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

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.


INTRODUCTION
European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG, now NRG Oncology) developed openlabel 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 O 6 -methylguanine-methyltransferase promoter methylation 7 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

METHODS
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 followup was assessed with the inverse Kaplan-Meier method.

EORTC 26951
Between August 1996 and March 2002, 368 patients were enrolled. The database was locked for analysis on June 21, 2019 with 61 of the randomly assigned 368 patients (17%) still alive. For all patients, the median follow-up for PFS and OS is 19 years. The median follow-up of surviving patients free of progression is 17.7 years (range . 0-21.3 years). The median follow-up of surviving patients is 17.8 years with range (. 0-21.7 years). For EORTC 26951, codeletion of 1p/19q by fluorescent in situ hybridization (FISH) was observed in 25% (80 of 316), 3 and IDH-1 or -2 mutation was detected by Sanger sequencing in 46% (83 of 182) of informative cases. Most (39 of 45, 87%) tumors classified as codeleted by FISH were IDH-mutant. One hundred fifteen (115) tumors were analyzed with genome-wide methylation arrays. 11-13 Finally, 139 tumors were assayed by next-generation sequencing (using Ion Torrent). 14 Table 1  . Detailed prognostic and predictive makers analyses are presented in the Data Supplement. Only methylguanine-methyltransferase promoter methylation as assessed with methylation arrays proved to be significantly predictive of benefit from PCV (HR 0.41; 95% CI, 0.25 to 0.67; P , .0001).

CONTEXT Key Objective
The very long-term survival of patients with anaplastic oligodendroglioma who received (neo)adjuvant procarbazine, lomustine, and vincristine chemotherapy in addition to radiotherapy as part of the initial treatment is unknown.

Knowledge Generated
In two independent prospective randomized trials, the benefit of (neo)adjuvant procarbazine, lomustine, and vincristine added to radiotherapy in anaplastic oligodendroglioma was demonstrated. With an estimated survival after 20 years in the 35% range, a sizeable proportion of patients with a 1p/19q codeleted oligodendroglioma (WHO classification 2021) achieve long-term survival. Relevance Long-term survival is possible in a significant proportion of patients with a 1p/19q codeleted oligodendroglioma, even in patients with histologically anaplastic tumors, emphasizing the importance of quality of survival and need for adequate supportive measures.

DISCUSSION
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 IDHmutant tumors without codeletion, although less robustly, which is consistent with results from RTOG 9802 for lowgrade gliomas and with temozolomide in EORTC 26053-22054 (CATNON) for anaplastic gliomas. [16][17][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][20][21][22][23][24][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][26][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.