For the past dozen years, drugs that inhibit the growth of new blood vessels - a strategy called anti-angiogenesis - have been the main hope of conventional oncology. These drugs were inspired by the work of the late Judah Folkman, MD of Harvard Medical School, who thought that tumors could be controlled by cutting off their blood supply. Drugs based on Folkman's concept include Avastin (bevacizumab), Erbitux (cetuximab) and Sutent (sunitinib). The clinical benefit of these agents, especially when used alone, is small. They are mainly used in conjunction with standard chemotherapy. Some doctors (such as Stanislaw Burzynski MD, PhD) believe that when used appropriately and in combination they have greater potential than is revealed in phase III clinical trials.

But now, a new study has raised the disturbing prospect that this class of drugs might have the contradictory effect of helping tumors invade normal tissues and organs, i.e., to metastasize. It is the process of metastasis that ultimately kills most patients with advanced cancer.

"People have thought that angiogenesis-inhibiting therapy should hinder metastasis, but these studies show this is not necessarily the case," says Gabriele Bergers, PhD, an associate professor at the University of California, San Francisco (UCSF), who wrote a paper on this with coworkers at UCSF and the Catalan Institute of Oncology-IDIBELL, in Spain.

Initially, anti-angiogenic drugs did shrink tumors. But then these tumors showed an unexpected surge in growth, spreading both locally and to distant organs. The authors believe that this increased invasiveness might be a tumor's response to the "starvation" induced by the drugs in question.

"A well vascularized tumor is well fed and happy," said UCSF scientist Douglas Hanahan, Ph.D. "It has no driving force to become more invasive. We hypothesize from the mouse models that if you cut off the tumor's blood supply this drives the cancer to become more invasive-more metastatic-as it seeks more oxygen and nutrients." Thus, the overall effect of giving anti-angiogenic drugs might be the opposite of what was intended.

This team tested the anti-angiogenic drug Sutent in mice that had been implanted with either pancreatic or brain cancer (glioblastoma). In both cases, tumors shrank or stabilized during the first few weeks of treatment. But after this initial period of apparent benefit, there was an adaptive response on the part of the tumor. For instance, the glioblastomas invaded the adjacent normal brain tissue, while pancreatic tumors metastasized to the animals' livers.

"Our animal studies are consistent with some clinical results that human glioblastomas adapt to the angiogenesis-inhibiting drugs," Bergers said. "Scientists have reported results from a clinical trial in which a subset of patients developed tumor recurrence at many sites during the course of treatment with bevacizumab [Avastin], an angiogenesis inhibitor. The recurrence was measured by MRI imaging."

What is the practical import of these findings? The authors believe that there is no reason to stop using these agents. "While anti-angiogenesis drugs are in general not proving to be an enduring success, this does not mean they aren't valuable therapies," Bergers said. "There is growing evidence that the drugs improve the quality of life, or even provide increased survival - typically of a few months for glioblastoma patients. The drugs also can reduce edema in brain tumors and in some instances restore memory and speech." But I am left wondering how drugs that seemingly increase the invasiveness of tumors also increase patients' survival.

It is time for a reappraisal of the actual effects of these drugs. This is imperative because of the extreme cost of many of these agents. Avastin can cost more than $100,000 per patient per year (and that's for the agent itself, not its administration - "parts, not labor," to quote Leonard Saltz, MD). The government needs to look critically at drugs that do not appreciably extend life and may even "alter the natural history of tumors by increasing invasion and metastasis," to quote the current paper.

Anti-angiogenesis has been a favorite concept of the cancer research establishment for many years. But it is turning out to be less effective and possibly more dangerous than expected. That is why I continue to believe that the greatest hope still resides in combining conventional with complementary and alternative medicine (CAM), such as is done at the German clinics that I wrote about in my recent special report.

--Ralph W. Moss, Ph.D.

References:

Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299-309.

Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206-220.

Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220-231.

O'Brien, Jennifer. Study sheds light on angiogenesis inhibitors, points to limitations, solutions. UCSF Press Release, March 2, 2009.