e13590 Background: As the treatment of non-central nervous system (CNS) malignancies improves, brain metastases (BM) are occurring more often in patients with controlled primary disease. In a retrospective analysis of 1953 patients with BM, 44.7% had a controlled primary tumor at the time of BM diagnosis. Given that prognosis after BM remains dismal, it is necessary to identify groups who might benefit from improved delivery of initial systemic therapy across the blood brain barrier (BBB). Methods: A retrospective literature review was conducted to estimate the proportion of patients with non-small cell lung cancer (NSCLC), breast cancer, and melanoma treated with chemotherapy in whom BM was the initial site of recurrence. Only studies explicitly reporting CNS metastasis with controlled extra-cranial (EC) disease on chemotherapy or reporting the first site of recurrence after chemotherapy were included. Results: Four studies of advanced NSCLC reported an average of 23% of patients who developed BM as an initial site of recurrence. Breast cancer cases varied by subtype with a range of 4 - 19%. In four papers reporting HER-2 status, an average of 14% of patients treated with traztuzumab had CNS metastasis with controlled EC disease. In three papers assessing patients with metastatic melanoma on chemotherapy, 4 – 25% initially progressed in the CNS. Conclusions: Of the 1024 patients treated with chemotherapy and achieving controlled systemic disease in this retrospective review, first recurrence in the brain was common: 23% in NSCLC, 12% in breast cancer, and 12% in melanoma. While chemotherapy controlled non-CNS disease, concentrations of these drugs were clearly subtherapeutic in the CNS. Preventing BM in patients with NSCLC, breast cancer, and melanoma will require novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in the treatment of the primary tumor. [Table: see text]
As systemic therapies for cancer become increasingly effective, there is generally a rise in the incidence of brain metastases as a site of first recurrence. This occurs because most antineoplastic agents do not reach the brain in therapeutic concentrations. Many approaches have been studied to improve drug distribution to the central nervous system (CNS) such as intra-arterial administration, osmotic blood-brain barrier (BBB) disruption, focused ultrasound, convection-enhanced delivery, development of CNS penetrant pro-drugs, and the use of vasoactive peptides to transiently disrupt the BBB. However, none of these has improved the prevention or treatment of CNS metastases. Regadenoson is an adenosine A2 agonist that is FDA approved for use in cardiac stress tests. In animals, it has been shown to transiently increase BBB permeability allowing high molecular weight dextran and chemotherapy to enter brain in higher concentrations. A clinical study designed to determine if regadenoson will perform similarly in humans has been CTEP approved and will soon be accruing patients through the Adult Brain Tumor Consortium. If the results are encouraging, future studies will focus on administering regadenoson concurrently with systemically administered chemotherapy in an effort to reduce the incidence of CNS metastases and to improve CNS drug delivery in patients with known brain metastases. This presentation will focus on the available pre-clinical and clinical data supporting this approach and the potential advantages and risks associated with transient BBB disruption in this setting.
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