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

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Treatment outcomes from mTMZ. Subjects with anaplastic glioma (black) and glioblastoma (white) and their individual (a) PFS and (b) OS are displayed individually. Six of 9 (67%) subjects had glioblastoma and their (c) PFS was 3.1 (95% CI N/A - 8.3) months and (d) OS was 12.5 (95% CI 8.6–16.3) months
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Fig1: Treatment outcomes from mTMZ. Subjects with anaplastic glioma (black) and glioblastoma (white) and their individual (a) PFS and (b) OS are displayed individually. Six of 9 (67%) subjects had glioblastoma and their (c) PFS was 3.1 (95% CI N/A - 8.3) months and (d) OS was 12.5 (95% CI 8.6–16.3) months

Mentions: The median number of mTMZ cycles received within the study group was 2 (range 0-19+), and the median time from initial diagnosis to first recurrence was 5.8 (range 2.4–128.6) months (Table 1). The number of prior adjuvant TMZ cycles received does not appear to correlate with the number of mTMZ cycles (Spearman correlation = −0.3914, p = 0.3053). The median progression free survival was 8.5 (range 1.5–153.0+) months and the median overall survival was 12.7 (range 7.1–153.0) months (Fig. 1a & 1b ). Because 6 of 9 subjects (67%) had recurrent glioblastoma, and they compromise the largest subgroup in our cohort with similar histological characteristics, we decided to combine their outcomes to estimate the benefit of mTMZ treatment. Their median progression free survival was 3.1 (95% CI N/A-8.3) months and their overall survival was 12.5 (95% CI 8.6–16.3) months (Fig. 1c & 1d).Fig. 1


Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
Treatment outcomes from mTMZ. Subjects with anaplastic glioma (black) and glioblastoma (white) and their individual (a) PFS and (b) OS are displayed individually. Six of 9 (67%) subjects had glioblastoma and their (c) PFS was 3.1 (95% CI N/A - 8.3) months and (d) OS was 12.5 (95% CI 8.6–16.3) months
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5120517&req=5

Fig1: Treatment outcomes from mTMZ. Subjects with anaplastic glioma (black) and glioblastoma (white) and their individual (a) PFS and (b) OS are displayed individually. Six of 9 (67%) subjects had glioblastoma and their (c) PFS was 3.1 (95% CI N/A - 8.3) months and (d) OS was 12.5 (95% CI 8.6–16.3) months
Mentions: The median number of mTMZ cycles received within the study group was 2 (range 0-19+), and the median time from initial diagnosis to first recurrence was 5.8 (range 2.4–128.6) months (Table 1). The number of prior adjuvant TMZ cycles received does not appear to correlate with the number of mTMZ cycles (Spearman correlation = −0.3914, p = 0.3053). The median progression free survival was 8.5 (range 1.5–153.0+) months and the median overall survival was 12.7 (range 7.1–153.0) months (Fig. 1a & 1b ). Because 6 of 9 subjects (67%) had recurrent glioblastoma, and they compromise the largest subgroup in our cohort with similar histological characteristics, we decided to combine their outcomes to estimate the benefit of mTMZ treatment. Their median progression free survival was 3.1 (95% CI N/A-8.3) months and their overall survival was 12.5 (95% CI 8.6–16.3) months (Fig. 1c & 1d).Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus