The path forward for radiation therapy in the management of low-grade gliomas

This is the authors' abstract. We don't add key points for this paper.

See the article by Breen et al in this issue, pp. 830–837. Low-grade gliomas (World Health Organization [WHO] grade II) are a minority of adult gliomas and occur predominantly in young adults. Unlike their higher-grade counterparts, they have a longer disease course that often extends over a decade. Early radiation dose escalation studies in high-grade gliomas demonstrated a dose-response relationship, with improved survival up to 60 Gy but no clear benefit beyond this dose.1 North Central Cancer Treatment Group (NCCTG) 86-72-51 was a landmark phase III randomized controlled trial that evaluated whether escalation of radiation dose in low-grade gliomas can improve outcomes. Patients with low-grade gliomas, histologically defined as either astrocytoma, oligodendroglioma, or oligoastrocytoma, were randomized to the standard arm of 50.4 Gy in 28 fractions versus the high-dose arm of 64.8 Gy in 36 fractions. The initial results of the trial were published in 2002 with a median follow-up of 6.4 years.2 Breen and colleagues now present the long-term results of this study, with a median follow-up of over 17 years, providing a long-term perspective on outcomes following radiation therapy in low-grade glioma patients.3 Similar to the original publication, the long-term results show no benefit to dose escalation to 64.8 Gy versus 50.4 Gy in progression-free survival or overall survival. These are consistent with results of the European Organisation for Research and Treatment of Cancer (EORTC) 22844 trial, which compared 45 Gy versus 59.4 Gy and was reported with a median follow-up of about 6 years.4 Since these trials accrued in the 1980s and 1990s, our understanding of the biology of low-grade glioma and the standard of care has increased significantly. Gliomas are now classified based on molecular features rather than histology alone per the WHO 2016 grading system,5 and oligoastrocytoma is no longer a recognized entity. Furthermore, the standard of care for most low-grade glioma patients is now a combination of radiation therapy and chemotherapy, based on the results of the Radiation Therapy Oncology Group 9802 trial demonstrating a significant survival benefit with the addition of procarbazine, lomustine, and vincristine.6 Similarly, techniques for delivery of radiation therapy have improved dramatically, with CT-based planning and intensity-modulated radiation therapy/volumetric arc therapy the current standard of care, offering unprecedented dose conformality and normal tissue sparing. As noted by Breen and colleagues, these changes over the past three decades mean that we cannot directly apply the results of NCCTG 86-72-51 to modern-day patients.3 Nevertheless, these long-term results carry important lessons for us in current efforts to improve the standard of care for low-grade gliomas. First, the lack of benefit with radiation dose escalation, now demonstrated across 2 randomized trials, suggests that any further efforts to escalate radiation dose should be investigated in biologically meaningful subsets of patients. Molecular studies have demonstrated the genetic and biologic heterogeneity of low-grade glioma, with consequent differences in clinical outcome. It may be that certain subsets of patients still benefit from dose escalation, though molecular marker information is not available from NCCTG 86-72-51 to investigate this. The EORTC 22033-26033 was an early step toward using molecular markers, stratifying patients by 1p deletion and demonstrating improved progression-free survival with radiation therapy compared with temozolomide in the isocitrate dehydrogenase (IDH) mutant and 1p/19q retained (molecular astrocytoma) group, but not in IDH wildtype or IDH mutant and 1p/19q codeleted groups.7 Another relevant subset comprises those who are histologically low-grade but IDH wildtype, with a clinical behavior more consistent with high-grade glioma. Perhaps these patients would benefit from higher dose radiation therapy to 60 Gy as is the current standard of care for glioblastoma.1 Other subsets may similarly exist, and future studies must stratify on molecular markers during randomization so hypotheses can be tested in specific subsets of patients rigorously. Second, this study provides valuable data on long-term toxicity and neurocognitive effects over nearly two decades of follow-up. A major concern with radiation therapy for low-grade glioma is treatment-associated toxicity, especially the risk for late adverse events in a disease with a long clinical course. Patients in clinic frequently want to discuss whether upfront radiation therapy is worth the risk of toxicity and neurocognitive decline versus delaying radiation therapy to time of progression. In the initial report, grade 3+ toxicity was observed in about 13% of patients in both arms. However, high-dose radiation was associated with higher rates of severe radiation-associated neurotoxicity, with 2-year incidence rates of 5% versus 2.5%. In the updated report, the rate of adverse events after 5 years was quite low in both arms, with only 2 patients in the low-dose arm and 3 in the high-dose arm experiencing grade 3+ events. Despite this favorable late-toxicity profile, the early neurotoxicity and brain necrosis associated with high-dose radiation raise concern about routine treatment to high doses in absence of a demonstrated clinical benefit. Neurocognitive function similarly was not appreciably impaired on long-term follow-up based on the Mini-Mental Status Exam (MMSE) and the Neurologic Function Score (NFS). This provides reassurance that partial brain radiation therapy, even at higher doses, is unlikely to have a high risk of severe long-term adverse effects. However, we can only draw limited conclusions here, because the MMSE and NFS have poor sensitivity to detect domain-specific deficiencies,8 assessment completion rate was low (<50% after 5 y), and quality of life (QoL) assessment was not included. These limitations highlight the critical importance of including sensitive and thorough prospective assessment of neurocognitive function and QoL in clinical trials in this population. Finally, this study suggests that the answer to long-term disease control in low-grade glioma patients lies in a combination of all therapeutic modalities, starting with maximum safe resection and proceeding with the optimal combination of radiation therapy with chemotherapy and/or targeted therapy. When treated with radiation alone, low-grade glioma patients will continue to progress and die from this disease, with rates of over 80% for both endpoints in the span of report of this trial. Radiation therapy alone is insufficient for long-term control in most patients with low-grade glioma, highlighting the need for further investigation of multimodality therapy, molecular markers, and detailed, prospective evaluation of long-term toxicity and QoL outcomes. None. This text is the sole product of the authors and no third party had input or gave support to its writing. No conflicts declared.