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Con: Clinical efficacy of Avastin may not be enough
Safety and long-term efficacy data for the colorectal cancer drug are lacking, one physician notes.
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Use of a cancer drug to treat eye disease — even in low, locally administered doses — may carry risks for physicians and patients if it is done before the treatment’s efficacy and safety are established, according to one retinal subspecialist.
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In an interview with Ocular Surgery News, Craig M. Greven, MD, expressed caution regarding the increasing acceptance of the use of intravitreally injected Avastin (bevacizumab, Genentech) for the treatment of retinal diseases. The drug is currently approved by regulators in the United States for the treatment of colorectal cancer. About a year ago, some ophthalmologists began using the drug systemically in patients with exudative age-related macular degeneration. Most proponents have now gravitated to intravitreal use of the drug for AMD at a much lower dosage.
Dr. Greven, however, said he remains concerned about the lack of safety data from the off-label intraocular use.
He noted that intravitreal Avastin “could be considered” in vitreoretinal conditions including exudative AMD, diabetic retinopathy and venous occlusive disease, “but at present we have no good data documenting the efficacy of intravitreal Avastin.”
Dr. Greven said retinal specialists “should be excited about the potential” being shown by intravitreal Avastin in these conditions, “but we need more information through prospective clinical trials to determine the safety and efficacy.”
“My instinct says that it should be investigated, but we shouldn’t just be pouring it into the eyes of our patients,” he added. Use of an unproven therapy, even if it seems promising in initial investigations, can expose not only the patient to medical risks but also the treating physician to potential legal liabilities, he said.
Salvage therapy?
At conferences and meetings over the past year, attendees have heard a number of speakers advocate the use of Avastin intravitreally as “salvage therapy,” Dr. Greven noted. Most of those speakers have described a remarkable positive change in patients who have undergone the Avastin injections.
Dr. Greven acknowledged that these early results seem promising, but he questioned the wisdom of halting a proven therapy too early, only to switch to an unproven one.
“My question here is, ‘What is salvage therapy?’” Dr. Greven said. “If someone ‘fails’ two injections of Macugen [pegaptanib sodium injection, Pfizer/OSI Pharmaceuticals], that doesn’t indicate they’ve failed Macugen. The selective VEGF-blockage of isoform 165 by Macugen typically has a slower effect, and so by quitting treatment after two injections and calling it salvage … well, it just may not have been enough time for the drug to work in that particular eye.”
The VISION trial (VEGF Inhibition Study in Ocular Neovascularization) has shown that patients treated with Macugen can have vision stabilized for up to 2 years, Dr. Greven said.
“So these physicians are abdicating a proven treatment with a good safety profile for a treatment that may cause immediate anatomic improvement, but you don’t know about its safety,” he said.
Pan-VEGF blockers
Immediate positive visual acuity improvements are sometimes not seen with Visudyne (verteporfin for injection, Novartis/QLT) or Macugen therapy, Dr. Greven said. On the other hand, pan-VEGF blockers such as Avastin “might have a good initial effect” to dry up subretinal fluid, but safety is still a concern.
“My paramount concern is the potential safety issues with this new class of agents we call pan-VEGF blockers,” Dr. Greven said.
Another Genentech drug, Lucentis (ranibizumab) is also a pan-VEGF blocker, Dr. Greven said. That drug, which is specifically formulated for use in the eye, has been accepted by the Food and Drug Administration for priority review, but it has not yet been approved for marketing in the United States.
“In well-designed trials, Lucentis has had some excellent visual improvement statistics, but has raised some red flags concerning strokes, although those figures haven’t been statistically significant,” he said. “Going forward, we’ll have to identify whether the risk of stroke is a real risk related to the drug or not. Since Avastin has a similar mechanism of action, we have to be concerned about Avastin intravitreally and about its systemic absorption.”
Dr. Greven noted that the half-life of Avastin is about 30 days, while Lucentis has a much shorter half-life of about 3 days.
“So if you’re giving your patients monthly injections, even though it’s a low dose, we just don’t know the long-term systemic complications,” he said.
Without that knowledge, Dr. Greven said, he is hesitant to jump on any drug’s bandwagon.
He noted the difference in age of the patient populations for cancer vs. AMD. The people typically treated with Avastin for colorectal cancer tend to be in their 50s and 60s. People treated for exudative AMD are typically in their 70s or 80s, and thus at an increased risk of cerebrovascular and vascular complications based solely on their age.
“It may not take much to push them over that risk edge,” he said.
Beyond systemic safety concerns, there are ocular safety concerns with any untested compound, Dr. Greven said.
“We don’t know the precise role of VEGF in the eye,” he said. “We think it’s important in the survival of the retinal pigment epithelium-choriocapillaris. By giving a pan-VEGF blocker, we may be causing damage to those structures.”
Despite his concerns, Dr. Greven said that with more pharmacologic agents currently available to retinal specialists, combination therapy “should be considered” in the future for management of AMD. He said physicians still must conduct combination trials to look at potential efficacy and safety issues with combination therapies.
Physicians in Europe and Israel are currently investigating Avastin in combination with photodynamic therapy and intravitreal triamcinolone, Dr. Greven noted, but no results of those investigations have been published.
The flip side
Dr. Greven noted that he and his colleagues who favor the use of intravitreal Avastin are “not so far apart ideologically.” All ophthalmic physicians want to help their patients see better, he said.
“Whenever you use a therapy that is outside normal indications, there may be potential medical and legal ramifications, but you need to refer to studies to back up your medical decisions,” he said. “As retinal surgeons treating these diseases, we do want Avastin and Lucentis to be safe and efficacious. But we need to find out if it is safe before using it and adding it to our armamentarium to fight this dreaded disease.”
For Your Information:
- Craig M. Greven, MD, can be reached at Wake Forest University Eye Center, Medical Center Blvd., Winston-Salem, NC 27157; 336-716-2732; cgreven@wfubmc.edu. Dr. Greven has served as a speaker for Eyetech/Pfizer and a consultant for Eyetech.
- Michelle Dalton is the Managing Editor of OSN SuperSite.com. She writes daily updates on developments in all aspects of ophthalmology.