Retina specialists pursue diverse treatment scenarios for wet AMD

Choice of an anti-VEGF dosing strategy is driven by scrutiny of clinical responses to therapy and OCT images that show progressive disease.

Optimal dosing of anti-VEGFs in the treatment of wet age-related macular degeneration, particularly in challenging cases in which patients respond poorly to monthly injections, is at the nexus of ongoing research.

Advanced imaging technology and recent research findings promise to drive the development of treatment strategies in which specialists customize treatment, maximize outcomes and prevent complications.

Current strategies include monthly injection, as-needed injection, treat-and-extend therapy, biweekly dosing, alternating biweekly dosing and 2-week or 4-week dosing of Lucentis (ranibizumab, Genentech), Avastin (bevacizumab, Genentech) or Eylea, also known as VEGF Trap-Eye (aflibercept, Regeneron).

Two-year results of the Comparison of Age-related Macular Degeneration Treatment Trials (CATT) showed ranibizumab and bevacizumab to be relatively equal in terms of safety and efficacy. In addition, as-needed injection of ranibizumab proved comparable to monthly injection.

Treatment approaches hinge at least partly on optical coherence tomography, which is used in conjunction with fluorescein angiography, indocyanine green angiography and clinical examination, Glenn J. Jaffe, MD, OSN Retina Board Member, said.

Glenn J. Jaffe

“If you’re giving anti-VEGF therapy every month regardless of how the patient is doing in terms of their visual acuity and their anatomic findings, but most particularly their anatomic findings, then it might not be as critical,” Dr. Jaffe said. “But I would say that the majority of retina specialists … are using OCT to help guide their treatment.”

OCT is particularly useful in detecting the presence of fluid deposits that herald disease persistence or progression, Dr. Jaffe said.

“The main way that people have used [OCT] has been to determine whether there’s fluid present in the retina, under the retina or under the retinal pigment epithelium and making treatment decisions based on the presence of that fluid according to a couple of different treatment strategies,” he said.

As-needed vs. treat-and-extend dosing

The CATT compared monthly treatment with as-needed treatment. Dr. Jaffe said that he primarily uses the as-needed treatment model in his practice.

“For that treatment, the patient is seen every month, and at those visits, if you see fluid — and the fluid can be intraretinal fluid, subretinal fluid or subretinal pigment epithelium fluid — you would give treatment with your drug of choice, whether it’s Lucentis or Avastin,” Dr. Jaffe said. “According to that treatment strategy, most of the time people will treat with a given drug, one or the other, until that drug doesn’t seem to be working. At that point, you might consider switching to the other one.”

The treat-and-extend method involves the use of a single agent, he said. Treatment typically begins with three successive monthly injections. The interval between subsequent injections is extended in 2-week increments, depending on anatomic findings.

In LUCAS (Lucentis compared to Avastin study), which is being conducted in Norway, patients are treated monthly and treatment is extended when the macula appears to be dry, he said.

“In that study, as an example, the time interval between treatments was extended by 2-week increments,” Dr. Jaffe said. “You get the retina dry. You had been treating it at 4-week intervals and you now extend it to 6 weeks. You give the injection at 6 weeks, and you see the patient back in 8 weeks. You extend it another 2 weeks.”

Commonly, the maximum interval between injections is about 3 months.

“Most people don’t go beyond that,” Dr. Jaffe said. “The idea behind that method is that there’s variability among individuals in the duration of response to the agents. According to that hypothesis, as an example, one individual might need injections every month and a half, and that will hold them. Another person might need them every month. Other individuals might get away with every 2 months, but they have a need for injections at a fairly regular interval that’s variable and depends on the patient.”

OCT plays a key role in both the as-needed dosing and treat-and-extend regimens, Dr. Jaffe said.

“The idea is that we’re looking for signs of active choroidal neovascularization … as reflected by the presence of fluid in the retina because of leaking from the choroidal neovascularization,” he said. “We’re trying to eliminate the signs of active choroidal neovascularization. We’re doing that in large part based on the OCT.”

Alternating treatment

Biweekly alternating ranibizumab and bevacizumab injections may be a viable treatment option for some patients who are not responding to monthly dosing of anti-VEGF medications, Andre J. Witkin, MD, said at the Wills Eye Institute Alumni Conference in Philadelphia.

Alternating treatment limits cost and may decrease the rate of tachyphylaxis, Dr. Witkin said in a subsequent interview.

Patients for whom to consider a regimen of biweekly alternating injections have signs of fluid on OCT despite at least 6 months of monthly injections, according to Dr. Witkin.

“Sometimes these patients will have some response on OCT if you bring them back earlier, at 2 weeks after their injection,” he said. “If you bring them back in another 2 weeks, then fluid has re-accumulated. If you see that, then you know that that patient may benefit from a more frequent dosing regimen.”

Some patients need ongoing, sustained treatment.

“You get a more continuous level of anti-VEGF medication in the eye,” Dr. Witkin said. “It’s possible that some patients just need a more continuous blockade of VEGF.”

Downsides of biweekly alternating injections include increased risk of infection, increased theoretical risk of systemic absorption, and the need for patients to invest large amounts of time, Dr. Witkin said. Patients who choose to receive this injection regimen should be aware of the potential risks and time investment.

Alternating treatment has become less common in recent years, Dr. Jaffe said.

“That was a method that people had done more commonly previously,” he said. “I think many fewer people use that method now.”

Pharmacokinetic dosing model

Michael W. Stewart, MD, and colleagues described a mathematical model comparing 2-week dosing with 4-week dosing of ranibizumab, bevacizumab and aflibercept. The model was designed to determine the relative benefits of more frequent dosing over less frequent dosing.

Study results showed that short-term biweekly dosing may be a viable option for eyes that show a response to treatment within 2 weeks of an injection but rebound with increased macular fluid after 1 month.

“They showed a few case reports of the same dosing strategy that we described, alternating biweekly injections,” Dr. Witkin said. “They showed similar findings to what we talked about, where patients who had recalcitrant fluid on OCT despite a long series of monthly anti-VEGF injections had a dramatic response to alternating biweekly injections of ranibizumab and bevacizumab.”

The clinical benefit of biweekly injections in eyes that responded poorly to monthly injections was attributed to the theoretical increase in trough levels of anti-VEGF binding activity, according to the study authors.

Aflibercept may afford higher trough levels of anti-VEGF binding activity, thus obviating the need for biweekly dosing in eyes with VEGF-mediated exudative AMD that seem to respond poorly to monthly ranibizumab or bevacizumab injections, the authors said. – by Matt Hasson

References:

CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
Csaky KG. Comparison of age-related macular degeneration treatment trials: what did we learn? Retina. 2012;32(3):413-416.
Curtis LH, Hammill BG, Qualls LG, et al. Treatment patterns for neovascular age-related macular degeneration: analysis of 284,380 Medicare beneficiaries [published online ahead of print Feb. 7, 2012]. Am J Ophthalmol. doi:10.1016/j.ajo.2011.11.032.
Katz G, Giavedoni L, Muni R, et al. Effectiveness at 1 year monthly versus variable-dosing intravitreal ranibizumab in the treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2012;32(2):293-298.
Saito M, Iida T, Kano M. Combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol. 2012;153(3):504-514.
Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab and aflibercept (vascular endothelial growth factor trap-eye). Retina. 2012;32(3):434-457.

For more information:

Glenn J. Jaffe, MD, can be reached at Duke University Eye Center, Box 3802, Durham, NC 27710; 919-684-4458; fax: 919-681-6474; email: jaffe001@mc.duke.edu.
Andre J. Witkin, MD, can be reached at Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107; 215-928-3197; fax: 215-928-0166; email: ajwitkin@gmail.com.
Disclosures: Dr. Jaffe is as a consultant for Heidelberg Engineering. Dr. Witkin has no relevant financial disclosures.