ANALYSIS OF a phase III trial has confirmed that conformal avoidance of the hippocampal dentate gyrus using intensity-modulated radiotherapy during whole-brain radiotherapy for brain metastases preserves neurocognitive function and improves patient-reported symptom burden while achieving similar intracranial control and survival.¹

According to data reported at the 2018 American Society for Radiation Oncology (ASTRO) and Society of Neuro-Oncology (SNO) Annual Meetings, the addition of hippocampal avoidance to whole-brain radiotherapy with memantine (an NMDA receptor antagonist that has been shown to be neuroprotective in preclinical models and a phase III trial) reduced the risk of cognitive function failure by 26% (P = .033), with no differences in toxicity, intracranial progression-free survival, or overall survival observed. Although age independently predicted for neurocognitive function, the neurocognitive function benefit of hippocampal avoidance did not differ by age, the authors noted.

Vinai Gondi, MD

“For patients with brain metastases eligible to receive whole-brain radiotherapy and whose survival is expected to be 4 months or longer, hippocampal avoidance using intensity-modulated radiation therapy should be considered standard of care,” said Vinai Gondi, MD, Co-Director, Brain and Spine Tumor Center Warrenville and Director of Research and Education at Northwestern Medicine Chicago Proton Center, in Warrenville, Illinois. “These data build upon decades of preclinical and clinical research in supporting the conclusion that the hippocampus is a cognition-specific organ at risk for all forms of brain irradiation.”

Study Background

AS DR. GONDI explained, several prospective randomized trials have observed a decline in cognitive function 4- to 6-months after whole-brain radiotherapy. These results led to decreased utilization of whole-brain irradiation along with a rapid rise in the adoption of stereotactic radiosurgery for patients with brain metastases. According to Dr. Gondi, multiple studies have also demonstrated that cognitive function is associated with the generation of new neurons within the hippocampus, specifically arising from a compartment of mitotically active and “exquisitely radiosensitive” neural stem cells located within the hippocampal dentate gyrus. 

“For patients with brain metastases eligible to receive whole-brain radiotherapy and whose survival is expected to be 4 months or longer, hippocampal avoidance using intensity-modulated radiation therapy should be considered standard of care."

— Vinai Gondi, MD

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Based on these data and preclinical studies showing that cranial irradiation leads to a loss of hippocampal neurogenesis and subsequent suppression of new memory formation, Dr. Gondi and colleagues hypothesized that conformally avoiding the hippocampus during cranial radiation using intensity-modulated radiotherapy may prevent these radiotherapy-related adverse cognitive effects.

Following the phase II NRG/RTOG 0933 trial, which demonstrated memory preservation after hippocampal avoidance, Dr. Gondi and colleagues sought to validate these findings with the phase III NRG-CC001 trial of whole-brain radiotherapy plus memantine, with or with hippocampal avoidance. Patients were randomly assigned to memantine plus whole-brain radiotherapy (30 Gy in 10 fractions) vs memantine plus hippocampal-avoidant whole-brain radiotherapy (30 Gy in 10 fractions). The study’s primary endpoint was time to neurocognitive function failure, defined as a decline in one of the following cognitive tests: Hopkins Verbal Learning Test– Revised, Controlled Oral Word Association, or Trail Making Test.

Prolonged Time to Cognitive Function Failure

AS DR. GONDI reported, 518 patients (median age = 61.5 years) were accrued from July 2016 to March 2018. At baseline, patient characteristics did not differ between treatment arms. Results of the study showed that avoidance of the hippocampal dentate gyrus during whole-brain radiotherapy with memantine prolonged the time to cognitive function failure. Rates of cognitive function failure at 6 months were 59.5% in the hippocampal-avoidant arm and 68.2% in the control arm (P = .03).

“Both the treatment arm and age retained significance following multivariate analysis,” said Dr. Gondi. “The adjusted hazard ratio for hippocampal avoidance was 0.74, meaning a 26% relative reduction in cognitive function failure with hippocampal avoidance.”

The investigators found no interaction between treatment arm and age, with similar hazard ratios for hippocampal avoidance for patients aged 61 and younger vs older than 61. In addition, they reported no differences between treatment arms with respect to treatment-related toxicity, intracranial progression-free survival, or overall survival.

“The evidence from this randomized trial strongly supports the hypothesis that the radiosensitivity of a neuroregenerative neural stem cell niche in the hippocampal dentate gyrus is central to the short-term cognitive effects of brain irradiation.”

— Vinai Gondi, MD

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As reported at the SNO Annual Meeting, the cognitive benefits of hippocampal avoidance were specific to executive function at 4 months and learning and memory at 6 months, and were complemented by improvements in patient-reported symptom burden at 6 months, specifically patient-reported cognition, fatigue, difficulty speaking and problems remembering things. These specific symptom burden improvements are consistent with the hypothesis of hippocampal avoidance and with the palliative intent of brain metastasis management, as explained by Paul D. Brown, MD, Professor, Department of Radiation Oncology of the Mayo Clinic, and co-principal investigator of this trial.

Paul D. Brown, MD

“These results contribute to the evolving debate over whether whole-brain radiotherapy and/or radiosurgery should be used in the management of patients with brain metastases since the prior trials of radiosurgery with or without whole-brain radiotherapy did not include the cognitive-protective strategies of memantine or hippocampal avoidance,” said Dr. Brown.

As Dr. Gondi explained, the addition of memantine to whole-brain radiotherapy in RTOG 0614 led to a 22% relative reduction in the risk of cognitive toxicity (hazard ratio [HR] = 0.78), whereas the addition of hippocampal avoidance to memantine in this trial led to an additional 26% relative reduction in the risk of cognitive toxicity (HR = 0.74). According to Dr. Gondi, these combined relative risk reduction of both measures together is comparable to contemporaneous trials favoring radiosurgery in lieu of whole-brain radiotherapy.

“Finally,” said Dr. Gondi, “the evidence from this randomized trial strongly supports the hypothesis that the radiosensitivity of a neuroregenerative neural stem cell niche in the hippocampal dentate gyrus is central to the cognitive effects of brain irradiation.” ■

DISCLOSURE: The study was supported by grants from NCORP, NRG Oncology, and the National Cancer Institute. Dr. Gondi is the owner of Radiation Oncology Consultants. Dr. Brown reported personal fees from UpToDate and personal fees from Novella Clinical outside the submitted work.

REFERENCE

1. Gondi V, Deshmukh S, Brown PD, et al: Preservation of neurocognitive function with conformal avoidance of the hippocampus during whole-brain radiotherapy for brain metastases: Preliminary results of phase III trial NRG Oncology CC001. 2018 Annual Meeting of ASTRO. Abstract LBA9. Presented October 23, 2018.