J Korean Neurosurg Soc.  2015 Nov;58(5):426-431. 10.3340/jkns.2015.58.5.426.

Continuous Low-Dose Temozolomide Chemotherapy and Microvessel Density in Recurrent Glioblastoma

• Woo JY
• Yang SH
• Lee YS
• Lee SY
• Kim J
• Hong YK

• KMID: 2191407
• DOI: http://doi.org/10.3340/jkns.2015.58.5.426

Abstract

OBJECTIVE
The purpose of this study was to evaluate the clinical efficacy of continuous low-dose temozolomide (TMZ) chemotherapy for recurrent and TMZ-refractory glioblastoma multiforme (GBM) and to study the relationship between its efficacy and microvessel density within the tumor.
METHODS
Thirty patients who had recurrent GBM following Stupp's regimen received TMZ daily at 50 mg/m2/day until tumor progression between 2007 and 2013. The median duration of continuous low-dose TMZ administration was 8 weeks (range, 2-64).
RESULTS
The median progression-free survival (PFS) of continuous low-dose TMZ therapy was 2 months (range, 0.5-16). At 6 months, PFS was 20%. The median overall survival (OS) from the start of this therapy to death was 6 months (95% CI : 5.1-6.9). Microvessel density of recurrent tumor tissues obtained by reoperation of 17 patients was 22.7+/-24.1/mm2 (mean+/-standard deviation), and this was lower than that of the initial tumor (61.4+/-32.7/mm2) (p-value=0.001). It suggests that standard TMZ-chemoradiotherapy reduces the microvessel density within GBM and that recurrences develop in tumor cells with low metabolic burden. The efficacy of continuous low-dose TMZ could not be expected in recurrent GBM cells in poor angiogenic environments.
CONCLUSION
The efficacy of continuous low-dose TMZ chemotherapy is marginal. This study suggests the need to develop further treatment strategies for recurrent and TMZ-refractory GBM.

Keyword

Glioblastoma; Temozolomide; Metronomic chemotherapy; Microvessel density

MeSH Terms

Disease-Free Survival
Drug Therapy*
Glioblastoma*
Humans
Microvessels*
Recurrence
Reoperation

Figure

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  Fig. 1 Glioblastoma with necrosis and hyaline thickening of vascular walls associated with radiation (A) hematoxylin & eosin (H&E) (×100). Area of radiation necrosis (B) (×200) with infiltration of viable tumor cells (arrow) (C) having Ki-67 positivity (D) (×400).

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  Fig. 2 Kaplan-Meier curves showing progression-free survival (PFS) (A) and overall survival (OS) (B).

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  Fig. 3 Vessels stained with cluster determinant 34 and a light counterstain of hematoxylin. Magnification : ×200. Area of low (A) and high (B) microvessel density.

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  Fig. 4 Kaplan-Meier curves of progression-free survival (A) and overall survival (B) according to microvessel density within the recurrent tumors (p-value : 0.144, 0.156, respectively). MVD : microvessel density.

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