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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

ASL-based blood flow is altered by mTMZ. a Spider plot of ASL blood flow in individual subjects. b Subject 5 had an initial increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, as a result of a new focus of tumor in the ipsilateral brain (arrowhead). c Subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks
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Fig2: ASL-based blood flow is altered by mTMZ. a Spider plot of ASL blood flow in individual subjects. b Subject 5 had an initial increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, as a result of a new focus of tumor in the ipsilateral brain (arrowhead). c Subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks

Mentions: Two types of correlative analysis were performed to help elucidate the antiangiogenesis and antitumor effects of mTMZ. The first type consisted of arterial spin labeling blood flow studies obtained serially in subjects at 6-week intervals during anatomic MRI scanning. It is noteworthy that there was marked variability in blood flow over time in our cohort during treatment (Fig. 2a), with two subjects initially experiencing a slight increase before a decrease was observed while two others had a gradual but consistent decline in blood flow. In particular, subject 5 had an increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, due to a new focus of tumor focus in the ipsilateral brain (Fig. 2b). Furthermore, subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks (Fig. 2c). These fluctuations in blood flow could be a result of alterations in the vascular physiology of the tumor, mTMZ treatment-induced changes in blood flow, or a combination of both.Fig. 2


Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas
ASL-based blood flow is altered by mTMZ. a Spider plot of ASL blood flow in individual subjects. b Subject 5 had an initial increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, as a result of a new focus of tumor in the ipsilateral brain (arrowhead). c Subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: ASL-based blood flow is altered by mTMZ. a Spider plot of ASL blood flow in individual subjects. b Subject 5 had an initial increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, as a result of a new focus of tumor in the ipsilateral brain (arrowhead). c Subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks
Mentions: Two types of correlative analysis were performed to help elucidate the antiangiogenesis and antitumor effects of mTMZ. The first type consisted of arterial spin labeling blood flow studies obtained serially in subjects at 6-week intervals during anatomic MRI scanning. It is noteworthy that there was marked variability in blood flow over time in our cohort during treatment (Fig. 2a), with two subjects initially experiencing a slight increase before a decrease was observed while two others had a gradual but consistent decline in blood flow. In particular, subject 5 had an increase in the normalized blood flow ratio from 0.70 at baseline to 0.92 at 6 weeks, followed by a decrease to 0.51 at 12 weeks and subsequently two successive increases to 0.72 and 1.53 at 18 and 24 weeks, respectively, due to a new focus of tumor focus in the ipsilateral brain (Fig. 2b). Furthermore, subject 9 had a gradual and sustained decrease of more than 50% in the blood flow ratio over time, from 0.91 at baseline to 0.39 at 54 weeks (Fig. 2c). These fluctuations in blood flow could be a result of alterations in the vascular physiology of the tumor, mTMZ treatment-induced changes in blood flow, or a combination of both.Fig. 2

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