AACR: Neoadjuvant Anti-VEGF Therapy Aids Local Control in Rectal Cancer

By Charles Bankhead
SAN DIEGO, 22 april 2008 -- In patients with advanced rectal carcinoma, adding bevacizumab (Avastin) to neoadjuvant chemotherapy and radiation led to 100% local control at four years, investigators in a small clinical study reported here. Therapy that included bevacizumab, which binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF), led to tumor downstaging in 12 of 22 evaluable patients, and four-year disease-free survival was 88%, Rakesh Jain, Ph.D., of Harvard, reported at the American Association for Cancer Research meeting. "I know of no other therapy in this patient population where we can even get close to 100% tumor control," Dr. Jain said. "Although this needs to be confirmed in a randomized trial against a placebo group, these are very impressive numbers."
The findings provide support for the concept of tumor vascular normalization. Tumor vasculature involves not only the formation of new vessels to feed the tumor but also disordered structure that impedes the therapeutic activity of cancer drugs and radiation, said Dr. Jain.
Bevacizumab destroys some of the tumor vasculature and helps normalize function in remaining blood vessels to make the tumor more susceptible to other forms of therapy, he said.
"Restoring order to blood vessels inside a tumor opens up a window of opportunity for treatment," said Dr. Jain.
The current study involved 24 patients with late-stage (T3/T4) nonmetastatic rectal cancer. They received four cycles of neoadjuvant therapy, consisting of:
bevacizumab 5 or 10 mg/kg on day one
5-fluorouracil 225 mg/m2/24 hours weekly during cycles two through four
external beam radiation at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks
Each patient had surgery seven to nine weeks after completion of neoadjuvant therapy.
Follow-up evaluation included serial tumor biopsies, FDG-PET scans, and examination of blood and urine samples for potential biomarkers.
Five of the 24 patients had no evidence of residual primary tumor after completion of neoadjuvant therapy.
In the remaining 19 patients residual microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 to ypT4).
Bevacizumab-induced blockade of vascular endothelial growth factor led to a decline in circulating endothelial cells by day three (P<0.01), and the level of circulating cells correlated with tumor response (T3 versus T0, P<0.05), Dr. Jain said.
Laser-capture microdissection identified a set of genes whose expression was altered by anti-VEGF therapy in cancer cells and in tumor-associated macrophages.
Dr. Jain reported no disclosures.
Primary source: American Association for Cancer ResearchSource reference:Willett CG, et al "Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study off neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer" AACR Meeting 2008; Abstract LB-304.