Treat-and-extend increasingly gains favor for individualized, proactive management of neovascular AMD

An appropriate treatment modality is key to the success of anti-VEGF therapy in neovascular age-related macular degeneration.

Over time, based on the results of clinical trials and their extensions, the revealing outcomes of real-life studies, and the long experience and consensus statements of many experts, the attitudes and habits of retina specialists have changed. In the United States, a treat-and-extend (T&E) regimen was favored by 66.2% of respondents to the 2015 American Society of Retina Specialists Global Trends survey, a combination of treat-and-extend and as-needed (PRN) by 18.8% and as-needed alone by 11.8%.

“Initially, people did one of two things. Some used the fixed regimens that were applied in the registration trials — MARINA and ANCHOR for Lucentis (ranibizumab, Genentech) and later VIEW1 and VIEW2 for Eylea (aflibercept, Regeneron). Others, after the PrONTO trial, were more comfortable using PRN,” K. Bailey Freund, MD, said.

Fixed regimens were mostly abandoned because patients in the real world are different from those in clinical trials. They have difficulty presenting for monthly treatment and often have more advanced disease.

“Monthly treatment may not make sense if the visual potential is very poor. Greater comfort level, long-term safety, and maintenance regimens with fewer injections and longer intervals between them seem to make more sense,” Freund said.

Source: Kevin Caldwell

On the other hand, as-needed treatment still carries the burden of monthly monitoring, which does not ensure timely treatment of recurrences.

“Patients often recur within a range of 6 to 7 weeks. They may still be dry at 1 month after treatment but start to leak again a couple of weeks after the visit. With T&E, you individualize the regimen to the patient’s recurrence pattern. In this way, you treat them fewer times, more effectively and with fewer visits,” he said.

Data from a number of randomized trials, such as the TREX-AMD, TREND and CAN-TREAT studies, have shown that treat-and-extend leads to similar visual and anatomic gains as monthly treatment.

The ‘magic’ interval

Regimens have been a highly debated issue since the beginning of anti-VEGF therapy, Jordi Monés, MD, PhD, said.

“When the trend changed from monthly to PRN, we went from the extreme of being maximum proactive and overtreating in some cases to the other extreme of being very reactive and undertreating lots of patients. We need to find the middle path, which means saving some injections but not undertreating. With T&E, we are mostly able to be ahead of the disease and treat it before it recurs,” he said.

Typically, treat-and-extend entails treating the patient monthly until the macula is dry. At that point, the interval to the next treatment is extended by 2 weeks. When the patient comes in after 1.5 months, an injection is performed independent of whether the macula is dry or not.

“If the disease is still inactive, the following interval will be 2 months and at every visit we extend by a further 2 weeks with the same criteria. Whenever we find some fluid, we shorten the interval by 2 weeks. Gradually, we find the magic interval for every patient, which is quite individual,” Monés said.

Rather than 2-week intervals, Freund said, intervals should be 1 to 2 weeks.

Charles C. Wykoff, MD, PhD, thinks of treat-and-extend in three phases: the monthly phase until the macula is dry; the treat-and-extend phase when patients are treated at each visit but the interval between visits is slowly increased; and a phase of consistent dosing at a fixed interval once the maximum tolerated interval is identified.

“Once recurrent exudation is identified at a given interval, I systematically decrease the interval between injections until I find the longest interval at which the macula remains dry between injections. I typically then maintain this interval going forward. Many patients have a consistent maximum tolerated interval for a given dose of a given medication,” Wykoff said. “When in the second phase, I usually extend by 2-week intervals, but if I am concerned about recurrence, for example in a monocular patient or in presence of a large choroidal neovascularization (CNV) lesion or extensive disease activity at baseline, then I will extend by 1-week intervals.”

How long to extend?

In 2015, a panel of experts published in Retina a review and consensus recommendations on treat-and-extend, in which treat-and-extend was defined as “an individualized proactive dosing regimen usually initiated by monthly injections until a maximal clinical response is observed, followed by increasing intervals between injections (and evaluations) depending on disease activity.”

“We defined the maximal response in terms of resolving the exudation and having a stable vision. If you start to extend the interval too soon, you may deprive the patient of potentially having a further gain in vision. If you feel that monthly has accomplished all that it can, then you start to extend by 1 to 2 weeks at a time. You see the patient at longer intervals but each time you give an injection,” Freund said.

The standard maximum extension is between 10 and 12 weeks, depending on the VEGF-suppressing durability of the drug that is used.

“My personal experience is that Eylea may have a slightly longer and more powerful drying effect, and so I might extend a little longer than I do with Lucentis. I also tend to use Eylea in eyes with type 1 macular neovascularization (NV) and in what I call aneurysmal type 1 NV but is more commonly referred to as polypoidal choroidal vasculopathy (PCV),” he said.

If there is recurrence of fluid within the interval, Freund recommends stepping back to a shorter interval and not extending again for about 6 months. More significant recurrence with hemorrhages may require going back to monthly dosing and continuing until the disease is stable enough to attempt extending again.

Recently, the possibility of extending by longer intervals has been investigated with aflibercept in the phase 4 ALTAIR study. Starting from week 16, the two arms of the study were extended by 2 weeks and 4 weeks at a time, respectively. The outcomes in terms of visual acuity and number of injections were comparable.

“These results prove that with Eylea you can safely extend by 4 weeks. This might also be possible with other agents, and some patients might be extended successfully by 4 weeks with any drug. However, the pharmacokinetics of aflibercept makes us feel more comfortable in extending by 4 weeks,” Paolo Lanzetta, MD, said.

“Interestingly, in the ALTAIR study in the 4-week adjustment arm, 50% and 40% of patients could be extended to 12 weeks or beyond or 16 weeks, respectively. This may have a great impact on the burden on patients and physicians,” he said.

Improving adherence

“We have learned a lot from our experience, and there is a lot we can do to minimize the burden and better individualize and optimize the outcomes of our treatments. There are proven factors affecting outcomes, for example, how fast is the access to treatment after AMD has been diagnosed. Studies have shown that the time to the first injection is very relevant in terms of visual acuity changes at 12 months. Now we know that adhering to the loading phase has an impact on the outcomes, and so does timely re-treatment and compliance to the treatment scheme,” Lanzetta said.

With elderly patients, the discontinuation rate is high. Studies have shown that within 5 years there is almost a 60% loss to follow-up, he said. One reason might be the long distance from the home to the hospital in some areas. Another important reason is that not all patients understand and appreciate the benefits of intravitreal injections.

“This is a reason to spend time with our patients and help them understand that AMD is a condition that needs repeated injections to prevent progressive vision loss. They need to know what to expect from the treatment and what to expect if we do not treat them properly,” Lanzetta said.

In his private practice, where he has the opportunity, time and human resources to follow patients with regular monitoring on a monthly basis, he likes to offer an individualized as-needed approach, but he prefers fixed regimens or treat-and-extend when he treats patients at the university hospital.

“Outside clinical trials and in a busy public hospital, patients who are on a PRN schedule are often undertreated and lose the initial gain, as shown by the SEVEN-UP study and by real-life reports such as the AURA study. With a fixed regimen of injections every 8 weeks or, alternatively, a T&E regimen with a minimum of seven to eight injections per year, we are happy to see that the majority of patients either maintain or gain vision,” Lanzetta said.

Criteria for treatment decisions

While the majority of U.S. retina specialists state they use treat-and-extend and a minority use as-needed dosing, many may use either depending on the clinical scenario, Wykoff said.

“For example, in an eye that dries quickly, one may try PRN first, and if there is recurrence of fluid, then switch to a treat-and-extend approach. In other words, they give patients an opportunity upfront, early in the course of management, to discontinue treatment. This is based on data from the PRN trials, including PrONTO, CATT, IVAN and HARBOR, that approximately 5% to 10% of patients may not need continued dosing once a dry retina is achieved,” Wykoff said.

Wykoff said he personally considers using as-needed dosing in eyes with small CNV that dry quickly with one or two injections.

“I may try to observe these eyes and not to re-treat them until they show re-accumulation of fluid. When they do, I switch from PRN to a treat-and-extend approach,” he said.

Freund has helped to refine the classification of neovascular lesions based on OCT and believes that treatment decisions should be guided by anatomic criteria rather than angiographic criteria.

“Most of the patients fall into the categories of either type 1 or type 3 NV lesions, that is to say, under the retinal pigment epithelium (RPE) or in the intraretinal spaces. I try a PRN regimen initially with type 3 because those lesions, if you treat them early, recur infrequently and have a low risk of severe hemorrhaging. Type 1, typically the large lesions, usually end up needing a T&E regimen because they often recur frequently and have a high risk of developing large hemorrhages. I regard PCV as a form of type 1 that often requires more of a maintenance strategy with more frequent dosing. Pure type 2 NV, which is under the retina but above the RPE, is not that common in AMD. It occurs more commonly in other diseases like myopic degeneration, angioid streaks and in the inflammatory neovascularization of multifocal choroiditis,” he said.

He said, however, that there is no permanent decision regarding treatment.

“You can switch back and forth. If PRN is not working, then you transition to T&E, and if you are on T&E and want to see if you can stop, you can go to monthly monitoring and PRN dosing,” Freund said.

Ultimately, all regimens that have been validated by trials lead to good results if used properly.

“The challenge is when practitioners decide to deviate from those regimens so they do PRN but only see the patient every 2 or 3 months. That’s when you have some patients recur long before their scheduled visit, and you often won’t catch the recurrence until there is some irreversible damage,” he said.

OCTA adds new dimension

Spectral-domain OCT was a major advance in guiding the management of AMD. It allows reliable identification of intraretinal and subretinal fluid and consistent, accurate comparisons between visits, Wykoff said. OCT angiography (OCTA) adds yet another dimension that physicians are still actively learning how to interpret and apply to patient care.

“With OCTA, we are able to image flow within CNV lesions, and I find it especially helpful in identifying subclinical lesions. With OCTA, we can readily visualize non-exudative CNV that are by definition not associated with intraretinal or subretinal fluid. Typically, these are below the RPE. In these eyes, there is a significantly increased rate of conversion to the exudative form, which then needs treatment,” he said.

An OCTA study by Philip J. Rosenfeld, MD, PhD, and colleagues was pivotal in identifying this type of subclinical CNV lesion, which was found to be the marker of a 15-fold increased chance of converting to exudative AMD.

This technology, Wykoff said, will enable a more sophisticated classification of CNV, helping to predict which patients require treatment and allowing more intimate monitoring of responses to intervention.

“It might allow for earlier, more individualized treatment decisions and hopefully better long-term outcomes while minimizing dosing in eyes that may not need treatment,” he said.

Long-term treatment

Early, proactive and long term are the three keys to successful treatment, according to Monés.

“Everyone understands that we need to treat early, some — but not everyone — understand that we need to treat proactively, and many refuse to accept that we need to treat long term,” he said. “AMD is not a 2-year disease, and we don’t want the SEVEN-UP results.”

Many of his patients have been on treatment for 5 to 6 years, receiving injections at long intervals even after the macula appeared to be dry.

“If the eyes stay quiet for 2 years, and I injected over those 2 years every 4 months, I try to stop, and sometimes they stay without activity and sometimes they recur, but at least I treat 4 years,” Monés said.

Freund was the first to propose the treat-and-extend protocol, and many of his patients have been on this regimen for 8 to 10 years.

“In the long term, my priority is to protect the health of a central macula with a regimen that a patient can follow for multiple years. I stop when I feel there is no real benefit in continuing treatment. It might be because vision is very poor and there is no point in continuing to treat, or if there is minimal risk of recurrence or significant further vision loss with a recurrence,” he said.

Preventing geographic atrophy

Most specialists agree that aiming at a completely dry macula in the long term may not always be the best strategy and that a small amount of subretinal fluid in specific types of lesions may persist from geographic atrophy.

“How dry the macula should be depends on the type of the lesion. In type 1, we should accept some persistence of subretinal fluid, inject every 3 months and keep the fluid stable. What we don’t want is intraretinal fluid, unless it is a cyst in a scar of a very advanced lesion,” Monés said.

“We had to challenge some of our assumptions because we are learning that having some subretinal fluid may not necessarily lead to poor visual outcomes. In fact, some of the trials have shown that patients with no fluid are more likely to develop geographic atrophy. Getting rid of every little bit of subretinal fluid is not necessarily essential,” Freund said.

There is accumulating evidence that eyes that have a certain growth pattern of neovascularization are less susceptible to macular atrophy, which is ultimately the cause of central vision loss.

“Allowing the shallow type 1 NV to enlarge and even extend under the fovea in the long term, 5 to 10 years, may be a strategy that allows the photoreceptors to survive when after they lose the nutritional support from an atrophic choroid,” Freund said.

He believes that future strategies might aim at using the disease to treat itself, by allowing for a controlled continuous proliferation of a benign form of sub-RPE vascularization to prevent some of the dry changes.

“I have already incorporated this strategy into my regimen. I don’t mind seeing lateral growth of certain type 1 lesions because I believe that in this neovascularization will actually prevent vision loss from the atrophic stage of the disease,” he said. – by Michela Cimberle

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• For more information:
• K. Bailey Freund, MD, can be reached at Vitreous Retina Macula Consultants of New York, 460 Park Ave., 5th Floor, New York, NY 10022; email: kbfnyf@aol.com.
• Paolo Lanzetta, MD, can be reached at IEMO – Istituto Europeo di Microchirurgia Oculare, Via M.A. Fiducio, 8; 33100 Udine, Italy; email: paolo.lanzetta@iemo.eu.
• Jordi Monés, MD, PhD, can be reached at Institut de la Màcula, Centre Mèdic Teknon, Carrer de Vilana, 12, 08022 Barcelona, Spain; email: jmones@institutmacula.com.
• Charles C. Wykoff, MD, PhD, can be reached at Retina Consultants of Houston, 6560 Fannin St., Suite 750, Houston, TX 77030; email: ccwmd@houstonretina.com.

Disclosures: Freund reports he is a consultant to Genentech, Novartis and Allergan and receives research support from Genentech/Roche. Lanzetta reports he is a consultant to Bayer, CenterVue, Genentech, Novartis, Roche and Topcon. Monés reports he is a consultant for Novartis, Roche, Alcon and Bayer. Wykoff reports he is a consultant for Genentech, Regeneron, Allergan and Alimera.

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