Abstract
Background/Aim: Oligodendrogliomas are rare malignant brain tumors with median survivals exceeding fifteen years after treatment with chemoradiation therapy. Long lifespans increase risk for adverse treatment effects. We retrospectively reviewed outcomes after early upfront radiation therapy (RT) or RT deferred until disease progression to determine whether toxicity and survivals were different.
Patients and Methods: At our institution, patients with WHO 2 oligodendrogliomas are offered observation until progression and WHO 3 tumors are offered chemotherapy followed by RT. We retrospectively reviewed long term outcomes of 80 consecutive patients with isocitrate dehydrogenase (IDH) mutant and 1p19q codeleted oligodendrogliomas treated between 2005 and 2021. We defined severe toxicity as stroke, dementia, and cerebral radiation necrosis.
Results: After maximal safe resection, 33/80 patients were treated with upfront RT followed by chemotherapy, 30/80 received upfront chemotherapy with radiation deferred until progression, and 17/80 patients received no therapy. Almost half (n=15/33, 45%) treated with early RT suffered radiation necrosis (n=3), stroke (n=2), or disabling dementia (n=9), compared with two patients (n=2/30, 6.7%) suffering radiation necrosis without disability who did not receive radiation until disease progression. There was no difference in progression-free or overall survival, median follow-up after WHO 3 diagnosis or number of deaths between the groups. The group treated with upfront RT had longer post-radiation follow-up duration.
Conclusion: Upfront RT was associated with a substantially higher rate of severe delayed toxicity, including radiation necrosis, stroke, and disabling dementia, without an apparent survival benefit. These findings support deferring RT until disease progression to reduce long-term treatment-related morbidity.
Introduction
Radiation therapy (RT)-induced brain injury arises in three phases: acute (days to weeks later), early-delayed (1-6 months later), and late delayed (>6 months). Acute and early-delayed injuries are usually transient and reversible without intervention (1). Late brain injury arises in up to 80% of pediatric brain tumor survivors three years later (2). They suffer worsening executive function, stroke, dementia, and small vessel ischemic disease, all increasing with time (3). In adults, cranial RT causes cognitive decline and dementia, brain parenchymal radiation necrosis, and strokes years later (4-6). Children and patients suffering from oligodendroglioma have long survivals, increasing the risk for RT toxicity. Deferring multimodal aggressive therapies to delay treatment-induced toxicity without jeopardizing long-term outcome would be of great benefit to patients (7).
Oligodendrogliomas are rare malignant brain tumors with median survivals exceeding ten years. Long survivals increase the risk for late effects of therapy. Treatment strategies that weigh anticipated adverse therapeutic effects against proposed benefits are especially important because of prolonged survival and lack of curative treatments. The brain cancer and its treatments may cause focal neurologic deficits, cognitive dysfunction, injury or death (8, 9). Resection of 90% of radiographically visible disease prolongs survival in IDH-mutant astrocytomas, but not oligodendrogliomas (10). Following resection, patients may remain asymptomatic and progression-free for years even without other treatment.
Cytotoxic chemotherapy with temozolomide or combination-therapy with procarbazine, lomustine (CCNU), and vincristine (PCV) can cause vomiting, constipation, peripheral neuropathy, cytopenias, neutropenic infections, and secondary malignancy (9, 10). RT has immediate, early delayed, and late delayed adverse effects. Immediate and early delayed effects are usually reversible. Late delayed effects are generally progressive. Late toxicity includes accelerated atherosclerosis with stroke, intraparenchymal hemorrhage, radiation-induced cerebral necrosis, and progressive cognitive decline with or without dementia. Neurocognitive decline in glioma patients alive more than six months after RT ranges from 50-90% (11, 12). The risk of serious toxicity increases with larger brain irradiation volumes (12, 13), radiation fields that include the circle of Willis and sensitive brain structures (14-16), and longer survival durations after RT (17-19). To delay potential long-term toxic effects, many patients with WHO grade 2 oligodendrogliomas do not receive immediate RT after their initial diagnosis and are monitored closely instead (20-22).
RT became standard of care for malignant gliomas upon early recognition that it improves seizure control and prolongs progression-free survival (PFS). Clinical trial assessment of treatment efficacy and late delayed toxicities in WHO 3 oligodendrogliomas with IDH mutation and 1p19q codeletion is complicated by long-term follow-up requirements with prolonged survivals. Similarly, large phase III prospective, cooperative group trials conducted in Europe (EORTC 26951) and the USA (RTOG 9402) published study conclusions in 2006 that initially found no benefit of adding chemotherapy to RT. Updated trial reporting in 2013 reversed this conclusion because prolonged follow-up demonstrated increased overall survival (OS) with the addition of PCV chemotherapy to RT (23). Later studies confirmed PCV efficacy with an increased median OS from 7.3 with RT alone to 14.7 years with the combination RT and PCV chemotherapy (24). Lassman et al. published a large multicenter case series review demonstrating a survival benefit to both PCV chemotherapy (dual alkylating regimen) and single agent temozolomide. They observed median OS was not inferior when RT was omitted from upfront regimens (25). Multiple Japanese retrospective studies confirmed deferring RT until progression of disease was not associated with a significant difference in OS (26-28).
Following EORTC 22845, patients with WHO 2 low grade gliomas were offered close post-surgical surveillance, not immediate radiation. Chemoradiation therapy was offered when radiographic progression, clinical deterioration, or pathologic progression to WHO 3 disease occurred (29). WHO 3 brain tumors were uniformly offered radiation and chemotherapy after a detailed discussion of the risks and benefits of these modalities of care. The primary goal was to assess the incidence of disabling radiation-induced neurotoxicity when RT was given first (in the upfront setting) vs. when given later (deferred until progression). The secondary goal of our study was to evaluate whether deferred RT was inferior to upfront RT in progression-free and overall survivals.
Patients and Methods
After institutional review board approval, we performed a retrospective review of oligodendroglioma patients with IDH mutation and 1p19q codeletion treated at our institution between 2005 and 2021. The last day of follow-up was defined as the last visit with a neuroimaging study available for review. The two chemotherapy regimens were temozolomide in 12/30 patients (150-200 mg/m2/day for five consecutive days every four weeks for 6-12 cycles) and 10 patients completed six or more cycles and PCV chemotherapy in 18/30 patients [lomustine (CCNU) 110 mg/m2 on day one, procarbazine 75 mg/m2 days 8 through 15, and vincristine 1.4 mg/m2 (capped at 2.1 mg) on days 8 and 28 in cycles of 6-8 weeks]. At least four and no more than six cycles of PCV were given and seventeen patients (17/18, 94%) completed more than four cycles.
Partial brain RT was delivered with 3D conformal or intensity modulated radiation therapy (IMRT) techniques, employing magnetic resonance (MR) – computed tomography (CT) coregistration for the determination of target volumes. Radiation treatment was delivered with standard fractionation (1.8-2.0 Gy/day) to doses of between 50 and 60 Gy. Severe RT toxicity was defined as (i) cognitive decline with employment disability or requiring assisted living facility, (ii) surgical resection showing mostly radiation necrosis, not neoplasm, on pathology review and (iii) cerebrovascular accident attributed to RT therapy.
PFS was calculated from the date of diagnosis with MR imaging until the first sign of radiological progression, death, or last follow-up. OS was also calculated from the date of diagnosis until the date of death or last follow-up. The Kaplan–Meier analysis was used to evaluate OS and PFS. The log-rank test was used for comparing the survival distributions. RStudio Team (2024). RStudio: Integrated Development for R. RStudio (PBC, Boston, MA, USA) was used for statistical analyses.
Results
Between 2005 and 2021, 80 patients underwent a maximal safe debulking surgery for IDH mutant and 1p19q co-deleted gliomas. All tumors were O6-methylguanine methyltransferase (MGMT) promoter methylated. Median age at diagnosis was 41years (range=21-79 years). Median follow-up after initial resection for these 80 patients was 7.5 years (90 months, range=1-307 months), including 11 patients lost to follow-up. At initial surgical resection, 36 patients had WHO 3 gliomas and 44 had WHO 2 disease. Pathologically-proven progression to WHO 3 disease occurred in 20 patients after a median follow-up of 101 months (range=26-291 months).
Following surgical resection, 33 patients received upfront RT (30 with and 3 without adjuvant chemotherapy), 30 patients received upfront chemotherapy without upfront RT (18 PCV, 22 Temozolomide), and 17 patients received no disease-modifying therapy (14 WHO 2 patients and 3 WHO 3 patients). One patient with WHO 3 disease at diagnosis remains progression-free four years after initial resection. One patient died nine years after a second resection demonstrated WHO 3 disease. The third untreated patient with WHO 3 disease progressed radiographically five years after initial surgery and remains alive. The 14 untreated WHO 2 gliomas remain progression-free with a median follow-up of 57 months (range=1-112) after diagnostic maximal surgical resection (Table I).
Demographic and clinical characteristics of the 80 patients who underwent maximal safe debulking surgery for isocitrate dehydrogenase (IDH) mutant and 1p19q co-deleted gliomas.
Most patients treated with upfront RT had WHO 3 disease (30/33) after a median follow-up of 130 months (10-305). RT was administered alone in three patients, with neoadjuvant PCV in five patients, and with temozolomide concurrently and adjuvantly in the rest (n=25). Serious radiation toxicity, including cognitive decline severe enough to require assisted living (six patients), causing work disability (three patients), parenchymal brain necrosis requiring neurosurgical evacuation (three patients), and cerebrovascular accident in the absence of stroke risk factors (three patients), occurred in almost half (15/33, 45%). Two thirds (20/33; 61%) remained progression free at last follow-up a median of 91 months (range=10-305) after diagnosis. One third (13/33; 29%) experienced progression of disease at a median of 57 months (range=5-204) after initial diagnosis. At progression, five patients received chemotherapy, three died without further therapy, two patients received additional RT, and two patients declined further therapy. There were a total of seven deaths in this cohort.
After a median follow-up of 92 months (range=5-307), most patients treated with upfront chemotherapy without upfront RT had WHO 3 disease (27/30). The duration of follow-up after RT completion was significantly shorter in this cohort; 20 months (range=3-96) vs. 116 months (7 to 229) in those treated with upfront RT (p<0.01). Serious radiation toxicity occurred in two patients (2/30; 6.7%), both of whom suffered cerebral radiation necrosis. One third of patients (11/30; 57%) remained clinically and radiographically progression-free. Among 19/30 (63%) patients who experienced progression of disease, most (14/19, 73.7%) received salvage RT for progression of disease a median of 61 months after initial diagnosis (range=8.6–219 months). There were seven deaths in this cohort.
Between the groups receiving upfront RT and those initially treated with chemotherapy alone without RT, median ages were similar (43 vs. 39), both groups contained three patients with WHO 2 gliomas, and the duration of follow-up after WHO 3 diagnosis was similar, 71 months (range=5-236 months) and 80 months (range=7-118 months), respectively. Seven patients died in each group, with 75% of patients alive at last follow-up with a greater number of never progressors in the upfront RT group (24/33 or 72.7% vs. 16/30 or 53.3%). Twenty WHO 2 patients in our cohort remained progression-free for a median of 5 years (1 to 220 months) after diagnosis, of whom 14 received no treatment after maximal safe resection (Figure 1 and Figure 2).
Progression-free survival. Time from initial surgical resection to progression of disease for the entire cohort (black), among those treated with upfront radiotherapy (yellow), initial therapy with chemotherapy alone (blue), or observation only without tumor-directed therapy (orange). Log rank test, p=0.45.
Overall survival. Time from initial surgical resection to death for the entire cohort (black), among those treated with upfront radiotherapy (yellow), with chemotherapy alone (blue), or observation only without tumor-directed therapy (orange). Log rank test, p=0.9.
Discussion
Upfront RT caused serious neurologic toxicity including death, stroke, and dementia in more patients who received upfront RT than in those who deferred RT until progression. Approximately half of the patients who received upfront RT suffered devastating neurologic toxicity and approximately half of the patients who received chemotherapy without upfront RT eventually required RT. The increased toxicity of upfront RT was associated with a longer duration of post-RT follow-up, consistent with the known increased incidence of severe and often irreversible late delayed adverse RT effects. OS and median follow-up after WHO 3 disease diagnosis was not significantly different between the groups, so the lack of toxicity related to decreased post-RT follow-up duration underscores the benefit of deferring RT until progression. Similarly, while only 14/30 patients in the deferred RT cohort ever received RT, this also supports a benefit to deferring RT, since survival outcomes are equivalent with less treatment in the deferred RT group. As in other publications, we observed twice as many upfront RT patients remained progression-free at seven years after diagnosis compared to those who were treated with chemotherapy alone, but since salvage RT was so effective, inferior PFS is probably not meaningful clinically. Some investigators found prolonged PFS did not predict prolonged OS in oligodendrogliomas (30).
Our small retrospective, single center study has several limitations, including only 80 patients at one institution. No patient treated with delayed RT suffered dementia and OSs were not inferior when RT was omitted from the initial treatment regimen. Because we only include cognitive injury severe enough to require a special care facility or become disabled from employment, we probably did not ascertain all cognitive injuries. Prospective neuropsychological testing with careful cognitive evaluation has detected additional cognitive deficits. Although these are milder deficits, they account for significant morbidity and are expected to increase in severity over time. No intervention can cure this disease, so treatment strategies that maintain a high quality of life over prolonged survivals are important. While the duration of follow-up after WHO 3 diagnosis and treatment initiation was similar between cohorts, the longer duration of post-RT follow-up among the upfront RT treatment patients allowed more time to acquire late RT effects, potentially biasing our results. However, this difference may underscore the importance of later RT, since later treatments in a situation where OSs are the same, means patients will have less time to develop toxicity that occurs later, in a time-dependent fashion. As other investigators have found, early RT provides no OS benefit.
Conclusion
We conclude (i) upfront RT causes more frequent, serious toxicity than delayed RT, (ii) patient discussions regarding increased serious disability risk and absence of survival benefit data may improve shared decision making before RT initiation, and (iii) clinical trials that include prospective neurocognitive testing may detect less severe, but significant treatment toxicities. Such novel treatments are in active development. Importantly, RT techniques have improved and clinical trials investigating Proton Beam RT are ongoing. VORASIDENIB, which became FDA-approved after the recent INDIGO trial, showed IDH inhibition delays chemotherapy and RT initiation (31). Treatments that reduce tumor size allow for smaller RT fields, which may reduce RT toxicity. Lastly, genomic studies may identify therapy-resistant disease or neoplasms expected to show rapid progression of disease. Such aggressive tumors may benefit from early aggressive interventions, including upfront RT (32). Recent retrospective studies have found chemotherapy regimens including dual alkylating agent therapy (procarbazine and lomustine) superior to single agent regimens (Temozolomide) (33). Our results build on prior observations that upfront treatment regimens omitting RT produce noninferior survival outcomes (34), while also quantifying a substantially increased risk of late RT-related toxicity with upfront radiation therapy.
Acknowledgements
Data was presented at the Society for Neuro-Oncology annual conference in Boston, MA in 2021 with invaluable support of Debra D’Angelo and the Weill Cornell Biostatistics Department. Updated Data analysis was facilitated by Dean Foster, PhD.
Footnotes
Authors’ Contributions
Alexis Demopoulos and Johnathan Knisely conceived the study, collected initial data, confirmed data entry accuracy, wrote the first manuscript draft, incorporated edits from other authors, and prepared the final manuscript draft for submission. Michael Schulder and Jian Yi Li revised the manuscript. Julia Gomez collected patient data over time. Reema Demopoulos completed statistical analysis on final data.
Conflicts of Interest
The Authors have no competing nor financial interests in relation to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received January 30, 2026.
- Revision received February 25, 2026.
- Accepted February 27, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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