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SAN ANTONIO -- Avoiding the hippocampus during whole-brain radiotherapy (WBRT) preserved cognitive function in cancer patients with brain metastases, a phase III trial found.

Among over 500 patients treated with WBRT plus memantine (Namenda), 59.5% of those in the hippocampal-avoidance group had cognitive function failure at 6 months compared with 68.2% of those in the control group (HR 0.76, P=0.03), reported Vinai Gondi, MD, of Northwestern Medicine Cancer Center Warrenville in Illinois.

"For brain metastasis patients eligible to receive whole-brain radiotherapy and whose survival is expected to be 4 months or longer, hippocampal avoidance using intensity-modulated radiotherapy should be considered standard of care," said Gondi during a late-breaking session here at the American Society for Radiation Oncology (ASTRO) meeting.

Intracranial progression-free survival (PFS) was similar between the two arms (HR 1.14, 95% CI 0.93-1.41, P=0.208), as was overall survival (HR 1.13, 95% CI 0.90-1.41, P=0.306).

In multivariate analyses, no differences were seen when examining patients by recursive partitioning analysis (RPA) class I or II, or receipt of prior radiosurgery; only treatment arm (HR 0.74, 95% CI 0.58-0.95, P=0.0198) and age were significant predictors of reduced cognitive function decline (≤61 vs >61, HR 0.60, 95% CI 0.46-0.79, P=0.0002).

In the hippocampal-sparing group, both age groups derived benefit: age ≤61 (HR 0.78) and age >61 (HR 0.69)

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

He explained that the combined benefit of memantine plus hippocampal avoidance was a 42% relative risk reduction of cognitive impairment for cancer patients with brain involvement compared with WBRT alone.

"These data build upon decades of preclinical and clinical research in supporting the conclusion that the hippocampus is a cognition-specific organ at risk from all forms of brain radiation," said Gondi.

Session discussant Christina Irene Tsien, MD, of Washington University in St. Louis, noted that cognitive impairment is observed in more than 50% of patients who receive radiation to the brain, and 20% of cancer patients overall. And that the approach used in this study appears to be cost-effective only in patients with longer prognoses (≥12 months), according to estimates from 2014 Medicare costs:

• WBRT alone: $6,513
• WBRT with hippocampal avoidance: $9,905
• Radiosurgery: $9,183
• Follow-up MRI: $646

She noted that cognitive function was continually tested in the trial, with the curves between the two groups separating around 3 months, suggesting that the approach might not be appropriate for those with a few months to live.

"Despite the patient selection, a third of the patients died before 4 months or earlier," said Tsien. "Perhaps those patients may not benefit from hippocampal-sparing RT."

"You have to be alive to benefit from preventing cognitive decline," she added.

Tsien also noted that the use of radiosurgery with checkpoint inhibitors or newer targeted therapies with improved central nervous system activity such as osimertinib (Tagrisso), tucatinib, and alectinib (Alecensa) could potentially eliminate the need for WBRT while improving outcomes overall.

In her conclusion, she congratulated the investigators and said that while there are multiple options now for patients with brain metastases -- best supportive care, radiosurgery, WBRT, systemic therapy -- that require a nuanced discussion on the balance of toxicity and outcomes, for "patients that require [WBRT], hippocampal-sparing should be standard of care."

The phase III NRG-CC001 trial randomized 518 patients to memantine plus WBRT ≥30 Gy without (n=257) or with (n=261) hippocampal avoidance. A series of cognitive tests were conducted -- Hopkins Verbal Learning Test-Revised, Trail Making Tests A and B, and the Controlled Oral Word Association Test -- with changes in the reliable score index of these defined as decline.

No significant differences in adverse events were observed between the two groups: 58.7% in the hippocampal-avoidance group had any grade ≥3 adverse event compared with 61.7% in the control group (P=0.53). And treatment-related toxicity was similar as well: 19.4% compared with 20.3%, respectively (P=0.83).

The groups were balanced by age (median 61-62), race (78.5%-80.2% white), education level, Karnofsky performance status (KPS), and primary tumor types (lung cancer 17.5%-19.5%, breast cancer 58.8%-59.8%), neurologic symptoms at baseline, RPA class, receipt of prior surgery or radiosurgery, and proportion with brain-only metastases. Eligibility includes those with excellent performance status (KPS ≥70) and brain metastases that were at least 5 mm outside the hippocampus.

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