Bevacizumab, Etoposide and Cisplatin Followed by Whole Brain Radiotherapy in Breast Cancer With Brain Metastases

Inclusion criteria:

* A histological confirmed invasive breast cancer.
* At least one measurable brain metastatic tumor. If the measurable brain lesion has previously received stereotactic radiosurgery, the tumor must be a progressive lesion after radiosurgery.
* Patients who had not received WBRT.
* Patients with HER2/neu overexpression or amplification and had received trastuzumab before the diagnosis of BM will be allowed but will be informed about other available treatment options such as lapatinib plus capecitabine.
* Karnofsky performance score (KPS) higher or equal to 30%.
* Patients must have adequate organ function and marrow reserve measured within 14 days prior to randomization
* Age 20 to 75 years.
* Patient's life expectancy is more than 3 months.
* All women of childbearing potential must have a negative pregnancy test obtained within 72 hours before starting therapy.
* 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 6 months after the completion of therapy.
* Patients (or a surrogate) must be able to comply with study procedures and sign informed consent.

Exclusion criteria:

* Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy.
* Patients who have history of disease progression or disease developed during prior cisplatin treatment.
* Patients who had leptomeningeal metastasis, either diagnosed by brain imaging study or confirmed by cerebrospinal fluid cytology examination.
* Patients who are eligible for and willing to receive brain surgery or stereotactic radiosurgery (SRS) as the initial treatment of BM.
* History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
* History of thrombotic disorders.
* Active gastrointestinal bleeding.
* Patients with a history of self-reported intra-cranial hemorrhage or evidence of bleeding in previous cranial imaging.
* Patients with clinical signs or symptoms of gastrointestinal obstruction and who require parenteral hydration and/or nutrition because of obstruction.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of first dose of bevacizumab.
* Clinically significant peripheral artery occlusive disease.
* Arterial thromboembolic event within the past 6 months, including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction.
* History of gross hemoptysis (e.g., ≥ 1 teaspoon of bright red blood).
* Other malignancy within 5 years except cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix.
* Psychiatric illness or social situation that would preclude study compliance.
* Serious non-healing wound, ulcer, or bone fracture.
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment.
* Prior minor surgery within 7 days.
* Concurrent chronic daily aspirin (\> 325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, non-steroidal anti-inflammatory agents known to inhibit platelet function.
* Concurrent therapeutic anticoagulation, but prophylactic anti-coagulation of venous access devices is allowed.
* History of allergic reaction to compounds of similar chemical composition to the study drugs.
* Pregnancy or lactation.