Cognitive outcomes in patients with low-grade glioma

For decades, radiotherapy has played a key role in the clinical management of patients with low-grade glioma (LGG). While there are numerous key clinical trials defining the standard of care in LGG, two pivotal examples which explore the impact of radiotherapy in this disease include EORTC 22845 and RTOG 9802.^1,2 While these trials were critical in defining when to use radiotherapy, they utilized relatively coarse assessments of cognitive function following therapy, limiting their ability to draw conclusions on the impact of these therapies on cognitive processing.

As our understanding of how and when to use radiotherapy has evolved significantly over time, so has our understanding of how radiotherapy impacts the normal brain and the clinical side effects that can result from cranial radiotherapy. Advancements in radiotherapy delivery have improved significantly over the past 20 years and data to guide a radiation oncologist in planning avoidance structures and protecting cognitive function continue to emerge. One such example is the benefit afforded through hippocampal avoidance and memantine in the treatment of patients with brain metastases demonstrated through prospective phase 3 trials.^3,4 Although it remains uncertain to what degree these data can be extrapolated to patients with glioma, it is now common for radiation oncologists to define the hippocampi as structures to avoid in the radiotherapy plan.

In a secondary analysis of EORTC 22044-26033, Klein and colleagues study the impact of brain radiotherapy and temozolomide monotherapy on memory function in patients with LGG.⁵ Briefly, patients with high-risk LGG were randomized to receive either radiotherapy alone or temozolomide chemotherapy alone and the primary results have been published.^6,7 This analysis reports the objective cognitive testing (specifically the visual-verbal learning test [VVLT]) prospectively conducted as part of the trial. Their work demonstrates that both groups showed an improvement over time, although improvement was delayed in patients treated with radiotherapy, and there were no differences in cognitive outcomes between treatment arms at 1 year. This suggests that the impact of cranial radiotherapy on memory function may be less significant than previously thought. As noted, both groups showed some improvement in memory from diagnosis and therapy over the study period.

While these data are helpful in guiding clinical decision-making and counseling patients, as the authors state, 12-month follow-up may be insufficient to identify the late effects of radiation on several cognitive processes. Interestingly there was no correlation found between the volume of irradiated tissue and memory function in this study. Unfortunately, advanced analysis of radiotherapy to certain brain sub-structures, including the hippocampus, was not performed in this study but will be an interesting area of future research.

Indeed, moving forward there are many exciting areas in development to reduce cognitive disturbance in patients receiving cranial radiotherapy. Currently, NRG-BN005 (NCT03180502) is actively enrolling patients with WHO grade II-III (IDH mutant) gliomas and randomizing them to receive intensity-modulated radiation therapy (IMRT) or proton beam radiotherapy (PBT) with a primary objective to determine the impact of these radiation techniques on cognitive outcomes over time as measured by a battery of cognitive tests.⁸ Advanced dosimetric analysis will allow for remarkable analysis to improve future practice.

As Klein et al. allude, however, it is clear that cognitive function is dependent on more than just the hippocampus, and future areas of research will work to detail the relationship between advanced cortical and subcortical neuroanatomy and its respective radiation dose tolerance.^9,10 Furthermore, as we continue to improve our understanding of the biology underlying radiation injury to the brain, we hope for improved pharmaceuticals that can serve as radioprotectants for normal brain while simultaneously not inhibiting the efficacy of radiotherapy.

The authors are to be congratulated for this important contribution to our understanding of treatment and its effects on cognitive outcomes. While this secondary analysis of EORTC 22044-26033 is reassuring, further refinement of treatments, including radiotherapy, are needed to ensure better outcomes, including tumor control and cognitive function.

Conflict of interest statement. D.M.T. reports research support from Blue Earth Diagnostics, Novocure, and the Eveleigh Family Foundation. P.D.B. reports personal fees from UpToDate, outside the submitted work.