Table 2. Common Barriers to Including Patients With Brain Metastases (BrM) in Clinical Trials.

Barrier	Example(s)	Potential solution(s)
Natural history of BrM is unpredictable	Complications such as hemorrhage can interfere with the evaluation of drug efficacy	Enroll patients based on a predefined eligibility quotient3
Patients with BrM have variable prognoses	Patients with multiple BrM have a worse prognosis than those with solitary lesions Perception of relative futility of treating patients with BrM due to poor survival Concurrent BrM and leptomeningeal disease may confound patient outcomes	Stratification by the Graded Prognostic Assessment3 or by the number of BrM (eg, 1 vs >1 brain metastasis), but larger sample sizes may be required Include strict baseline MRI protocols to rule out leptomeningeal disease and to assess the burden of parenchymal BrM
Discordant phenotype between primary malignant tumor and BrM	Discordance in the molecular profile of BrM with that of the primary tumor may be problematic for molecularly targeted clinical trials	Investigate molecular underpinnings of BrM through preclinical models and tissue biobanks Develop noninvasive methods to sample and assess BrM (eg, liquid biomarker assays)
Evaluation of treatment response in the CNS is challenging after treatment with radiotherapy	Regression of a BrM may be due to a delayed treatment effect postradiotherapy Progression of a BrM postradiotherapy (particularly SRS) may be attributed to radiation necrosis	Use brain-specific response criteria Develop better techniques to distinguish radiation necrosis vs disease progression
The CNS activity of certain systemic therapies is unknown	High risk of CNS progression if systemic therapies are unlikely to have CNS activity	Incorporate CNS end points into early-phase clinical trials and/or perform CNS substudies to determine intracranial efficacy/penetration Incorporate close monitoring of the CNS radiographically; patients with CNS progression with stability of extracranial disease should be given an opportunity to stay on trial while receiving local therapy to the brain Exclude patients with leptomeningeal disease and those with untreated or unstable parenchymal BrM
Differential effect of systemic therapy on CNS and extracranial disease	It may be difficult to ascertain extracranial benefit of systemic therapy if patients withdraw from the study due to CNS progression	Patients with CNS progression with stability of extracranial disease should be given an opportunity to stay on trial while receiving local therapy to the brain Select appropriate overall and intracranial-specific outcomes Ensure adequate monitoring of CNS disease among patients with BrM at baseline
Logistical barriers associated with neurologic-specific end point assessments	Evaluating neurologic-specific quality of life and neurocognition may be time consuming and costly	Consider self-administered patient-reported outcome assessments

Abbreviations: CNS, central nervous system; MRI, magnetic resonance imaging; SRS, stereotactic radiosurgery.