title: Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Oncology Center, UZ Brussel, Brussels, Belgium. Bart.Neyns@uzbrussel.be
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Alicia
authors.initials: A
authors.lastname: Tosoni
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D019496:Cancer Vaccines / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008231:Lymphopenia / Q000139:chemically induced; D008545:Melanoma / Q000188:drug therapy*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D007155:Immunologic Factors; D003606:Dacarbazine; D000077204:Temozolomide