A Phase II Study of Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis
18 Years
75 Years
Female
Breast Neoplasms, Leptomeningeal Metastasis, Brain Metastases
Trial Information
A Phase II Study of Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or 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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Response rate of central nervous system (CNS) metastasis
Outcome Description:
The response criteria for brain parenchymal metastasis is measured according to the volumetric response criteria with modification. CNS lesion(s) which have a ≧ 50% volumetric reduction of in the absence of progressive neurologic signs and symptoms will be considered as responsive. The response criteria for leptomeningeal metastasis is defined as disappearance of carcinoma cells of three consecutive cytology examination of cerebrospinal fluid (CSF) after chemotherapy. For patients with both brain and leptomeningeal metastases, both criteria need to be met to be considered as responsive.
Outcome Time Frame:
1 year
Safety Issue:
No
Principal Investigator
Yen-Shen Lu, MD, PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Department of Oncology, National Taiwan University Hospital
Authority:
Taiwan: Department of Health
Study ID:
201010077M
NCT ID:
NCT01281696
Start Date:
January 2011
Completion Date:
December 2013
Related Keywords:
- Breast Neoplasms
- Leptomeningeal Metastasis
- Brain Metastases
- Breast cancer
- CNS metastasis
- Brain metastasis
- Leptomeningeal metastasis
- Bevacizumab
- Etoposide
- Cisplatin
- Breast Neoplasms
- Neoplasms
- Neoplasm Metastasis
- Neoplasms, Second Primary
- Brain Neoplasms
- Meningeal Carcinomatosis
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