Background
Molecular subgroup analysis of the RTOG 9402 phase III trial (289 patients, anaplastic oligodendroglial tumors). Evaluated whether IDH1 mutation status (and a germline single nucleotide polymorphism rs55705857 associated with IDH-mutant gliomas) could identify patients who benefited from PCV chemotherapy plus RT vs RT alone — beyond what 1p/19q codeletion alone predicted. Tissue available for IDH analysis in 210/291 patients; 74% were IDH mutant.
Interventions and follow up
Arm A: PCV + radiotherapy
Arm B: Radiotherapy alone
Primary endpoint: Overall survival by IDH status (retrospective analysis)
mFollow up: Long-term (≥10 years)
Arm B: Radiotherapy alone
Primary endpoint: Overall survival by IDH status (retrospective analysis)
mFollow up: Long-term (≥10 years)
Results
OS (IDH mutant, CRT vs RT): 9.4 vs 5.7 years, HR 0.59 (95% CI 0.40–0.86), P=.006
OS (IDH wild-type, CRT vs RT): 1.3 vs 1.8 years, HR 1.14 (P=.67) — no benefit
10-year OS rate (IDH wild-type): 6% (CRT) vs 4% (RT) — equivalent, dismal
1p/19q codeleted + IDH mutant: 14.7 vs 6.8 years, HR 0.49, P=.01
Non-codeleted + IDH mutant: 5.5 vs 3.3 years, HR 0.56, P<.05
OS (IDH wild-type, CRT vs RT): 1.3 vs 1.8 years, HR 1.14 (P=.67) — no benefit
10-year OS rate (IDH wild-type): 6% (CRT) vs 4% (RT) — equivalent, dismal
1p/19q codeleted + IDH mutant: 14.7 vs 6.8 years, HR 0.49, P=.01
Non-codeleted + IDH mutant: 5.5 vs 3.3 years, HR 0.56, P<.05
Adverse events
Main adverse events: Retrospective molecular analysis — no new toxicity data (refer to 2006 primary trial).
Conclusions
IDH mutation identified patients with anaplastic oligodendroglial tumors who benefit from PCV+RT — including non-1p/19q codeleted patients with IDH mutations. IDH wild-type patients had dismal outcomes regardless of treatment (median OS ~1.3–1.8yr) and did not benefit from CRT. IDH mutation is a stronger predictor of chemotherapy benefit than 1p/19q codeletion alone.
Key Limitations
Key Limitations: Retrospective molecular analysis — not a pre-specified primary endpoint. Only 74% of patients had IDH testing available — survivor bias possible. IDH testing was not available at time of original enrollment. The number of IDH wild-type anaplastic oligodendrogliomas is small (~26%), limiting statistical power. Current WHO 2021 classification has renamed IDH wild-type "anaplastic oligodendroglioma" — most would now be classified as IDH wild-type astrocytoma or GBM.
Clinical Context
This analysis reinforced that IDH mutation is the key driver of treatment sensitivity in anaplastic gliomas. WHO 2021 now defines oligodendroglioma by IDH mutation + 1p/19q codeletion, and astrocytoma by IDH mutation alone (without codeletion). IDH wild-type anaplastic glioma is now effectively reclassified as GBM equivalent. PCV+RT is standard for 1p/19q codeleted anaplastic oligodendroglioma; for IDH-mutant non-codeleted tumors, RT+TMZ or PCV are options per CATNON and NOA-04 data.
References