RTOG 9802

Background

RTOG 9802 was a phase III randomized trial evaluating radiotherapy (RT) plus PCV chemotherapy (procarbazine, lomustine/CCNU, vincristine) versus RT alone in patients with high-risk grade 2 (low-grade) glioma. High-risk was defined as age ≥40 years or subtotal resection. At the time of design, RT was the standard adjuvant treatment for grade 2 glioma after surgery, but the role of chemotherapy was unknown. RTOG 9802 was designed to determine whether adding PCV chemotherapy to RT could improve survival in this slowly progressive but ultimately fatal brain tumor. Long-term follow-up (NEJM 2016) revealed the definitive OS benefit 12 years after trial initiation.

Interventions and follow up

Arm A: Radiotherapy 54 Gy alone
Arm B: Radiotherapy 54 Gy followed by adjuvant PCV (procarbazine + lomustine + vincristine) × 6 cycles
Primary endpoint: Overall survival (OS)
mFollow up: 11.9 years (NEJM 2016 long-term update)

Results

mOS: 13.3 years (RT+PCV) vs 7.8 years (RT alone), HR 0.59, 95% CI 0.42–0.83, P=.003
mPFS: 10.4 vs 4.0 years, HR 0.50, P<.001
10-yr OS: 60% vs 40%
1p/19q codeleted mOS: not reached vs 13.5 years, HR 0.31
IDH-mutant (retrospective) mOS: not reached vs 9.3 years, HR 0.42

Adverse events

Grade ≥3 hematologic (chemotherapy): neutropenia 39%, thrombocytopenia 22%
Grade ≥3 non-hematologic (PCV): nausea/vomiting 11%, fatigue 7%, neurologic 8%
Vincristine peripheral neuropathy (all grades): 17%
Discontinuation: 8 patients (6.4%) discontinued PCV early due to toxicity
Sequencing: PCV administered post-RT reduces acute RT-related side-effect overlap; long-term RT-related cognitive effects not formally assessed

Conclusions

Radiotherapy plus PCV chemotherapy significantly prolonged both OS (13.3 vs 7.8 years, HR 0.59) and PFS (10.4 vs 4.0 years, HR 0.50) compared to RT alone in high-risk grade 2 glioma, with the most dramatic benefit in 1p/19q-codeleted tumors, establishing RT followed by PCV as the standard of care for high-risk LGG and demonstrating the long-term chemosensitivity of grade 2 gliomas, particularly those with 1p/19q codeletion (IDH-mutant oligodendroglioma).

Key Limitations

Long trial duration (1998–2002 enrollment) — molecular characterization (IDH, 1p/19q, TERT) performed retrospectively on available archival tissue, not prospectively defined; 1p/19q and IDH status available only for a subset (40–60% of enrolled patients); 2016 WHO classification (IDH-mutant, 1p/19q) not used at enrollment — enrolled patients included both IDH-mutant and IDH-wildtype grade 2 gliomas; temozolomide vs PCV comparison not addressed (EORTC 22033 addressed chemo schedule but not PCV vs TMZ directly); PCV toxicity (especially vincristine neuropathy, procarbazine interactions with MAOIs) compared unfavorably to TMZ; RTOG 9802 does not address upfront chemo vs RT-first sequencing (EORTC 22033).

Clinical Context

RTOG 9802 (with the complementary EORTC 26951 and RTOG 9402 oligodendroglioma trials) established that grade 2 gliomas with IDH mutation and 1p/19q codeletion are exquisitely chemosensitive, and that combined modality treatment substantially extends survival. The 2016 WHO CNS classification reconceptualized low-grade glioma as molecularly defined: IDH-mutant 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype GBM. ASCO/ESMO guidelines support RT + PCV (or RT + TMZ) for high-risk grade 2 glioma, with the strongest evidence in 1p/19q-codeleted tumors. The INDIGO trial (vorasidenib in IDH-mutant grade 2 glioma, NEJM 2023) now offers an oral IDH inhibitor option that can defer chemoradiation for selected lower-risk grade 2 patients, further reshaping the treatment landscape.

References