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

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2016

Erschienen:

2016

Enthalten in:

Zur Gesamtaufnahme - volume:16

Enthalten in:

BMC cancer - 16(2016), 1 vom: 22. Nov., Seite 914

Sprache:

Englisch

Beteiligte Personen:

Wong, Eric T [VerfasserIn]
Timmons, Joshua [VerfasserIn]
Callahan, Amy [VerfasserIn]
O'Loughlin, Lauren [VerfasserIn]
Giarusso, Bridget [VerfasserIn]
Alsop, David C [VerfasserIn]

Themen:

7GR28W0FJI
Antineoplastic Agents, Alkylating
Arterial spin labeling
Biomarkers
Clinical Trial, Phase I
Dacarbazine
EC 3.4.24.24
EC 3.4.24.35
Interleukin
Journal Article
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Matrix metalloproteinase
Metronomic temozolomide
Recurrent glioma
Temozolomide
YF1K15M17Y

Anmerkungen:

Date Completed 26.09.2017

Date Revised 02.12.2018

published: Electronic

Citation Status MEDLINE

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM266457258