Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis
Condition: Breast Neoplasms; Leptomeningeal Metastasis; Brain Metastases
MeSH terms: Breast Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms; Meningeal Carcinomatosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Bevacizumab, etoposide, cisplatin; Intrathecal methotrexate
Intervention type(s): Drug; Drug
Intervention description(s): Bevacizumab (15mg/kg) on D1, etoposide (70mg/m2) on D2-D4, cisplatin (70mg/m2) on D2; 21 days a cycle, for a maximum of 6 cycles; Additional intrathecal methotrexate only given in patients with leptomeningeal metastasis
Other intervention name(s): Bevacizumab (Avastin); Methotrexate
Intervention MeSH terms: Bevacizumab; Methotrexate; Etoposide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Breast cancer; CNS metastasis; Brain metastasis; Leptomeningeal metastasis; Bevacizumab; Etoposide; Cisplatin