Abstract
BackgroundThe 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.DiscussionGBM 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.SummaryAlthough 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.
Highlights
The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours
Non-randomised phase II trials in recurrent GBM patients demonstrated high response rates ranging from 20% with single agent TMZ [27], to 30% with single agent AZD2171 (Cediranib, a small molecule VEGFR inhibitor) [24], 20% with single agent bevacizumab, and even to 57% when bevacizumab was combined with irinotecan [14,15,16,17,28]
The relevance of angiogenesis inhibition in the treatment of GBM has been placed in the unique context of malignant brain tumours
Summary
Clinical experiences One of the aggravating symptoms of high-grade astrocytomas is increased intracranial pressure, a direct result of oedema caused by leaky tumour vasculature. Angiogenesis inhibitors are effective in reducing these symptoms, or in reducing the need for corticosteroid treatment in recurrent GBM patients [19,20,21,22,23,24,25,26] This rapid effect of anti-VEGF therapy is suggested to be due to a normalization of vascular permeability resulting in a reduction of peritumoural oedema and intracranial pressure, and is even more active than corticosteroid therapy alone (Figure 1A-C) [21,24]. Vessel normalisation is believed to explain the synergy between bevacizumab and chemotherapy in advanced colorectal cancer patients [9,57] In confirmation of this concept, it was recently reported that anti-VEGF treatment of subcutaneous melanoma grafts results in vessel normalisation and concomitant better delivery of MRI contrast agents and oxygen to the tumour [58]. The discussion continues as to whether combining anti-angiogenic treatments with other chemotherapies is beneficial or detrimental (or somewhere inbetween)
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