Is there evidence for concurrent chemotherapy in CATNON (Concurrent and Adjuvant Temozolomide (temozolomide) in Non-1p/19q deleted anaplastic glioma) and CODEL (Chemotherapy versus Observation after radiotherapy in IDH-mutant, 1p/19q codeleted anaplastic oligodendroglioma) trials for patients with Gross Total Resection (GTR) or Subtotal Resection (STR)?

Evidence for Concurrent Chemotherapy in CATNON and CODEL Trials for GTR/STR Subsets

Key Recommendation

Based on the most recent evidence from the CATNON trial, concurrent temozolomide with radiotherapy does not improve survival outcomes in patients with non-1p/19q codeleted anaplastic gliomas, regardless of resection status (GTR or STR), while adjuvant temozolomide significantly improves overall survival.

CATNON Trial Evidence

The CATNON trial is a phase 3 randomized study specifically investigating the role of concurrent and adjuvant temozolomide (TMZ) in patients with newly diagnosed 1p/19q non-codeleted anaplastic gliomas. The second interim analysis of this trial provides the most definitive evidence on this question 1:

• Concurrent TMZ with radiotherapy showed no survival benefit (HR 0.97,99.1% CI 0.73-1.28, p=0.76)
• Adjuvant TMZ significantly improved overall survival (median OS 82.3 months vs 46.9 months; HR 0.64,95% CI 0.52-0.79, p<0.0001)
• This analysis did not specifically report outcomes by extent of resection (GTR/STR)

The ASCO-SNO guidelines from 2022 incorporated these findings, stating that "for 1p19q non-codeleted, grade 3, anaplastic astrocytoma, the available evidence supports RT plus adjuvant TMZ based on the recent interim analysis of the CATNON trial, obviating concurrent TMZ as a reasonable option" 2.

CODEL Trial Information

The CODEL trial is designed for patients with 1p/19q codeleted oligodendrogliomas (both low-grade and anaplastic) 2:

• This ongoing trial compares RT plus PCV versus RT plus TMZ
• Complete outcome data are still pending
• No specific data regarding GTR/STR subgroups have been published

Treatment Recommendations by Molecular Subtype

For IDH-mutant, 1p/19q Non-codeleted Anaplastic Gliomas (CATNON population):

1. Maximal safe surgical resection when possible
2. Radiotherapy (54-60 Gy in 1.8-2 Gy fractions)
3. Adjuvant temozolomide (12 cycles) 2, 3
4. Concurrent temozolomide is not recommended based on the CATNON trial results 1

For IDH-mutant, 1p/19q Codeleted Anaplastic Gliomas (CODEL population):

1. Maximal safe surgical resection when possible
2. Radiotherapy (54-60 Gy)
3. PCV chemotherapy is currently recommended based on historical data 2
4. The CODEL trial will provide more definitive guidance on whether TMZ can replace PCV in this population

Extent of Resection Considerations

While the CATNON and CODEL trials do not specifically report outcomes stratified by extent of resection (GTR vs STR), the general treatment approach remains the same regardless of resection status 2:

• Maximal safe resection is always the goal
• Adjuvant therapy decisions are primarily guided by molecular status rather than extent of resection
• Neither trial has published subgroup analyses specifically addressing whether GTR or STR patients benefit differently from concurrent chemotherapy

Clinical Implications

1. For non-1p/19q codeleted anaplastic gliomas:

   • Omitting concurrent TMZ simplifies treatment without compromising outcomes
   • Focus should be on completing the full course of adjuvant TMZ (12 cycles) after radiotherapy

2. For 1p/19q codeleted anaplastic gliomas:

   • Current standard remains RT followed by PCV
   • CODEL results will clarify whether TMZ can replace PCV in this population

Common Pitfalls to Avoid

1. Assuming concurrent TMZ is beneficial for all high-grade gliomas - the CATNON trial clearly demonstrates this is not the case for non-codeleted anaplastic gliomas
2. Making treatment decisions without complete molecular profiling (IDH mutation status and 1p/19q codeletion status are essential)
3. Undertreatment with inadequate adjuvant therapy, which has proven survival benefit
4. Overtreatment with concurrent chemotherapy when not indicated, potentially increasing toxicity without benefit

In conclusion, the current evidence does not support the use of concurrent temozolomide with radiotherapy in patients with non-1p/19q codeleted anaplastic gliomas regardless of resection status, while adjuvant temozolomide provides significant survival benefit. For 1p/19q codeleted gliomas, we await final results from the CODEL trial to determine the optimal chemotherapy regimen.