Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis

Inclusion Criteria:

1. A histological confirmed invasive breast cancer
2. Patient with at least one measurable brain metastatic tumor (≧10mm on T1-weighted gadolinium enhanced MRI or contrast-enhanced CT) or leptomeningeal metastasis with positive CSF cytology study.
3. Patient whose brain parenchymal metastatic tumors either progress after WBRT, develop new lesions after WBRT, or CNS metastatic tumor do not response to WBRT according to image study 3 months after treatment. Patients with leptomeningeal metastasis does not necessarily need whole brain radiotherapy before enrollment.
4. Patients with Her2/neu overexpression or amplification will be allowed but will be informed about other available treatment options such as lapatinib plus capecitabine.

5. Patients must have adequate organ and marrow reserve measured within 14 days prior to randomization as defined below:

   • Absolute neutrophil count ≧1,000/mcL
   • Platelets ≧75,000/mcL
   • Total bilirubin ≦ 1.5 X upper normal limit
   • AST(SGOT)/ALT(SGPT) ≦ 2.5 X upper normal limit; for patients with liver metastases AST(SGOT)/ALT(SGPT) ≦ 5 X is allowed
   • Serum creatinine ≦ upper normal limit or creatinine clearance ≧50ml/min
   • Hemoglobin≧8.0 gm/dL
   • PTT ≦ upper normal limit; INR ≦ 1.5
   • Proteinuria ≤ 1+, if > 1+, urine protein must be ≦ 1 g/24 hours
6. Patient age 18 to 75 years
7. Patient's life expectancy is more than 2 months
8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, 2 or 3
9. All women of childbearing potential must have a negative pregnancy test obtained within 72 hours before starting therapy
10. Patients with reproductive potential must use effective contraception (hormone or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 2 months after the completion of therapy
11. Patients (or a surrogate) must be able to comply with study procedures and sign informed consent

Exclusion criteria:

1. Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy
2. Patients whose CNS metastasis progressed or developed during prior cisplatin treatment
3. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
4. History of thrombotic disorders
5. Active gastrointestinal bleeding
6. Patients with a history of self-reported intra-cranial hemorrhage
7. Patients with clinical signs or symptoms of gastrointestinal obstruction and who require parenteral hydration and/or nutrition because of obstruction
8. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of first dose of bevacizumab
9. Clinically significant peripheral artery disease
10. Arterial thromboembolic event within the past 6 months, including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction
11. History of gross hemoptysis (i.e. ≥ 1 teaspoon of bright red blood)
12. Other malignancy within 5 years except cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
13. Psychiatric illness or social situation that would preclude study compliance
14. Serious non-healing wound, ulcer, or bone fracture
15. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment
16. Prior minor surgery or needle biopsies within 7 days
17. Concurrent chronic daily aspirin (> 325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, non-steroidal anti-inflammatory agents known to inhibit platelet function
18. Concurrent therapeutic anticoagulation, but prophylactic anti-coagulation of venous access devices is allowed
19. History of allergic reaction to compounds of similar chemical composition to the study drugs
20. Pregnancy or lactation