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

Abstract

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.

Glioblastoma and Other Primary Brain Malignancies in Adults

“…87 A watch and wait approach with regular MRI surveillance may be appropriate for younger patients with a WHO grade 2 IDH-mutant glioma, minimal residual disease, and no neurologic symptoms related to the tumor, with the goal to delay treatment-associated adverse effects (eg, fatigue, short-term memory loss). Post hoc analysis of the cooperative group NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9802 67 showed that patients with high-risk IDH-mutant WHO grade 2 glioma (ie, patients aged 40 years and older or with subtotal resections) benefited from the addition of procarbazine, lomustine, and vincristine to radiotherapy (IDH-mutant 1p/19q codel [37 patients]; overall survival, 13.9 years [radiotherapy] vs not 68 Both EORTC 26951 and RTOG 9402 studies demonstrated a progressionfree survival of more than 30% at 20 years in patients with 1p/19q codeletion, indicating that durable disease control was feasible with this regimen. Procarbazine, lomustine, and vincristine also improved overall survival for patients with IDH-mutant tumors without 1p/19q codel, 68 consistent with the results from RTOG 9802.…”

“…Post hoc analysis of the cooperative group NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9802 67 showed that patients with high-risk IDH-mutant WHO grade 2 glioma (ie, patients aged 40 years and older or with subtotal resections) benefited from the addition of procarbazine, lomustine, and vincristine to radiotherapy (IDH-mutant 1p/19q codel [37 patients]; overall survival, 13.9 years [radiotherapy] vs not 68 Both EORTC 26951 and RTOG 9402 studies demonstrated a progressionfree survival of more than 30% at 20 years in patients with 1p/19q codeletion, indicating that durable disease control was feasible with this regimen. Procarbazine, lomustine, and vincristine also improved overall survival for patients with IDH-mutant tumors without 1p/19q codel, 68 consistent with the results from RTOG 9802. Temozolomide is an acceptable alternative to procarbazine, lomustine, and vincristine.…”

“…50,51 Patients with IDH-mutant 1p/19q non-codel tumors have a median overall survival of 7-8 years 64,66 ; whereas patients with 1p/ 19q-codel oligodendrogliomas have a median overall survival of 13 to 14 years after chemoradiation. 66,68 Recurrence rates of malignant meningiomas are 50% to 90% with a 5-year overall survival of 20% to 50%. 100,101 The 10-year overall survival of patients with ependymal tumors is approximately 80%, but prognosis depends on patient age, tumor grade, tumor location, and site-specific molecular genetics.…”

Final Report of EORTC 26951 and RTOG 9402 for Anaplastic Oligodendroglial Tumors

“…On the basis of median 18-19 years of follow-up duration, the authors exhibited that progression-free survival of oligodendroglioma could be significantly improved by PCV plus RT. 1 Briefly, the study provides impressive results of two important and large-scale analyses were performed in random-effects models with Stata software (version 12.0 7 ). Heterogeneity across meta-analyses was calculated via Cochran Q chi-square test, a derived I 2 statistic .…”

“…6 Then, we noticed some important but unstable results because the 95% CI was quite close to 1, such as overall survival (OS) on oligodendroglioma in EORTC 26951 (hazard ratio, 0.60; 95% CI, 0.35 to 1.03) and OS on isocitrate dehydrogenase-mutant astrocytoma in RTOG 9402 (hazard ratio, 0.60; 95% CI, 0.34 to 1.03). 1 Given the vulnerability of the results provided, we performed a mini meta-analysis of the two trials by using a randomeffects model 1 and revealed that PCV plus RT could significantly improve both OS and progression-free survival in all patients with grade 3 oligodendroglioma and isocitrate dehydrogenase-mutant astrocytoma (all P , .05; Fig 1). Through mini meta-analysis, we further confirmed the results of the current study in a more robust and reliable manner.…”