Randomised Phase II Study of Metronomic Chemotherapy Plus the Same Aromatase Inhibitor Compared to Metronomic Chemotherapy Alone in Women With Hormone Receptor Positive, Her-2 Non-Overexpressing Advanced Breast Cancer Whose Disease Has Progressed While Receiving an Aromatase Inhibitor, Correlating Response With Circulating Endothelial Progenitor Cells, VEGF and VEGFR
- Compare the clinical benefit rate (complete response, partial response or stable
disease for > 24 weeks) in postmenopausal women with metastatic breast cancer treated
with metronomic chemotherapy with vs without aromatase inhibitor therapy.
- Compare the time to progression in these patients
- Compare the overall survival of these patients.
- Compare the safety and toxicity of these regimens in these patients.
- Correlate tumor response with markers of angiogenesis (circulating endothelial
progenitor cells, VEGF, VEGF-C, VEGFR-2, and VEGFR-3).
- Determine the relative contribution of methotrexate and prednisolone to metronomic
chemotherapy as assessed by change in circulating endothelial progenitor cell, VEGF,
and VEGFR levels during serial addition of each drug.
OUTLINE: Patients are stratified according to site of metastases (visceral vs non-visceral
only) and number of lines of prior chemotherapy in the metastatic setting (0 vs 1-2).
Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive aromatase inhibitor (anastrozole, letrozole, or exemestane) as
previously prescribed. Patients also receive oral cyclophosphamide once daily on days
1-28 and oral methotrexate twice on days 15, 16, 22, and 23 of course 1. For all
subsequent courses, patients receive oral cyclophosphamide once daily and oral
prednisolone once daily on days 1-28 and oral methotrexate twice on days 1, 2, 8, 9,
15, 16, 22, and 23. Treatment with cyclophosphamide, methotrexate, and prednisolone
repeats every 28 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I.
Patients undergo blood sample collection at baseline, in weeks 2, 4, 6, and 10, every 4
weeks until disease progression, and then at 4 weeks after disease progression. Blood
samples are assessed for circulating endothelial progenitor cell levels by flow cytometry
and VEGF, VEGF-C, VEGFR-2, and VEGFR-3 levels by ELISA immunoassays.
After completion of study therapy, patients are followed every 3 months.
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
Clinical benefit response rate (complete response, partial response, or stable disease for > 24 weeks)
Wong Nan Soon, MBBS, MRCP, FAMS
National Cancer Centre, Singapore