Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

Abstract

Background: The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect.

Discussion: GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients.Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function.

Summary: Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM.

Figure 1

MRI scans of recurrent GBM treated with bevacizumab. MRI scans of a typical patient with recurrent GBM, treated with bevacizumab 10 mg/kg every 3 weeks plus daily temozolomide 50 mg/m². Top row T1; middle row T2; bottom row ADC (apparent diffusion coefficient. ADC c is lacking). Column (A) scans pre-treatment, showing cystic and tumour component, large midline shift, and large vasogenic oedema. Column (B) 3 days after start, showing reduced contrast enhancement, and slightly reduced midline shift. Column (C) 21 days after start, showing reduced contrast enhancement but a larger size (no progression based on Macdonald criteria), reduced midline shift, and reduced oedema. Column (D) 88 days after start, showing decreased size of tumour and cystic component, stable reduction of contrast enhancement, normalised midline shift, and slight increase of oedema. Column (E) 188 days under treatment, showing increased tumour size and cystic component, increased midline shift, and increased oedema (also in the other hemisphere).

Figure 2

Recurrent GBM: resection and autopsy material, post bevacizumab. (A, B) Recurrent GBM resection material, obtained 6 weeks after last infusion of bevacizumab. Tumour cells co-opt pre-existent vessels with relatively intact BBB (arrows). (A) H&E staining 20×. (B) Glut-1, BBB marker, 20×. (C, D) Recurrent GBM: autopsy was performed 10 weeks after the last infusion of bevacizumab. Near tumour sample shows tumour cells invading along white matter tracks. (C) H&E 20×. (D) Glut-1 BBB marker, 10×.

Figure 3

Recurrent GBM: autopsy material, post bevacizumab. GBM cells invade almost the whole brain of this recurrent GBM patient (2C, D). H&E stained autopsy specimen of neocortex of the hemisphere opposite to tumour location, 10 weeks after the last infusion of bevacizumab.

Figure 4

Schematic drawing: pre-treatment and during treatment. Schematic drawing of high-grade glioma, pre-treatment (A), and with anti-VEGF treatment (B). (A) Contrast leakage (white) occurs around leaky tumour vessels enhancing the tumour area on MRI. Capillaries in surrounding tissue are not leaky. (B) Contrast-enhanced area is strongly reduced under anti-VEGF treatment. Tumour cells migrate furtively into the surrounding tissue and co-opt existing vasculature.