EORTC 26951

Background

EORTC 26951 was a phase III randomized trial evaluating adjuvant PCV chemotherapy (procarbazine, lomustine, vincristine) after standard radiotherapy versus RT alone in patients with newly diagnosed anaplastic oligodendroglioma or oligoastrocytoma (grade 3 glioma). At the time of design, RT was standard for anaplastic glioma, and the role of chemotherapy was undefined. EORTC 26951 enrolled patients between 1991 and 2000; the 2013 Lancet Oncology long-term update (median follow-up 140 months) provided the definitive survival analysis, revealing the importance of 1p/19q codeletion as a predictive biomarker and the substantial OS benefit in molecularly defined oligodendroglioma.

Interventions and follow up

Arm A: Radiotherapy 59.4 Gy alone
Arm B: Radiotherapy 59.4 Gy followed by adjuvant PCV (procarbazine + lomustine + vincristine) × 6 cycles
Primary endpoint: Overall survival (OS); secondary: PFS, neurocognitive function
mFollow up: 140 months (14-year update, Lancet Oncol 2013)

Results

Overall mOS: 42.3 months (RT+PCV) vs 30.6 months (RT alone), HR 0.75, 95% CI 0.60–0.95, P=.018
1p/19q codeleted mOS: not reached (RT+PCV) vs 112 months (RT alone), HR 0.56, 95% CI 0.31–1.03, P=.059
1p/19q intact mOS: 25 vs 21 months, HR 0.83, P=.34 (NS)
10-yr OS (1p/19q codeleted): RT+PCV 51% vs RT 25%

Adverse events

Grade ≥3 hematologic (PCV): leukopenia 20%, thrombocytopenia 18%
Peripheral neuropathy (vincristine, all grades): ~35%
Nausea/vomiting Grade ≥3: 12%
Treatment delays/discontinuation: 24% of patients did not complete all 6 PCV cycles
Other: long-term RT cognitive effects not formally quantified; post-RT PCV had acceptable tolerability in this Grade 3 population vs the older Grade 2 RTOG 9802 cohort

Conclusions

Adjuvant PCV after radiotherapy significantly improved OS in anaplastic oligodendroglioma/oligoastrocytoma (42.3 vs 30.6 months, HR 0.75), with the most dramatic and durable benefit concentrated in 1p/19q-codeleted tumors (mOS not reached vs 112 months), establishing that 1p/19q codeletion defines a subset of anaplastic glioma with exceptional long-term survival from combined modality treatment.

Key Limitations

Histologic diagnosis (oligodendroglioma vs oligoastrocytoma) at enrollment was based on pre-2016 WHO criteria — before IDH/1p19q molecular classification; 1p/19q analysis performed retrospectively on a subset (~70%) of available tissue; the P-value for 1p/19q codeleted OS benefit (P=.059) did not reach strict statistical significance due to sample-size limitations, but the magnitude (mOS not reached vs 112 months) is compelling; PCV toxicity and complexity vs TMZ not directly compared in this trial; RTOG 9402 provides complementary data with a neoadjuvant PCV design; IDH mutation status not available (predates IDH testing era); local histology review and 1p/19q FISH quality variable across enrolling centers.

Clinical Context

EORTC 26951 and RTOG 9402 (companion trial, PCV+RT vs RT, anaplastic oligodendroglioma) together established the long-term chemosensitivity of 1p/19q-codeleted anaplastic oligodendroglioma with combined RT + PCV, achieving mOS not reached in the EORTC 26951 1p/19q-codeleted cohort at ~14 years. Per the 2016 WHO classification, these patients are now classified as IDH-mutant, 1p/19q-codeleted oligodendroglioma (grade 3) and treated with RT + PCV or RT + TMZ. ASCO/ESMO guidelines support RT + PCV for 1p/19q-codeleted anaplastic oligodendroglioma. An ongoing question is temozolomide vs PCV (both active, but TMZ is less toxic and more convenient); the CODEL trial evaluated TMZ vs PCV strategies, with results favoring PCV for PFS, though TMZ-based regimens remain widely used.

References