High-grade glioma before and after treatment with radiation and Avastin: Initial observations

Abstract

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent "normalization" after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers.

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…We developed a mathematical index of vascular normalization (comprising various indirect markers of normalization) and found this to be a strong predictor of individual patient outcomes ). In addition to these findings, studies reporting results of serial GBM biopsy and autopsy specimens before and after anti-VEGF therapy have suggested a pattern of structurally more normal vessels after therapy (Fischer et al 2008;di Tomaso et al 2011).…”

Class 3 semaphorins: physiological vascular normalizing agents for anti‐cancer therapy

“…1). Some Sema3 Androgen ablation ↑ PVC coverage, pruning of immature vessels [189] Glioblastoma (n = 31) Cediranib (AZD2171) ↓ Microvessel density, ↓ permeability a [35,37] Glioblastoma (n = 30) Cediranib ↓ Microvessel density, ↑ perfusion, ↓ permeability b [38] High-grade glioma (n = 5) Bevacizumab ↓ Tortuosity and glomeruloid vessels, thin-walled blood vessels [190] Rectal (n = 32) Bevacizumab ↓ Microvessel density, ↑ PVC coverage, ↓ IFP, improved delivery of FDG per vessel [34] HER2 + breast cancer with brain metastasis (n = 22) Lapatinib ↓ Tortuosity, loss of small abnormal vessels [191] Advanced soft-tissue refractory sarcoma (n = 15) Sorafenib ↓ Microvessel density, ↓ IFP [192] Bevacizumab, humanized anti-VEGF monoclonal antibody; cediranib (AZD2171), oral pan-VEGF receptor tyrosine kinase inhibitor with activity against platelet-derived growth factor receptors and c-Kit; FDG, fluorodeoxyglucose; HER2, human epidermal growth factor receptor 2; IFP, interstitial fluid pressure; lapatinib, tyrosine kinase inhibitor that targets epidermal growth factor receptor (also known as erbB1) and HER2 (also known as erbB2); PVC, perivascular cell; sorafenib, a small molecule Raf kinase and VEGF receptor kinase inhibitor.…”

Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma

“…19 A pathologic study of human gliomas that progressed on bevacizumab showed an increased number of bone marrow derived cells in these tumor specimens. 29 Salvage chemotherapy after tumor progression on bevacizumab provided only transient tumor control; 19 patients treated with a variety of drug regimens had an estimated 6-month PFS rate of 0%. This is similar to a 6-month PFS rate of 2% from a study in which patients with tumor progression continued bevacizumab but changed the concurrent cytotoxic chemotherapy, mostly from irinotecan to carboplatin, 11,12 and data demonstrating that initiating irinotecan after disease progression on bevacizumab monotherapy are ineffective.…”