• Safety and toxicity [ Designated as safety issue: Yes ]
  
• Overall survival exceeding 5 months in patients with HER2-negative disease [ Designated as safety issue: No ]
  
• Overall survival exceeding 5 months in patients with HER2-positive disease [ Designated as safety issue: No ]
  

• Overall survival [ Designated as safety issue: No ]
  
• Progression-free survival [ Designated as safety issue: No ]
  
• Complete response rate [ Designated as safety issue: No ]
  
• Time to best response [ Designated as safety issue: No ]
  
• Quality of life [ Designated as safety issue: No ]
  

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 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.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer metastatic to the central nervous system (as documented by brain biopsy, cytology [analysis from cerebrospinal fluid]) OR radiographic evidence of brain metastasis with a diagnosis of systemic breast cancer
• Patients must have stable or no systemic disease as determined by a CT scan of the chest, abdomen, and pelvis
• HER2-positive or -negative disease by fluorescent in situ hybridization (FISH) or immunohistochemistry
• Patients with HER2-positive disease and signs of intracranial herniation and/or spinal block may first undergo intraarterial chemotherapy off study (with carboplatin, methotrexate, and trastuzumab [Herceptin®] by the same routes used on study) until radiographically shown to be safe to undergo blood brain barrier disruption, at which point they may be enrolled in the study
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Female
• Menopausal status not specified
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 6 weeks
• Hematocrit ≥ 25%
• WBC ≥ 2,500/mm³
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥100,000/mm³
• Creatinine clearance ≥ 50 mL/min (eligible for full-dose methotrexate) (30-49 mL/min allowed for patients receiving reduced-dose methotrexate)
• Bilirubin ≤ 2.0 times upper limit of normal
• LVEF normal by echocardiogram or MUGA
• Adequate pulmonary and cardiac function to tolerate general anesthesia as determined by physical examination and history
• No New York Heart Association class III-IV heart disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known allergy to trastuzumab (HER2-positive patients), carboplatin, methotrexate, or sodium thiosulfate
• No hepatitis B or C positivity

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection (e.g., HIV)
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• Prior surgery or biopsy allowed
• Prior chemotherapy and radiation therapy for metastatic breast cancer allowed
• No radiation or cytotoxic chemotherapy within the past 4 weeks (except trastuzumab or hormone therapy that has been part of the patient's ongoing treatment [e.g., aromatase inhibitors for estrogen receptor positive patients])
• No noncytotoxic regimens (e.g., targeted oral agents) within the past 2 weeks
• No investigational agents within the past 4 weeks
• No other concurrent anticancer agents or therapies