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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 metr...

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Autores principales: Wong, Eric T., Timmons, Joshua, Callahan, Amy, O’Loughlin, Lauren, Giarusso, Bridget, Alsop, David C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120517/
https://www.ncbi.nlm.nih.gov/pubmed/27876012
http://dx.doi.org/10.1186/s12885-016-2945-2
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author Wong, Eric T.
Timmons, Joshua
Callahan, Amy
O’Loughlin, Lauren
Giarusso, Bridget
Alsop, David C.
author_facet Wong, Eric T.
Timmons, Joshua
Callahan, Amy
O’Loughlin, Lauren
Giarusso, Bridget
Alsop, David C.
author_sort Wong, Eric T.
collection PubMed
description 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/m(2)/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.
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spelling pubmed-51205172016-11-28 Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas Wong, Eric T. Timmons, Joshua Callahan, Amy O’Loughlin, Lauren Giarusso, Bridget Alsop, David C. BMC Cancer Research Article 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/m(2)/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. BioMed Central 2016-11-22 /pmc/articles/PMC5120517/ /pubmed/27876012 http://dx.doi.org/10.1186/s12885-016-2945-2 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Wong, Eric T.
Timmons, Joshua
Callahan, Amy
O’Loughlin, Lauren
Giarusso, Bridget
Alsop, David C.
Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title_full Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title_fullStr Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title_full_unstemmed Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title_short Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
title_sort phase i study of low-dose metronomic temozolomide for recurrent malignant gliomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120517/
https://www.ncbi.nlm.nih.gov/pubmed/27876012
http://dx.doi.org/10.1186/s12885-016-2945-2
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