Wong, EricTimmons, JoshuaCallahan, AmyO’Loughlin, LaurenGiarusso, BridgetAlsop, David2016-12-022016Wong, Eric T., Joshua Timmons, Amy Callahan, Lauren O’Loughlin, Bridget Giarusso, and David C. Alsop. 2016. “Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas.” BMC Cancer 16 (1): 914. doi:10.1186/s12885-016-2945-2. http://dx.doi.org/10.1186/s12885-016-2945-2.1471-2407http://nrs.harvard.edu/urn-3:HUL.InstRepos:29625993Background: The treatment goal for recurrent malignant gliomas centers on disease stabilization while minimizing therapy-related side effects. Metronomic dosing of cytotoxic chemotherapy has emerged as a promising option to achieve this objective. Methods: This phase I study was performed using metronomic temozolomide (mTMZ) at 25 or 50 mg/m2/day continuously in 42-day cycles. Correlative studies were incorporated using arterial spin labeling MRI to assess tumor blood flow, analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 activities in the cerebrospinal fluid (CSF) as surrogates for tumor angiogenesis and invasion, as well as determination of CSF soluble interleukin-2 receptor alpha (sIL-2Rα) levels as a marker of immune modulation. Results: Nine subjects were enrolled and toxicity consisted of primarily grade 1 or 2 hematological and gastrointestinal side effects; only one patient had a grade 3 elevated liver enzyme level that was reversible. Tumor blood flow was variable across subjects and time, with two experiencing a transient increase before a decrease to below baseline level while one exhibited a gradual drop in blood flow over time. MMP-2 activity correlated with overall survival but not with progression free survival, while MMP-9 activity did not correlate with either outcome parameters. Baseline CSF sIL-2Rα level was inversely correlated with time from initial diagnosis to first progression, suggesting that subjects with higher sIL-2Rα may have more aggressive disease. But they lived longer when treated with mTMZ, probably due to drug-related changes in T-cell constituency. Conclusions: mTMZ possesses efficacy against recurrent malignant gliomas by altering blood flow, slowing invasion and modulating antitumor immune function.en-USMetronomic temozolomideRecurrent gliomaArterial spin labelingMatrix metalloproteinaseInterleukinJournal Article2016-12-0210.1186/s12885-016-2945-2