RTOG 9402

Background

RTOG 9402 was a phase III randomized trial evaluating neoadjuvant PCV chemotherapy (procarbazine, lomustine, vincristine) followed by radiotherapy versus RT alone in patients with newly diagnosed anaplastic oligodendroglioma or oligoastrocytoma (grade 3 glioma). Conducted in parallel with EORTC 26951 (which used adjuvant PCV), RTOG 9402 differed in timing of PCV delivery (before rather than after RT) and dosing schedule. The 2013 JCO long-term update (median follow-up 11.3 years) provided the definitive analysis with 1p/19q codeletion as a retrospective biomarker, demonstrating the landmark survival outcomes in molecularly defined oligodendroglioma.

Interventions and follow up

Arm A: Radiotherapy 59.4 Gy alone
Arm B: Neoadjuvant PCV × 4 cycles → radiotherapy 59.4 Gy
Primary endpoint: Overall survival (OS)
mFollow up: 11.3 years (2013 JCO update)

Results

Overall mOS: 4.9 years (PCV+RT) vs 4.4 years (RT alone), HR 0.79, 95% CI 0.60–1.04, P=.10 (trend, NS)
1p/19q codeleted mOS: 14.7 years (PCV+RT) vs 7.3 years (RT alone), HR 0.59, 95% CI 0.37–0.95, P=.03
1p/19q intact mOS: 2.6 vs 2.7 years, HR 0.85, P=.45 (NS)
10-yr OS (1p/19q codeleted): 51% (PCV+RT) vs 24% (RT alone)

Adverse events

Grade ≥3 hematologic (neoadjuvant PCV, intensive schedule): Grade 4 neutropenia 49%, Grade 4 thrombocytopenia 29%, Grade ≥3 leukopenia 73%
Treatment-related deaths: 5 potential (3 PCV, 2 RT)
Vincristine neuropathy (all grades): 35%
Discontinuation: 19% of PCV arm did not complete all 4 cycles due to toxicity
Comparison: neoadjuvant PCV hematologic toxicity substantially higher than EORTC 26951 adjuvant PCV schedule (intensive dose difference)

Conclusions

Neoadjuvant PCV followed by radiotherapy significantly prolonged OS in 1p/19q-codeleted anaplastic oligodendroglioma (14.7 vs 7.3 years, HR 0.59), confirming and extending the EORTC 26951 findings and establishing that 1p/19q codeletion defines a subset of grade 3 glioma with exceptional response to PCV chemotherapy, with median survival now exceeding 14 years in the combined modality arm.

Key Limitations

Overall OS in the full population not significant (P=.10) — benefit driven entirely by the 1p/19q codeleted subgroup; 1p/19q available retrospectively in ~80% of patients; intensive neoadjuvant PCV schedule associated with high hematologic toxicity (Grade 4 neutropenia 49%) — more toxic than EORTC 26951 adjuvant PCV; 5 treatment-related deaths; pre-2016 WHO histologic criteria — some enrolled patients would now be classified as IDH-wildtype GBM (poor prognosis regardless of 1p/19q); IDH mutation status unavailable; neoadjuvant vs adjuvant PCV sequencing not directly compared; RTOG 9402 and EORTC 26951 results consistent — codeletion drives benefit regardless of PCV timing.

Clinical Context

RTOG 9402 and EORTC 26951 together define the treatment paradigm for anaplastic oligodendroglioma: RT + PCV yields mOS 14.7 years (RTOG) and not-yet-reached (EORTC) survival in 1p/19q-codeleted patients, representing the longest median survival of any grade 3 CNS tumor. Per 2016 WHO, these are now IDH-mutant, 1p/19q-codeleted oligodendroglioma (grade 3). ASCO/ESMO guidelines support RT + PCV (or RT + TMZ) for these patients. The CODEL trial (RTOG 1072) evaluated TMZ-based vs PCV-based strategies, with results suggesting PCV had superior PFS. Temozolomide remains widely used due to tolerability and oral convenience. The long-term OS data from these two trials are the most compelling evidence in neuro-oncology for the impact of molecularly defined chemosensitivity on survival outcomes.

References