title: Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  mTMZ possesses efficacy against recurrent malignant gliomas by altering blood flow, slowing invasion and modulating antitumor immune function.
authors.affiliation: Brain Tumor Center & Neuro-Oncology Unit, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA. ewong@bidmc.harvard.edu.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Brain Tumor Center & Neuro-Oncology Unit, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Timmons
authors.affiliation: MRI Research, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Callahan
authors.affiliation: MRI Research, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: O'Loughlin
authors.affiliation: MRI Research, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Giarusso
authors.affiliation: MRI Research, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Alsop
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000134:cerebrospinal fluid; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D003606:Dacarbazine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077204:Temozolomide
keywords: Arterial spin labeling; Interleukin; Matrix metalloproteinase; Metronomic temozolomide; Recurrent glioma