Stereotactic Radiosurgery or Hippocampus Avoidance Whole-Brain Radiation Therapy with Memantine in Treating Patients with 5 or more Brain Metastases

Summary

Objectives

PRIMARY OBJECTIVES:
I. To compare the overall survival in patients with five or more brain metastases who receive stereotactic radiosurgery (SRS) compared to patients who receive hippocampal-avoidant whole-brain radiation therapy (HA-WBRT) plus memantine hydrochloride (memantine).
II. To compare the neurocognitive progression-free survival in patients with five or more brain metastases who receive SRS compared to patients who receive HA-WBRT plus memantine.

SECONDARY OBJECTIVES:
I. To compare time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.
II. To evaluate if there is any difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.
III. To evaluate number of salvage procedures following SRS in comparison to HA-WBRT plus memantine.
IV. To evaluate the individual cognitive test results following SRS in comparison to HA-WBRT plus memantine.
V. To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.
VI. To evaluate the time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT plus memantine.
VII. To prospectively validate a predictive nomogram for distant brain failure.
VIII. To compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.
IX. To evaluate patient’s quality of life, as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) + Brain Cancer Module (BN20), European Quality of Life-5-Dimensional (EQ-5D), Eastern Cooperative Oncology Group (ECOG) performance status, for those who receive SRS compared to those who receive HA-WBRT plus memantine.
X. Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.
XI. Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes.
XII. Collect whole-brain dosimetry on all patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis (hippocampal dosimetry will be retrospectively assessed).
XIII. Collect imaging parameters and workflow details relating to the radiosurgery planning MRIs (including timing of MR prior to radiosurgery, magnet field strength, contrast type/dose/timing, use of image post-processing, and formal reviewed by radiology) to be prospectively correlated with tumor control outcomes (local control, intracranial control).
XIV. Evaluate serial changes in imaging features found in routine magnetic resonance imaging (MRI) images (T2w changes, morphometry) that may predict tumor control and/or neurocognitive outcomes

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo 10 fractions of HA-WBRT daily for up to 3 weeks.

ARM II: Patients undergo 1 fraction of SRS.

After completion of study treatment, patients are followed up at 8 weeks, 4, 6, 9, 12, 16, and 24 months, then annually afterwards.