Last week I wrote about research at the University of California San Francisco (UCSF) showing that in experimental animal systems the anti-angiogenic drug sunitinib (Sutent) actually facilitated the spread of cancer. This week I will describe work being done at the University of California, San Diego (UCSD) that, while quite different in its methodology, supports the same general conclusion.

These "knock out" mice were then bred with another strain of mouse that spontaneously develops mammary tumors. In their offspring, blood vessels did not increase as much as they would have otherwise, although the remaining vessels were organized better than expected. At the same time, the spontaneous tumors in these "anti-angiogenic" mice grew larger and were more likely to enter a more advanced stage of the disease, according to research published in the British journal, Nature (Stockmann 2008).

"Common dogma predicts that reducing VEGF makes the tumor smaller, but the tumor got larger," said Dr. Cheresh, MD, who is a professor and vice chair of pathology at UCSD's Moores Cancer Center.

To be clear, there was some indication in the UCSD study that giving Avastin increased cells' susceptibility to cytotoxic chemotherapy. This is in line with clinical observations over the past ten years showing that anti-angiogenic drugs only work when they are administered with (not instead of) standard chemotherapy.

How effective is Avastin? A 2009 study of advanced colorectal cancer in older people showed that progression-free survival went from 6.2 months with chemo to 9.2 months when Avastin was added, a gain of 3 months. (The patients were all 65 or older.) The median overall survival was 19.3 months when Avastin was added compared to 14.3 months with chemo alone, a gain of 5 months. There was no statistical difference in the objective response rates. This is similar to what has been seen in previous studies in younger people.

So the take-away message is not that Avastin and the other anti-angiogenic drugs are worthless or intrinsically harmful. But they are a two-edged sword, which in some circumstances (especially when given alone) may have the paradoxical effect of promoting cancer's virulence and invasiveness. They seem useful when added to 5-FU-based chemotherapy. This complicated picture bears little resemblance to the intense hype that accompanied their introduction about a decade ago.

--Ralph W. Moss, Ph.D.

References:

Kabbinavar FF, Hurwitz HI, Yi J, Sarkar S, Rosen O. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. 2009;27:199-205.

Stockmann C, Doedens A, Weidemann A, et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008;456:814-818.