Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study

Abstract

Purpose: A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).

Patients and methods: Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ.

Results: Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure.

Conclusion: BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.

Fig 1.

(A) Western blot analysis showing decrease in phosphorylated vascular endothelial growth factor receptor 2 (pVEGFR2) 14 days after first dose of bevacizumab (BVZ) in one patient in stratum A (upper panel, lane 2) and two patients in stratum B (lower panels, lane 2). pVEGFR2 appears stable to increased after the second dose of BVZ in the same patient in stratum A (upper panel, lane 3) and decreased in two patients in stratum B (lower panels, lane 3). (B) Percentage change in pVEGFR-2 relative to baseline (T0) 14 days after first dose of BVZ (T1) and 48 hours after second dose of BVZ (T2). PBMC, peripheral blood mononuclear cells.

Fig 2.

Percent change in (A) diffusion, (B) phosphorylated vascular endothelial growth factor receptor 2 (pVEGFR2), (C) maximum cerebral blood volume (CBV 3D Max), and (D) maximum permeability (K_ps 3D Max) parameters as compared with baseline by stratum during the first four courses of treatment. RPS, receptor phosphorylation status.

Fig A1.

Supratentorial glioblastoma multiforme in an 8-year-old girl (rows 1-4) and brainstem glioma in a 4-year-old girl (rows 5 to 8) at three time points: day 0, day 14, and 2 months later. Row 1: axial fluid attenuated inversion recovery (FLAIR) images demonstrate T2 hyperintensity within the right frontal lobe and right parietal lobe white matter at baseline that appears to decrease over time. Row 2: axial T1 images with gadolinium at baseline demonstrate enhancing foci of tumor in the right frontal lobe and right parietal lobe. There is decrease in enhancement in the right frontal lobe and parietal lobe lesions at day 14. Increased enhancement is noted in the right frontal lesion 2 months later. Row 3: axial T1 permeability maps demonstrate marked increased permeability in the right frontal and mild increased permeability in the right parietal lobe. At day 14, there is decrease in permeability in both lesions. With tumor progression at 2 months, there is increase in permeability within the right frontal lesion. Row 4: Axial apparent diffusion coefficient (ADC) maps demonstrate mild restricted diffusion at day 14 within the tumor which then increased 2 months later. Row 5: axial FLAIR images demonstrate T2 hyperintensity in the pons with predominance on the right. Row 6: axial T1 images with gadolinium demonstrate ring enhancement in the right pons at baseline with central necrosis. There is decreased enhancement and necrosis at day 14 and increased solid enhancement 2 months later. Row 7: axial T1 permeability image demonstrates increased permeability in the medial component of the brainstem glioma at baseline that diminishes by day 14 and then increases at 2 months. Row 8: axial ADC maps demonstrate increased diffusion in the central portion of the tumor with restricted diffusion around the margins at baseline and day 14 scans. There is more restricted diffusion within the tumor at 2 months.