Randomized Phase II Study of Induction Bevacizumab, Etoposide and Cisplatin Followed by Whole Brain Radiotherapy (WBRT) Versus WBRT Alone in Breast Cancer With Untreated Brain Metastases

Brain metastasis (BM) occurs in about 20% to 35% of metastatic breast cancer (MBC) patients. In contrast to recent advances in systemic treatment of MBC, there is much room for improvement in treatment of BM. At present, the standard treatment for inoperable/not suitable for radiosurgery BM is whole-brain radiotherapy (WBRT), but with only a median overall survival (OS) of 6 to 12 months and a high brain relapse rate ranging from 30% to 100%.

In MBC, 70% to 80% of patients with BM are presented with more than two brain metastatic tumors and are not candidate for both surgical treatment and stereotactic radiosurgery (SRS). Unlike patients with solitary or oligo-brain metastatic tumors, for whom the addition of local treatments such as surgery or SRS has been shown to improve OS and relapse rate; for patients with multiple brain metastases, WBRT remained the only standard treatment and improvements are desperately awaited.

Brain was once considered as a "sanctuary" area for systemic drugs due to the protection of blood-brain-barrier (BBB). Although some preclinical studies suggest that the BBB could be disrupted during the growth of brain metastatic tumor, the amount of chemotherapy drugs be delivered to brain tissue was still far lower than that could be achieved in serum. Bevacizumab, a vascular endothelial growth factor antibody, has shown the ability to "normalize" the peri-tumoral vessels in preclinical models. The investigators hypothesized that with the addition of bevacizumab, the chemotherapy drugs-etoposide and cisplatin, which were shown also to have some activity for BM-will be delivered more efficiently into the once "sanctuary" brain parenchyma, thus increasing the efficacy of BM treatment.

Recently, the research team have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy by a multi-center phase II study. The basic concept of preconditioning, as referred to starting bevacizumab 1 day before chemotherapy, is that normalization effect takes time to mature. In that study, 35 patients were enrolled. Twenty seven patients (77.2%; 95%CI 59.9-89.6) achieved brain tumor volumetric response, defined as a ≥50% reduction in the volumetric sum of all measurable brain lesions in the absence of increasing steroid use, development of new brain lesion, or progressive neurologic symptoms. With a median follow-up of 11.0 months, the median CNS progression free survival (PFS) was 6.7 months (95% CI 5.1 to 8.3 months), and OS was 9.4 months (95% CI 7.3 to 11.5 months).

At present, lapatinib is the only molecular targeted agent proven effective for MBC patients with BM. The CNS response rate of first-line lapatinib plus capecitabine was 65% in WBRT-naïve, HER2-positive MBC patients with BM. However, the median CNS PFS is still disappointingly short at 5.5 months and the result is limited to MBC patients who are HER2-positive.