Systemic complications of intravitreal VEGF explored

July 15, 2008

The systemic complications associated with anti-vascular endothelial growth (VEGF) factor therapy for colon cancer are well documented. Those associated with intravitreal injection of anti-VEGF agents to treat neovascular age-related macular degeneration (AMD) seem to occur infrequently. Monitoring of these events has been limited thus far, however. Good methods need to be developed for post-marketing surveillance of anti-VEGF agents used to treat patients with AMD.

Key Points

Baltimore-The systemic complications associated with anti-vascular endothelial growth factor (VEGF) therapy for colon cancer are well documented. Those associated with intravitreal injection of anti-VEGF agents to treat neovascular age-related macular degeneration (AMD) seem to occur infrequently, however, and monitoring of these events has been limited thus far. Good methods need to be developed for post-marketing surveillance of anti-VEGF agents used to treat patients with AMD, according to Diana V. Do, MD, assistant professor of ophthalmology, retina division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.

"In a perfect world, efficacy, safety, and cost considerations would be incorporated into the development of an ideal treatment," Dr. Do said. "The first question we should ask is: Why are we even concerned about safety with the use of VEGF inhibitors? Safety concerns arise from the published medical literature on the use of systemic VEGF inhibitors in patients with cancer."

Compared with patients who received chemotherapy alone, Dr. Do said, patients with metastatic colorectal cancer who were treated with a combination of chemotherapy and systemic anti-VEGF agents had an increased incidence of adverse events such as thromboembolic events, hypertension, proteinuria, hemorrhage, and gastrointestinal perforation. These serious complications are listed in the patient information for bevacizumab (Avastin, Genentech).

Given the potential for these serious adverse events when anti-VEGF agents are used systemically, investigators have hypothesized that use of intravitreal anti-VEGF agents is safer because only a small amount is given directly in the eye.

The safety of ranibizumab (Lucentis, Genentech), an anti-VEGF drug, and pegaptanib (Macugen, Pfizer) was monitored during the MARINA and ANCHOR trial and the VISION trial for 2 years and 1 year, respectively. The drugs also were assessed in masked fashion by ophthalmologists who used standardized definitions of adverse events.

Hypertension

These methods may be subject to limitations, however, according to Dr. Do. For example, she said, a question exists regarding the reliability of blood pressure measured in ophthalmology clinics to diagnose hypertension. Other considerations include the validation of adverse events, adequate follow-up for nonfatal events, and validation of fatal events by hospital records or death certificates.

In light of these limitations, Dr. Do evaluated the safety monitoring data in the MARINA and ANCHOR trials of ranibizumab. She said the baseline patient demographics were similar in all groups, and the groups had a wide range of choroidal neovascular lesion types. Patients who had cardiovascular disease were included, but subjects could have been excluded at the discretion of the investigators because of contraindications to the use of investigational drugs or a higher risk for complications.

In the MARINA and ANCHOR trials, although systemic hypertension is a common complication with systemic administration of anti-VEGF agents, intravitreal administration of these drugs is not associated with hypertension. Intravitreal ranibizumab also is not associated with proteinuria. Non-ocular hemorrhages occurred more often in patients treated with ranibizumab but included mostly epistasis and ecchymosis.