EORTC 26951 and RTOG 9402 were two independent prospective randomised and practice-changing phase III studies. Prof. Martin J. van den Bent of the Department of Neurology, Erasmus MC Cancer Institute in Rotterdam, Netherlands and colleagues reported on 22 June 2022 in the Journal of Clinical Oncology very long-term mature and final survival analyses nearly 30 years after these studies were conceived. Both studies showed that the addition of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy lengthens disease control and survival relative to radiotherapy alone as first-line treatment for anaplastic oligodendroglial tumours, particularly among 1p/19q codeleted cases. With an estimated survival after 20 years in the 35% range, a sizeable proportion of patients with a 1p/19q codeleted oligodendroglioma achieve long-term survival.
Anaplastic oligodendroglial tumours are chemotherapy-sensitive brain tumours. EORTC 26951 and RTOG 9402 studies reported initially that adding PCV to radiotherapy improved progression-free survival (PFS), but not overall survival (OS). However, with longer follow-up, improved OS was also observed, particularly in patients with 1p/19q codeleted tumours.
The importance of 1p/19q codeletion, IDH 1 and 2 mutations, and MGMT in tumour DNA was not established when these studies were launched. However, both studies centrally analyzed available tumour tissue retrospectively. Nearly 30 years since EORTC 26951 and RTOG 9402 were launched, the authors report in the latest article extremely long-term follow-up of fully mature and final survival data from both studies and results in molecular subgroups in line with the current WHO classification of tumours of the central nervous system. The median follow-up duration in both studies was 18-19 years.
For EORTC 26951, median 14-year and probable 20-year OS 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% confidence interval [CI] 0.63 to 0.98; p = 0.033), with 1p/19q 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 = 0.063).
For RTOG 9402, the 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 = 0.08), with 1p/19q 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 = 0.02).
The studies show similar long-term survival even without tumour recurrence in a significant proportion of patients after first-line treatment with PCV added to radiotherapy. The authors commented that long-term survival observed emphasizes also the need to better understand the long-term side effects, such as cognitive function and ability to continue living independently many years after treatment. The risk of late neurocognitive injury from early radiotherapy combined with efficacy of PCV prompted the POLCA investigators to defer radiotherapy altogether for codeleted cases. The results from that study are awaited, however, there is concern that initial treatment with chemotherapy alone may be detrimental for survival.
The authors also commented that ability to conduct and report extremely long-term survival results demonstrates the critical importance of governmentally funded networks in conducting clinical studies, particularly for indolent tumours with long follow-up required for full maturity, that are impossible for a commercial sponsor.
Lassman AB, Hoang-Xuan K, Polley M-YC, et al. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors. JCO; Published online 22 June 2022. DOI: 10.1200/JCO.21.02543