Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas

BMC Cancer. 2016 Nov 22;16(1):914. doi: 10.1186/s12885-016-2945-2.


Background: 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.

Keywords: Arterial spin labeling; Interleukin; Matrix metalloproteinase; Metronomic temozolomide; Recurrent glioma.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Administration, Metronomic
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Alkylating / administration & dosage*
  • Antineoplastic Agents, Alkylating / adverse effects
  • Biomarkers
  • Dacarbazine / administration & dosage
  • Dacarbazine / adverse effects
  • Dacarbazine / analogs & derivatives*
  • Female
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / mortality
  • Glioma / pathology*
  • Humans
  • Male
  • Matrix Metalloproteinase 2 / cerebrospinal fluid
  • Matrix Metalloproteinase 9 / cerebrospinal fluid
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Neovascularization, Pathologic
  • Survival Analysis
  • Temozolomide
  • Treatment Outcome


  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • Dacarbazine
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Temozolomide