Update on anti-angiogenesis therapy for ovarian and cervical cancers

In the early 1970s, Dr. Judah Folkman hypothesized that tumors couldn't grow without new blood vessels forming to meet the tumors' increasing metabolic demands and that by inhibiting this so-called angiogenesis, tumor growth could be held in check.^2,3 Although his group went on to isolate an endogenous factor key to developing this characteristic tumor vasculature in rats,⁴ the technology lagged behind for developing a drug that could neutralize the effect of this factor. (And technology wouldn't catch up for nearly two decades.) Dr. Folkman and his global hypothesis were criticized, and further investigation came to a standstill.

But years later, advances in biotechnology revived this concept. Researchers were able to identify the angiogenesis-stimulating factor as vascular endothelial growth factor (VEGF)⁵ and to produce a VEGF-neutralizing antibody in mice.⁶ Humanization of the mouse anti-VEGF antibody⁷ led to the development of bevacizumab (Avastin, Genentech, San Francisco, CA), the first biologic, anti-angiogenesis therapy approved by the Food and Drug Administration (FDA) to treat cancer.

VEGF inhibition doesn't just starve the tumor

Bevacizumab's immediate mechanism of action is to bind and inactivate VEGF and to thus block endothelial cells from being activated and proliferating.¹⁰ Originally, the inhibition of tumor angiogenesis was thought to simply "starve" a tumor of nutrients and oxygen. But there's more to it than that. Studies show that VEGF inhibition can also induce "vascular normalization," that is, restore normal structure, function, and flow to malignant tumors, which characteristically have disorganized, leaky tumoral vessels. This, in turn, improves delivery of oxygen, nutrients, and cytotoxic chemotherapy to the tumor.¹¹ Although bevacizumab's complete mechanism of action has yet to be elucidated, the pressing need for new agents has driven clinical investigation of this drug.

Bevacizumab was first studied in patients with clear-cell renal cell cancer, based on its unique VEGF-driven biology, and four common solid tumors with high therapeutic need: breast, lung, colon, and prostate cancer.¹² The drug's effectiveness in early phase II trials-judging by both tumor shrinkage and by tumor stabilization-justified conducting randomized, phase III trials to examine the addition of bevacizumab to standard chemotherapy in each site.

The first of these trials to show a survival advantage was a colorectal cancer trial.¹³ In this large study, patients treated with bevacizumab had improved median times to progression of 6 months and median survival times of 2 months. While these differences might seem modest, they were statistically significant. Moreover, the investigators and the FDA considered them clinically significant. When bevacizumab was added to standard treatment, similar trials in metastatic lung and breast cancers prolonged time to progression to a statistically significant degree: by 2 months in metastatic non-small cell lung cancer and by 4 months for metastatic breast cancer.^14,15 Evidence from these trials sufficiently impressed the FDA for them to approve bevacizumab when given with standard chemotherapy to treat these cancers.