Evolving Treatment Strategies for Exudative AMD
The combination of verteporfin PDT and triamcinolone is already changing practice patterns.

Jason S. Slakter, MD (Moderator): Treatment strategies for age-related macular degeneration (AMD) are evolving at a rapid pace. Until 2000, thermal laser photocoagulation was the only therapy for exudative AMD.

Then, we moved into the era of photodynamic therapy (PDT) with verteporfin (Visudyne), and now, with the FDA approval of pegaptanib sodium (Macugen), we've entered the pharmacotherapeutic era.

We'll likely see the introduction of other products over the next couple of years, and we'll also be closely examining how we might combine treatments to obtain the best possible outcomes.

With changes occurring so rapidly, this conversation could be completely different over the course of the next few months. But from our point of view as retinal specialists, these changes are good because it means we're expanding our armamentarium of treatment choices.

The goals of this panel discussion are to shed light on how we're treating patients today and to address the challenges that accompany our widening range of treatment options.

DOES THERMAL LASER STILL HAVE A ROLE?

Dr. Slakter: Let's start with thermal laser therapy. What is its role today? Do you think pharmacotherapeutics or other therapies will replace it now or in the near future?

Stuart L. Fine, MD: Thermal laser therapy still has a place for treating well-defined extrafoveal choroidal neovascularization (CNV) in ocular histoplasmosis, AMD and other conditions where CNV threatens vision loss. I haven't seen any data from pharmacotherapeutic clinical trials that would make me eliminate laser photocoagulation for well-defined extrafoveal CNV.

This may change, but for now, I don't envision that intraocular injections at regular intervals for an indefinite period will replace what could be a single laser treatment for a well-defined lesion.

Alexander J. Brucker, MD: The recurrence rate in classic, well-defined, extrafoveal membranes is still rather high, which raises the question of whether combination therapy would be more appropriate.

Michael L. Klein, MD: I still start with laser therapy for that particular lesion type, given the alternatives with their disadvantages over time. If you're monitoring the patient closely and there's a recurrence, then you can use other methods.

Mark W. Johnson, MD: Thermal laser therapy also can work very well for classic, stage 1 retinal angiomatous proliferation (RAP) lesions in an extrafoveal location. I have patients who are doing very well a year or two or three after laser destruction of a stage 1 lesion.

Richard F. Spaide, MD: Those types of lesions don't necessarily progress rapidly, and the visual acuity response of patients with retinal lesion anastomoses to PDT may be no different from those who do not have retinal lesion anastomoses. However, at least in the short term, these patients seem to respond particularly well to the combination of photodynamic therapy with verteporfin and intravitreal triamcinolone.

Dr. Slakter: We're obviously very much in the infancy of understanding RAP lesions.

VERTEPORFIN AND BEYOND

Dr. Slakter: Do you restrict verteporfin PDT to predominantly classic lesions?

George A. Williams, MD: The Centers for Medicare and Medicaid Services' (CMS) coverage criteria are the result of a comprehensive and reasonable review of the best available data, and I think those coverage criteria are reasonable based on my own personal analysis of the data. PDT has clinical benefit for patients with predominantly classic lesions. So as a general rule, those are the criteria I follow.

Dr. Slakter: Has the introduction of pegaptanib altered your treatment plan?

Dr. Williams: Yes. Pegaptanib is my first-line therapy for larger occult and minimally classic lesions, which I define as larger than four disc areas. I can tell a patient with larger occult and minimally classic lesions with some confidence that pegaptanib appears to have a better effect than verteporfin PDT. However, that's comparing one trial to another, which is always a challenging situation.

David R. Chow, MD: I use verteporfin PDT, either alone or in combination with triamcinolone, as primary therapy for predominantly classic lesions and smaller minimally classic lesions. The introduction of pegaptanib hasn't altered my approach very much. As my experience with pegaptanib grows, I've had concerns about patients adhering to the protocol, which they find very difficult. At least half of the patients I started on pegaptanib had an issue with protocol adherence.

EXPLORING COMBINATION THERAPY

Dr. Slakter: How effective is combination PDT and triamcinolone in treating AMD?

Dr. Brucker: I use a combination of PDT and triamcinolone in about half of the PDT treatments I perform.

Dr. Slakter: Last year, a poll taken among attendees of the annual meeting of the American Society of Retina Specialists in San Diego showed that 80% were using combination therapy. Dr. Spaide, can you explain the rationale behind using PDT and triamcinolone and summarize some of the recent studies?

Dr. Spaide: If you look at the histopathology of fresh CNV in AMD, blood vessels make up a small part of the invading tissue. Most of the tissue is made up of inflammatory cells, lymphocytes, glial cells and fibroblasts. We've concentrated on destroying the blood vessels because of the angiographic appearance, but it would be good to have a combination of therapies directed against the vascular and inflammatory components of invading tissue.

In addition, the effects of PDT are brief, and there's a stimulus on the blood vessels to regrow. Looking at the histopathology again, the vascular endothelial growth factor (VEGF) that's present co-localizes with the macrophages from the invading tissue, suggesting the macrophages elicit at least part of the blood vessel growth.

We did a pilot study¹ of 26 patients with CNV secondary to AMD, 13 with no prior treatment and 13 with prior failed PDT treatment. Patients were treated with PDT immediately followed by a 4-mg intravitreal injection of triamcinolone.

Patients with no previous treatment had visual acuity improvement. Those who were losing vision while on normal PDT therapy maintained their visual acuity. They had a 0.44-line improvement over 12 months, which wasn't statistically significant. Augustin and colleagues² recently reported and have submitted for publication their study of 199 patients whom they treated in a similar fashion. Their patients had a mean improvement in visual acuity of about 1.2 lines after 1 year of follow-up. In addition, they needed an average of 1.2 treatments during that 1-year follow-up. My colleagues and I had similar results: Patients required about 1.24 treatments over the first year.

At the 2004 meeting of the American Academy of Ophthalmology, several clinicians presented papers on combining PDT with triamcinolone. Bhavsar³ reported a retrospective review of 26 eyes of 23 patients with minimally classic subfoveal CNV; 12 eyes had RAP lesions. They were treated with PDT and 4 mg of triamcinolone. Median follow-up was 6 months. Thirteen eyes experienced an increase in visual acuity; 23 eyes gained acuity or lost less than 3 lines. Roth and colleagues⁴ treated 72 eyes and reported stable vision in 81% of eyes. Johnson and colleagues⁵ reported a majority of their patients had either improved or stabilized vision.

Dr. Fine: Does it matter when the triamcinolone is given with respect to the administration of PDT?

Dr. Spaide: That's not know because it hasn't been studied. It is being done in different ways in various practices. In my practice, we usually do both on the same day, as a matter of convenience for the patients.

Elias Reichel, MD: I've often treated retinal vascular diseases with triamcinolone; however we're a bit shy about using it with PDT. When I looked at our original

PDT data using optical coherence tomography (OCT), I found that the number of treatments was probably over-called in the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) investigations. Therefore, the issue of whether we're reducing the number of treatments with intravitreal triamcinolone may not be exactly correct. Subretinal fluid in cystoid macular edema (CME) may clear with one, two or three intravitreal triamcinolone treatments.

RAP lesions however, seem to respond to PDT plus triamcinolone in a way we don't see with PDT, laser alone or laser with triamcinolone. RAP lesions may be one pathology that's really sensitive to this treatment. We may have to pigeonhole different treatments for different forms of the disease, but, in general, I'm not using a lot of intravitreal triamcinolone. I'd like to see a large study before we get too involved because intravitreal injections are not without risk.

Dr. Klein: I rely primarily on PDT for most lesions, but I'm using triamcinolone more frequently. I reserve it for lesions where I feel PDT won't be as effective as I'd like. Also, I'll add it in cases where I feel we're not getting very far after the first PDT treatment.

Dr. Chow: I use PDT plus triamcinolone in about 80% of cases. I have concerns about endophthalmitis, and steroid-related intraocular pressure spikes are certainly an issue.

In my opinion, one of the greatest values of adjunctive steroid use with PDT is that it addresses the macular edema overlying the CNV, an underappreciated cause of vision loss that, until now, we may not have addressed specifically. I think triamcinolone is quite valuable in cases where OCT shows retinal thickening or subretinal fluid, or an obvious clinical case where a lesion is leaking.

Dr. Fine: I use PDT alone as initial treatment if I'm dealing with a small, classic neovascular lesion. I reserve triamcinolone for what I perceive to be treatment failures. I don't wait until we do eight treatments in 2 years, but I do give patients, particularly those with small neovascular lesions, an opportunity to have PDT alone initially.

Dr. Johnson: I agree with those who have pointed out the need for more long-term information. We don't know whether patients who've received combination therapy will have better acuities in 2 or 3 years than patients who undergo PDT alone. Many questions remain unanswered. For example, how will patients with active neovascular lesions do when their steroid-induced cataracts are removed? Are patients at risk of toxicity from multiple triamcinolone injections? Given the lack of long-term, randomized clinical trial data, I believe it is premature to consider combination treatment the proven standard of care. In part, a patient's own risk tolerance helps determine when I use triamcinolone.

I review with my patients the limits of our knowledge and the potential benefits of combination therapy, before I involve them in the decision about adding triamcinolone to the first PDT treatment or trying PDT alone.

I prefer an initial trial of PDT alone for most lesions to identify patients who respond exceptionally well without the added risks of a triamcinolone injection.

Dr. Brucker: If we can use science to justify the use of triamcinolone and apply our understanding of the pathophysiology of what's occurring, then we should be able to justify its use in all cases. Although I agree with what you're saying, I can't justify not using triamcinolone if I believe its effect is beneficial. As I mentioned earlier, I will do PDT alone and if it fails, then I combine it with triamcinolone. More and more, I'm combining PDT and triamcinolone when the lesion is small to give the patient what I believe may be his best chance for success.

Dr. Johnson: I agree with your approach in principle, but in my experience, the combination doesn't have a consistent effect. Because of that and because we haven't had a solid clinical trial of combination therapy yet, I like to involve my patients in deciding whether to take the extra risk associated with combination treatment.

Dr. Spaide: The risk-benefit ratios in combination treatments are not completely qualified at present.

CHARTING A FUTURE COURSE

Dr. Slakter: AMD is complex. You can look at a photograph and decide it looks like a classic membrane, but if you look at an OCT scan of that membrane, you might think differently. If you see intraretinal cystic changes, you may suspect a retinal angiomatous complex. There's a lot more to these lesions than a simple angiographic characterization. At one end of the spectrum, we have conditions such as polypoidal choroidal vasculopathy, where laser therapy would likely be very effective. On the other end of the spectrum, we have RAP lesions, where no monotherapy is working well.

Dr. Spaide: We could go back and examine our data on control patients, particularly where OCT was used, and analyze the many lesion characteristics. Maybe we'll see factors we haven't been looking at that are important predictors.

Dr. Fine: It's reassuring that we have a rationale for using an anti-inflammatory agent in CNV to combat all the inflammatory cells seen microscopically. But we shouldn't jump from the rationale and conclude, "We should use an anti-inflammatory agent." Medical history is replete with examples of strong rationales that aren't supported by clinical trials.

Dr. Williams: We simply don't know how combination therapy with verteporfin PDT and steroids will shake out. Our growing clinical consensus is valuable, but in a disease as complex and multifactorial as AMD, it's incumbent upon physicians to take the lead and design the studies to provide the information we need. We owe it to our patients to produce better data.

REFERENCES

1. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2003;110:1517-1525.

2. Augustin AJ, Offermann I, Schmidt-Erfurth U. Verteporfin in combination with intravitreal triamcinolone for CNV due to AMD. 2005 ARVO paper presentation 3567.

3. Bhavsar A. Combined verteporfin photodynamic therapy and intravitreal triamcinolone in the treatment of minimally classic subfoveal CNV with or without RAP lesions. 2004 AAO poster presentation P0163.

4. Roth DB, Walsman S, Modi A, et al. Intravitreal triamcinolone combined with photodynamic therapy for exudative macular degeneration. 2004 AAO paper presentation PA044.

5. Johnson RN, Yang SS, McDonald HR, et al. Combined photodynamic therapy and intravitreal triamcinolone acetonide for AMD. 2004 AAO poster presentation P0147.