A Phase 2 Trial of Capecitabine Concomitantly With Whole Brain Radiotherapy(WBRT) Followed by Capecitabine and Sunitinib for Central Nervous System, (CNS) Metastases in Breast Cancer
Central nervous system (CNS) metastases is the most common type of brain malignancy, and
breast cancer is the second most common type of malignancy to cause CNS metastases. Although
the incidence of CNS metastases is less common than bone or visceral metastases, it is
associated with poorer prognosis and is relatively unresponsive to systemic therapies. The
incidence of CNS metastases in breast cancer has been estimated as 1-16% in clinical series,
with higher rates (18-30%) in autopsy series. Recently a trend towards increasing CNS
relapse has been noted, up to 25-34%. This may be partly explained by the increasing use of
contrast-enhanced magnetic resonance imaging (MRI), heightened awareness by patient or
clinicians, or an alteration in the natural history of breast cancer with improvements in
systemic therapies, resulting in a prolongation of survival. Therefore, with improvements in
treatments, metastases are better controlled, resulting in the CNS becoming a sanctuary for
residual disease. The treatment of CNS metastases in breast cancer remains challenging.
Surgical resection of tumor will prolong survival only in patients with a single lesion and
with well controlled systemic disease. For patients with multiple lesions, whole brain
radiotherapy (WBRT) remains the backbone in the management of CNS metastases. Recently the
use of stereotactic radiosurgery alone or in combination with WBRT has been explored.
Although better local control was achieved with the combination therapy, minimal overall
survival benefit was seen. This may be secondary to the competing risk of death from
systemic (extra-CNS) progression. The use of systemic agents including chemotherapy and
hormonal therapy has been generally disappointing. This is often attributed to the
impermeability of the blood-brain and blood-tumor barriers. Furthermore, P-glycoprotein
(Pgp), a drug efflux pump encoded by the multidrug resistance gene, mdR1, is expressed in
brain endothelial cells. Therefore, agents such as doxorubicin, cyclophosphamide,
5-fluorouracil, paclitaxel, docetaxel and vinorelbine, which are active against breast
cancer, may either penetrate CNS poorly, or be transported out of the CNS environment.
However, the blood brain barrier may be more leaky and permeable than previously thought in
patients with CNS metastases, and these agents may achieve therapeutic concentrations in the
CNS. As evidence for this, patients without prior exposure to agents such as
cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and doxorubicin, can have
significant objective responses in the CNS metastases. Today, most patients would have
received these agents in the adjuvant setting, thus emphasizing the importance of both
chemo-sensitivity together with CNS penetration, in the treatment of CNS metastases.
This is a single arm, open label, phase II drug study. This study will be conducted at the
Breast Care Center at Baylor College of Medicine and its affiliated hospital, and at Ben
Taub General Hospital in Houston. Patients who were diagnosed with CNS metastases (brain +/-
leptomeningeal disease) will be identified prospectively. All eligible patients will receive
capecitabine concurrently with WBRT followed by combination capecitabine with sunitinib.
WBRT will be administered at 30 Gy in 10 fractions together with capecitabine to be given on
the first day of WBRT at 1000 mg/m2/day and continued daily for 14 days. After a 7 days rest
period, capecitabine will be restarted at 2000mg/m2/day for 14 days followed by a 7 days
rest period. This will be given together with sunitinib at 37.5 mg daily. This is the dosing
determined by the phase I study with capecitabine and sunitinib. Dose reduction and/or
treatment postponement will be done for significant toxicity. Capecitabine with sunitinib
will be administered until disease progression in either CNS and/or non-CNS sites. Efficacy
assessments will be performed on all subjects via imaging studies in the CNS and extra-CNS
sites 8 weeks after starting study, then every 12 weekly. Neurological examination will be
performed at baseline, 3 weeks after starting treatment, then every 6 weekly. Assessment of
treatment toxicity will be performed at baseline, 3 weeks after starting treatment, then
every 3 weekly using the NCI Common Toxicity grading system. Clinical and laboratory
parameters will be assessed until disease progression or withdrawal from study (due to
unacceptable toxicity or withdrawal of consent). Subjects with progression of CNS and / or
extra-CNS disease will be considered progressors. Subjects withdrawn from treatment will be
followed for survival until death.
Primary endpoint: 1. To determine progression free survival. Progression will be defined by
progression in either CNS or extra-CNS metastases. Secondary endpoint: 1. To assess the
toxicities associated with the regimen 2. To determine the overall objective response in CNS
disease 3. To determine the overall objective response in extra-CNS disease 4. To determine
the overall survival.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression free survival form initiation of WBRT with capecitabine to the time of first documented progression at any site (CNS or non-CNS site) or death due to any cause.
Mothaffar` Rimawi, MD
Baylor College of Medicine, Breast Center
United States: Food and Drug Administration
|Lester and Sue Smith Breast Center at Baylor College of Medicine||Houston, Texas 77030|