Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors

European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG, now NRG Oncology) developed open-label randomized phase III trials (EORTC 26951 and RTOG 9402) in the 1990s testing the addition of procarbazine, lomustine, (CCNU) and vincristine (PCV) chemotherapy to radiotherapy (RT) for newly diagnosed anaplastic oligodendroglial tumors. Both studies reported initially that adding PCV improved progression-free survival (PFS) but not overall survival (OS).^1,2 However, with longer follow-up, improved OS was also observed, particularly in patients with chromosome 1p/19q codeleted tumors.^3,4 The importance of 1p/19q codeletion,⁵ isocitrate dehydrogenase (IDH) 1 and 2 mutations,⁶ and O⁶-methylguanine-methyltransferase promoter methylation⁷ in tumor DNA was not established when these trials were launched. However, both trials centrally analyzed available tumor tissue retrospectively.^3,4 Now, nearly 30 years since EORTC 26951 and RTOG 9402 were launched, we report extremely long-term follow-up of fully mature and final survival data from both trials and results in molecular subgroups in line with the current WHO Classification of Tumors of the Central Nervous System.⁸

Entry criteria, trial design, stratification factors, and statistical methods were described previously and are detailed in the Data Supplement (online only). Briefly, RT was administered to a total dose of 59.4 Gy in 33 fractions of 1.8 Gy each in both studies. In EORTC 26951, patients received up to six cycles of adjuvant PCV after RT; in RTOG 9402, patients received up to four cycles of intensified PCV before RT.⁹ Molecular analyses were performed centrally post hoc. PFS was defined as the time from random assignment to disease progression or death from any cause, whichever occurred first. Progression was defined locally using the Macdonald criteria.¹⁰ OS was defined as the time between random assignment and death due to any cause. Duration of follow-up was assessed with the inverse Kaplan-Meier method.

EORTC 26951 and RTOG 9402 were practice-changing phase III trials. Here, we report very long-term mature and final survival analyses nearly 30 years after the trials were conceived. Both trials showed that the addition of PCV chemotherapy to RT lengthens disease control and survival relative to RT alone as first-line therapy for anaplastic oligodendroglial tumors, particularly among 1p/19q codeleted cases. We confirm the 40% reduction in the risk of death in both trials from adding PCV to RT in patients with 1p19q codeleted tumors, with a median survival after random assignment of approximately 14 years and estimated PFS and OS probabilities at 20 years from random assignment of 30% and 35%, respectively. Therefore, durable disease control and long survival are possible after PCV-based chemoradiotherapy as first-line treatment for patients with anaplastic oligodendroglioma. PCV chemoradiotherapy also improves survival for patients with IDH-mutant tumors without codeletion, although less robustly, which is consistent with results from RTOG 9802 for low-grade gliomas and with temozolomide in EORTC 26053-22054 (CATNON) for anaplastic gliomas.^16-18 Our data show the long-term outcome in these patients with molecularly classified gliomas and reinforce the importance of PCV as a therapeutic chemotherapy regimen for gliomas with IDH mutation and especially 1p/19q codeletion, despite the transition by many to temozolomide as the drug of choice because of lower toxicity and perceived equivalence of efficacy.^19-25 The long-term survival observed also emphasizes the need to better understand the long-term adverse effects of treatment, such as cognitive function and ability to continue living independently many years after treatment. The risk of late neurocognitive injury from early RT combined with efficacy of PCV prompted some investigators to defer RT altogether for codeleted cases (ClinicalTrials.gov identifier: NCT02444000 from which results are eagerly awaited). A concern, however, is that initial treatment with chemotherapy alone may be detrimental for survival.^25-27 Finally, our ability to conduct and report extremely long-term survival results demonstrates the critical importance of governmentally funded networks in conducting clinical trials, particularly for indolent tumors with long follow-up required for full maturity, that are impossible for a commercial sponsor.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI/NIH.

The EORTC 26951 and the RTOG 9402 studies were each presented in part at the 24th meeting of the Society for Neuro-Oncology, November 21-24, 2019, Phoenix, AZ.

Supported by NRG Oncology Operations grant U10CA180868, NRG Oncology SDMC grant U10CA180822, NCORP grant UG1CA189867, and the NRG Specimen Bank grant U24CA196067 from the National Cancer Institute (NCI). Further supported by a donation from the Kankerbestrijding/ KWF from the Netherlands through the EORTC Cancer Research Fund, by the EORTC Translational Research Fund Grant No. TRF 01/02, by AstraZeneca EORTC Translational Research Grant No. AZ/01/02, by the Dutch Cancer Society Grants DDHK 2005-3416 and EMC 2007-3932, by grants from Stichting StopHersentumoren.nl, the Dutch Foundation for Scientific Research ZonMw (95110051 and 92003560) Programme Translational Research (PTO). A.B.L. was supported in part by The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital, The Michael Weiner Glioblastoma Research Into Treatment Fund, and NCI/NIH grants P30CA013696 and UG1CA189960.

NCT00002569 (RTOG 9402); NCT00002840 (EORTC 26951)