OBJECTIVES:
Primary
* Determine the safety and toxicity associated with blood-brain barrier disruption comprising transfemoral mannitol followed by methotrexate and carboplatin with or without trastuzumab (Herceptin®) in women with brain metastasis secondary to breast cancer. (Phase I)
* Determine if overall survival exceeds 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-positive or HER2-negative disease treated with this regimen. (Phase II)
Secondary
* Determine the overall survival of these patients.
* Compare the event-free and overall survival, steroid use, response rates, and time to best response in patients with HER2-positive vs HER2-negative disease.
* Assess the quality of life of patients treated with this regimen.
* Assess the neuropsychological effects of this treatment regimen in these patients.
* Determine cerebrospinal fluid levels of trastuzumab before and after blood-brain barrier disruption.
OUTLINE: This is a multicenter, phase I, pilot, dose-finding study of carboplatin followed by a phase II, open-label study.
* Phase I: Patients undergo osmotic blood-brain barrier disruption (BBBD) comprising mannitol by transfemoral catheterization followed by methotrexate intra-arterially (IA) over 10 minutes and carboplatin IA over 10 minutes on days 1 and 2. Patients also receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after each dose of carboplatin; leucovorin calcium IV or orally every 6 hours on days 3-9; and pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) SC beginning on day 4 and continuing until blood counts recover (7-10 days). Patients with HER-2 positive disease receive trastuzumab (Herceptin®) IV over 90 minutes within 48 hours prior to BBBD and then weekly for 3 weeks (between BBBD therapy sessions). Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive decreasing doses of carboplatin and/or methotrexate if the proposed dose is not well tolerated. Dose-limiting toxicity is defined as grade IV hematologic toxicity with delay in subsequent treatment courses for 4 weeks OR grade III/IV nonhematologic toxicity without recovery in 14 days during the course of treatment.
* Phase II: Patients undergo BBBD as in phase I and receive carboplatin and methotrexate at the doses determined in phase I. Patients also receive sodium thiosulfate, leucovorin calcium, and pegfilgrastim or G-CSF as in phase I. Patients with HER2-positive disease also receive trastuzumab as in phase I.
Neuropsychological assessment is performed at baseline, every 6 months during treatment, every 6 months for 1 year, and then annually thereafter. Quality of life is assessed at baseline, every 3 months during treatment, at the completion of study treatment, every 6 months for 1 year, and then annually thereafter.
After completion of study therapy, patients are followed periodically.
PROJECTED ACCRUAL: A total of 78 patients will be accrued for this study.
