Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects

Temozolomide is an oral alkylating agent with established antitumor activity in patients with primary brain tumors and melanoma. The originally approved temozolomide dosing regimen is 150 to 200 mg/m(2) per day (Days 1 to 5 every 28-day cycle [5 of 28 days]). However, extended dosing regimens (eg, 7 of 14 days, 21 of 28 days, 6 of 8 weeks, or continuously daily) allow for administration of a higher cumulative dose per cycle and have been shown to deplete O(6)-methylguanine-DNA methyltransferase, which may enhance cytotoxic activity. This article reviews efficacy and safety data from studies that investigated dose-dense temozolomide regimens in patients with recurrent glioma and advanced metastatic melanoma. The clinical benefits of these dose-dense regimens compared with the standard 5 of 28-day regimen have yet to be established. Although the toxicity profile of dose-dense temozolomide is generally similar to that of the standard 5 of 28-day regimen, it is associated with an increased incidence and severity of lymphocytopenia. The clinical management of temozolomide-associated lymphodepletion and the potential risks and benefits of extended dosing with temozolomide are discussed. Preclinical and clinical evidence suggests that temozolomide-associated lymphodepletion may enhance the host immune response to tumor-associated antigens and/or immunotherapy and may overcome tumor-mediated immunosuppression. Further studies exploring the clinical implications of lymphodepletion are warranted.