the prolonged exposure of 12 cycles of adjuvant therapy appears to be the primary mechanism of benefit.
Furthermore, these results have implications for the WHO 2021 classification. Many of the IDH-mutated tumors in this trial that had CDKN2A/B homozygous deletions would now be classified as Astrocytoma, IDH-mutant, WHO grade 4. Even in these higher-grade IDH-mutated tumors, the CATNON data suggests that the adjuvant temozolomide strategy is highly effective.
The lack of benefit in IDH wild-type patients is equally important. It prevents the over-treatment of patients who are unlikely to respond and highlights the urgent need for novel therapies in the IDHwt population, which remains the most challenging subset of gliomas to treat.
Conclusion: A New Benchmark in Care
The CATNON trial establishes radiotherapy followed by 12 cycles of adjuvant temozolomide as the definitive standard of care for patients with IDH-mutated, 1p/19q non-co-deleted anaplastic gliomas. The survival benefit is not only statistically significant but clinically profound, extending median survival by over six years. Clinicians should prioritize molecular testing for IDH status to guide these treatment decisions, ensuring that IDHmt patients receive the necessary adjuvant therapy while avoiding the potential toxicities of concurrent temozolomide where it lacks proven benefit.
Funding and Clinical Trial Information
This study was funded by MSD. The trial is registered with ClinicalTrials.gov, NCT00626990.
References
van den Bent MJ, Ghisai SA, Wick W, et al. Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial. Lancet Oncol. 2026 Jan;27(1):45-56. doi: 10.1016/S1470-2045(25)00614-X.
