Baseline and Time-Dependent Predictors of Cognitive Decline for Brain Metastasis Patients Treated with Radiotherapy– A Secondary Analysis of the ATHENA Trial

Purpose/Objective(s)

The extent to which radiotherapy contributes to cognitive decline, versus baseline characteristics and subsequent events such as systemic therapy administration, intracranial progression, and systemic progression, is unclear. This secondary analysis of a Phase 2 Randomized Controlled Trial (NCT05503251) aimed to evaluate the impact of baseline and time-dependent clinical and treatment characteristics on cognitive decline.

Materials/Methods

This is a planned secondary analysis of a clinical trial in which patients with brain metastases were randomized 1:1 to either brain radiation alone or brain radiation with neuropsychology evaluation and intervention. Previous endpoint analyses showed no difference in cognitive decline between control and intervention arm. The following baseline characteristics were collected: type of radiation (stereotactic radiosurgery versus IMRT WBRT), Karnofsky Performance Status (KPS), sex, education level, primary tumor histology, age, brain metastases at time of cancer diagnosis, extracranial disease control, extracranial metastases, number of brain metastases, brain tumor volume, previous brain radiation, receipt of any systemic therapy, and receipt of chemotherapy. Receipt of systemic therapy after trial enrollment, intracranial disease status, systemic disease status, and survival were evaluated for at least 12 months after trial enrollment. Cognition was measured by Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association Test, and Trail Making Test A/B. Cognitive decline defined as a decline on at least one assessment using the reliable change index. Analyses were performed using Gray’s test and Fine-Gray regression model.

Results

Between August 2022 and June 2024, 110 patients were enrolled on the ATHENA Trial and eligible for analysis. On univariable analysis (UVA), only KPS >70 vs. ≤ 70 (p = 0.044) was predictive of cognitive preservation. Increased brain tumor volume (p=0.044), intracranial progression (p=0.034), and systemic progression (p = 0.005) were predictive of cognitive decline. On multivariable analysis of the four significant variables on UVA, KPS > 70 retained an association with cognitive preservation (p=0.011) and systemic progression retained an association with cognitive decline (p=0.026).

Conclusion

For brain metastases patients treated with radiotherapy, baseline performance status and systemic progression may be more predictive of cognitive decline than traditional implicating factors such as type of radiation, age, number of brain metastases, or systemic therapy administration. Cognitive intervention strategies for any patient with poor performance status or progressing systemic disease may be warranted. These findings will be further investigated with multi-institutional ATHENA Consortium data.