High grade primary CNS gliomas hold some of the worst prognoses of any
malignancy, with the vast majority of patients dying within two years of diagnosis, even
with aggressive modern treatments. Surgical resection and radiotherapy are
cornerstones of treatment when possible. In spite of many years of research, only
recently has management with chemotherapy been able to prolong survival in patients
with high grade gliomas, albeit only modestly at best. Topoisomerase I (TOP1)
inhibitors target an enzyme critical for DNA replication and cell-cycle progression; they
cross the blood-brain barrier and have antitumor activity against glioblastoma cells in
vitro. The most frequently associated toxicities are neutropenia and diarrhea, but are
often manageable. The two most used agents are irinotecan and topotecan. Due to
enhanced cytochrome CY3A4/5 enzyme activity, irinotecan dose must be adjusted with
concomitant enzyme-inducing antiepileptic drug usage; the data is less clear regarding
the effects on topotecan. Clinical trials in patients with recurrent malignant glioma have
evaluated TOP1 inhibitors as monotherapy and in combination with other agents. There
is evidence for using topotecan with radiotherapy. Irinotecan has limited efficacy as
monotherapy, but shows promise in combination with other agents, particularly
temozolomide and bevacizumab. Newer generation TOP1 inhibitors are currently being
evaluated in phase I trials. TOP1 inhibitors show promising activity in patients with
primary CNS malignancies and warrant further study.
Keywords: Bevacizumab, glioblastoma, irinotecan, malignant glioma,
topoisomerase, topotecan topoisomerase, CNS, brain tumor.
