The advent of anti-angiogenesis therapy has been a welcome advance in cancer treatment, yet it has been associated with some controversy. The initially proposed mechanism of benefit, namely, starving the cancer by elimination or reduction of tumor vasculature, does not seem to fit with clinical observations, particularly the of lack of a clear dose-response relationship and the lack of benefit in the absence of concomitant cytotoxic therapy5,6,8,9
. Theoretically, administration of anti-VEGF should reduce the effect of chemotherapy by reducing the supply of drug via elimination of blood vessels. Additionally, the resulting hypoxia should reduce the effectiveness of drugs5,6
. Yet, no anti-VEGF trial in patients with metastatic disease has shown a decline in OS compared to chemotherapy alone6
. One possible explanation for these findings is vascular normalization whereby anti-VEGF treatments, when used in judicious doses, can normalize abnormal vessel structures, potentially leading to increased blood perfusion. In fact, a number of pre-clinical studies have shown that anti-angiogenic agents can improve oxygenation and/or drug delivery6
. However, human data on increased blood perfusion, oxygenation or drug levels are lacking.
To this end, our data provide three key insights. First, vascular changes in rGBM after anti-angiogenic therapy, including increased perfusion, clearly occur and occur durably. Importantly, perfusion does not increase in all patients, only in about one quarter of the patients. Second, vascular changes occur not only in regions most traditionally associated with rGBM – that is, in the area of blood-brain barrier breakdown – but also in surrounding areas. Third, and most provocative, this increase in blood perfusion is associated with prolonged survival.
The most straightforward explanation for these observations is that the increased tumor blood perfusion is simply a result of decreased permeability of normalized blood vessels – as the patient group with increased tumor blood perfusion had the highest VNI. This is consistent with a mathematical model showing that high vascular permeability can lead to perfusion stasis, and conversely, a decrease in permeability can increase perfusion15
and another model showing that the decreased permeability also leads to a reduction in edema16
. We have previously shown in pre-clinical data that edema reduction alone by cediranib can account for increased survival without affecting tumor growth4
. However, edema control alone does not fully explain the improved survival – as we also observed direct metabolic effects of cediranib in rGBMs in some of the longer surviving patients10
. There are two potential explanations for this metabolic response.
First, since cediranib is a multi-receptor tyrosine kinase inhibitor and some of these receptors are present on GBM cells8
, it is conceivable that the normalized vessels permit a better delivery of cediranib to the GBM cells leading to a better anti-tumor effect. Killing of cancer cells surrounding blood vessels can open up compressed blood vessels, and in turn, also increase blood perfusion17
. Thus cediranib acts as a combined vascular normalizing agent and anti-cancer agent both contributing to increased tumor blood perfusion. Consequently, the patients with increased blood perfusion - and a higher VNI - benefit from both better anti-edema and anti-cancer effects. This could potentially explain why some patients with decreased blood perfusion had no OS gain - despite decreased vascular permeability and edema – suggesting a lack of anti-cancer effect by cediranib in these patients.
A second explanation might be that vascular remodeling and resulting increased perfusion and delivery improve the innate immune response18,19
, an emerging and compelling concept. A recent study offers evidence that targeting abnormal polarization of tumor-associated macrophages (TAMs) can normalize tumor vessels and also enhance antitumor immunity19
. Also, a more even distribution of blood perfusion with a subsequent reduction in areas of hypoxia and acidosis6
can further increase immune response as hypoxia and also low pH compromise the cytotoxic functions of tumor-infiltrating immune cells20
. Thus, patients whose tumor blood perfusion did not increase did not benefit from immunostimulation resulting from reduced hypoxia.
In summary, our data are consistent with the vascular normalization hypothesis, and suggest that improvement in survival in response to anti-VEGF therapy may be mediated by mechanisms other than vascular pruning and tumor “starvation”. Whether bevacizumab has similar effects in glioblastoma remains to be determined and is a high-priority research question for the field.