Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy

Abstract

Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC).Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m 2 /day; days 2-4) and cisplatin (70 mg/m 2 ; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria.Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a !80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.

Breast cancer brain metastases: biology and new clinical perspectives

“…In a recent preclinical mouse tumor model mimicking postsurgical adjuvant or metastatic therapy, a VEGF pathway-targeting antibody drug (bevacizumab) with chemotherapy (paclitaxel) resulted in antitumor activity in a metastatic setting [ 72 ]. Based on these data and those already mentioned, preliminary clinical studies are ongoing and have shown some efficacy in the therapeutic role of targeting VEGF in combination with chemotherapy or radiation therapy [ 32 , 73 , 74 ].…”

Advances in drug delivery to high grade gliomas

“…A window period between anti-VEGF antibody bevacizumab and cytotoxic agents may enhance drug delivery to tumor tissue through bevacizumab-induced vascular normalization. In particular, administering bevacizumab 1 day earlier slightly improved the tumortargeting of etoposide and cisplatin in patients with brain metastases of breast cancer (33). The results of this study were yet limited by the lack of a control arm.…”

“…Selective influx of liposomes occurred at 0-8 h after injury, while the barrier closed between 8 and 24 h after injury, consistent with reports on albumin infiltration. In particular, administering bevacizumab 1 day earlier slightly improved the tumortargeting of etoposide and cisplatin in patients with brain metastases of breast cancer (33). The aforementioned strategies for BBB opening may be invasive, not specific and lack precise control over the site and timing of BBB opening, which may limit their clinical translation.…”

Anti-CCR4 Monoclonal Antibody Mogamulizumab Followed by the GDP (Gemcitabine, Dexamethasone and Cisplatin) Regimen in Primary Refractory Angioimmunoblastic T-Cell Lymphoma

“…In patients with mycosis fungoides/Sézary syndrome, removal of immunosuppressive T reg and malignant T cells by mogamulizumab may restore the number and function of natural killer cells [13]. CCR4-expressing neoplastic T cells (fig.…”