The role of topotecan in the treatment of brain metastases.

Despite advances in the treatment of systemic malignancies, the prognosis for patients with brain metastases continues to be dismal. Because the majority of cytotoxic agents seem to be unable to penetrate the blood-brain barrier, the role of chemotherapy in the treatment of brain metastases remains controversial. However, growing amounts of both laboratory and clinical data suggest that a few of the newly developed cytotoxic agents can cross the blood-brain barrier and may have a role in the treatment of patients with brain metastases. Topotecan, a novel topoisomerase I inhibitor, freely crosses the blood-brain barrier and may be clinically effective in both the therapeutic and prophylactic settings in patients with brain metastases. Recent studies have demonstrated the antitumor activity of topotecan against brain metastases, with objective response rates ranging from 33%-63% in patients with various solid tumors. The antitumor response in the central nervous system was often greater and occurred more quickly than the systemic antitumor response to topotecan treatment. This result may be explained by the lack of exposure of brain metastases to previous cytotoxic agents, suggesting a role for topotecan in patients with brain metastases. Early studies have also suggested that topotecan, an apparent radiosensitizer, may be particularly effective in combination with radiotherapy, the current standard of care for patients with brain metastases. In addition, preliminary data suggest that topotecan in combination with temozolomide (another cytotoxic agent that can cross the blood-brain barrier) may have synergistic antitumor activity against brain metastases. This review summarizes the available preclinical and clinical evidence for the role of topotecan in the treatment of brain metastases and concludes with three case studies.