The MFORTE trial revealed a significantly higher rate of brain-only progression in the lurbinectedin arm (27% vs 10%). This pattern suggests the drug's effective systemic control and lack of CNS penetration combine to unmask the brain as a primary sanctuary site for relapse over time.

Unlike the standard chemotherapy regimen TCHP, the newer drug T-DXd can cross the blood-brain barrier. This is a crucial advantage for high-risk HER2-positive breast cancer patients, as it offers the potential to prevent brain metastases, a common and devastating site of recurrence for this cancer subtype.

As novel therapies like blinatumomab and ponatinib achieve excellent systemic control of B-ALL, central nervous system (CNS) relapse emerges as a primary hurdle. This was noted in this trial and others, highlighting a critical unmet need to develop effective, non-chemotherapeutic strategies for CNS prophylaxis and treatment.

For patients with otherwise well-controlled disease who develop isolated oligoprogression in the brain, evidence suggests a better survival outcome from adding local therapy (like SRS) and continuing the current effective systemic therapy, rather than switching the systemic regimen entirely.

The concept of an impermeable blood-brain barrier is less relevant once brain metastases are established. The barrier becomes highly permeable, or 'leaky,' allowing even large molecules like antibody-drug conjugates (ADCs) to penetrate the CNS. This suggests that any therapy systemically active in the periphery has potential CNS activity.

When treating testicular DLBCL, administering systemic methotrexate for CNS prophylaxis before testicular radiation is crucial. Reversing the order can cause a severe skin reaction known as radiation recall, a critical and potentially dangerous complication.

While blinatumomab-TKI combinations avoid systemic chemotherapy toxicity, they are associated with higher rates of central nervous system (CNS) relapses. This necessitates an increased number of intrathecal chemotherapy doses to prevent CNS disease, a critical nuance for managing this 'simpler' approach.

For TNBC patients with newly discovered, asymptomatic brain metastases, the practical approach is to start systemic therapy immediately while planning for CNS-directed treatment. This contrasts with strict clinical trial protocols that require CNS treatment and stabilization first, which can dangerously delay systemic control of extracranial disease.

For elderly patients (e.g., age 79) with diffuse large B-cell lymphoma, clinicians are avoiding CNS prophylaxis. Retrospective data suggests current methods lack benefit, and the risk of harm from intrathecal or high-dose methotrexate outweighs the unproven advantage, especially given the patient's age and potential frailty.