The main purpose of this study is to investigate the efficacy of bevacizumab, etoposide and cisplatin in treating breast cancer patients with central nervous system metastasis (including brain parenchymal and leptomeningeal metastasis).

Brain metastases are increasingly important causes of morbidity and mortality in breast cancer patients. Whole brain radiotherapy (WBRT) and surgery remains the standard treatment for brain metastases. However, the median overall survival after brain and leptomeningeal metastasis were only 8.5 months and 16 weeks respectively There is lack of standard treatment for brain metastasis progression post WBRT. Chemotherapy was considered mostly poor for treatment response because of the blood brain barrier. However, this has been questioned because tumor can disrupt the normal function of blood brain barrier. For example, etoposide and cisplatin had been used for treatment for breast cancer patients with brain metastasis. The overall response rate of central nervous system (CNS) was 39 %, disease control rate was 60%, although the median overall survival was 31 weeks only. The role of targeted therapies is actively being assessed. Recently, a phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer showed that CNS objective response rates were 6% to lapatinib monotherapy and 20% to lapatinib plus capecitabine. Although the result is promising, the treatment population is limited in the HER2 overexpression breast cancer.

Bevacizumab, an anti-angiogenic agent, has been approved to combine with several chemotherapy agents in breast, lung and colon cancer. It was once considered contraindicated in patients with brain metastases due to the possibility of intracranial bleeding. However, two studies involving the use of bevacizumab for treating brain metastatic tumors of non-squamous or peripherally located squamous lung cancer showed no report of brain hemorrhage. In addition, bevacizumab has been approved to treat primary brain aggressive tumors recently.

In the institution, the investigators treated three breast cancer patients with multiple brain metastases using bevacizumab plus etoposide and cisplatin (B-EP). All of them have been treated for at least two lines of chemotherapy before brain metastases occurred. All of them received WBRT for brain metastases and one of them also received craniotomy with brain tumor resection plus local stereotactic radiosurgery. The follow up magnetic resonance imaging (MRI) had revealed recurrent metastatic brain tumors in one patients, and recurrence of leptomeningeal metastasis in another two patients. One patient who has multiple brain parenchyma metastases showed objective response on MRI after two cycle of B-EP treatment, and remained progression free for more than 5 months. The other two patients with leptomeningeal metastasis had intrathecal and intraventricular (via Ommaya reservoir) methotrexate treatment for more than eight doses. They were near stupor before B-EP treatment. Both had best clinical response of full recovery of consciousness and absence of cancer cells in cerebrospinal fluid. One survived eight months after the diagnosis leptomeningeal metastasis, and the other two were still alive six months after the diagnosis of leptomeningeal metastasis .

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been used in various studies for evaluation of anti-angiogenic condition. In breast cancer, DCE-MRI has been used as an early predictive marker for response. Glioblastoma patients have also been evaluated with DCE-MRI to determine reduction of vessel permeability after bevacizumab treatment.

Proton magnetic resonance spectroscopy (1H-MRS) has been used to different benign brain tumors from malignant ones. The utilization of 1H-MRS, especially in human brain tumors, coupled to both routine MRI and functional MRI techniques provides greater information concerning tumor grading and extension and characterization of the normal surrounding tissue than what is possible with any other imaging technique alone. To analyze proton spectroscopy before and after bevacizumab may give us further information about the mechanism of B-EP on CNS metastasis.

Therefore, the investigators propose to conduct a phase II clinical trial to test the efficacy of B-EP regimen in breast cancer patients with CNS metastasis along with brain DCE-MRI to demonstrate the antiangiogenesis efficacy.

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