Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas

Protracted low dose temozolomide (75 mg/m(2)/day on days 1-21 of 28 days) offers potential advantages over standard temozolomide schedules (200 mg/m(2)/day on days 1-5 of 28 days) including greater cumulative drug exposure and depletion of O-6-alkylguanine DNA alkyltransferase levels, theoretically overcoming intrinsic chemoresistance. We retrospectively review our experience in 25 patients with pathologically proven low grade gliomas (LGG) treated with protracted low dose temozolomide to primarily quantify its toxicity and secondarily to assess efficacy. None had previously received radiation. Tumor response was graded based on changes in tumor size, steroid requirements, and clinical exam. About 243 cycles of protracted low dose temozolomide were administered. Three patients (12%) were changed to standard temozolomide dosing due to side effects, including intractable nausea (n = 2) and multiple cytopenias (n = 1). The most frequent toxicities were fatigue (76%), lymphopenia (72% [48% high grade]), constipation (56%), and nausea (52%). High grade toxicities (other than lymphopenia) included secondary malignancy, pruritis, hyponatremia, neutropenia, leukopenia, and cognitive decline (n = 1 for each). Tumor response rate was 52% and and disease control rate was 84%. Six month PFS was 92% and 12 month PFS was 72%. Response rates and PFS were independent of pathological subtype, deletion status, and indication for chemotherapy. Protracted low dose temozolomide has a distinct spectrum of toxicities compared to standard dosing but is well tolerated in most patients and may provide improved response rates compared to standard dosing. The results of larger randomized trials are needed to assess its potential advantages over other management schemes.