In discussing treatment options for patients with wet age-related macular degeneration (AMD), it is difficult to define any one "right" treatment, given the tremendous heterogeneity of the disease process. Vascular endothelial growth factor (VEGF) is but one of the broad-spectrum inflammatory mediators present in the milieu of neovascular membranes. We first introduced dexamethasone as an adjunct in AMD treatment in an effort to ameliorate the action of many of these varied agents. From our first treatment using dexamethasone as an adjunct in verteporfin-assisted (Visudyne, Novartis) photodynamic therapy (PDT), to the eventual incorporation of an anti-VEGF agent, and finally leading to the prospective PDEX (PDT plus Lucentis and Dexamethasone) II trial, we have attempted to establish a safe and effective protocol to optimize patient outcomes.

BACKGROUND
Biochemical and histological analyses of extracted membranes and numerous animal models demonstrate that broad-spectrum inflammation is present in neovascular membranes. Inflammatory factors include, but are not limited to, increased production of VEGF, intracellular adhesion molecule (ICAM-1), matrix metalloproteinase (MMP), monocyte colonizing protein (MCP), interleukin-8 (IL-8), and free radical production.

Treatment for AMD has evolved over the past 30 years from nonselective destructive laser treatment to targeted photoactivated dyes (PDT) and injectable antiangiogenic compounds (pegaptanib [Macugen, Eyetech], ranibizumab [Lucentis, Genentech], bevacizumab [Avastin, Genentech]). The emergence of targeted anti-VEGF agents brought a new era to the management of AMD and provided hope that improved visual outcomes could be achieved with reduced ocular risks. Although pegaptanib was the first to be approved by the US Food and Drug Administration, the adoption of bevacizumab and subsequent emergence of ranibizumab provided new gold standards with respect to visual outcomes. Data from the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) trials suggested that monthly anti-VEGF treatments could provide sustained and significant visual improvement. These extremely favorable results had to be tempered with the fact that they were achieved with rigorous adherence to monthly injections over a 24-month period. Attempts to reduce the treatment frequency or prolong the treatment-free intervals resulted in suboptimal visual outcomes (PIER [Phase 3b, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration], PrONTO [Prospective Optical Coherence Tomography OCT Imaging of Patients With Neovascular Age-Related Macular Degeneration Treated With Intra-Ocular Lucentis], VISION [VEGF Inhibition Study In Ocular Neovascularization]).

PDEX I TRIAL
The PDEX I trial was a nonrandomized retrospective analysis of 105 consecutive patients who underwent treatment with PDT and dexamethasone with or without an anti-VEGF agent from April 2005 through June 2006. (For more information, see "Intravitreal Dexamethasone as an Adjunct in the Treatment of Neovascular AMD," in Retina Today Nov/Dec 2007; available at www.retinatoday.com.) The value of that analysis was limited by all the features that traditionally limit such studies: nonstandardized Snellen acuities, heterogeneity in lesion size and type, prior treatments, variability in follow-up, and treatment regimens. Despite these limitations, however, one of the major outcomes was in demonstrating the relative safety of intravitreal dexamethasone (IVD) over long-term follow-up (>12 months). This was a welcome finding, especially compared with the steroid adjunct that was commonplace at the time, triamcinolone acetonide. In fact, none of the IVD patients experienced a pressure greater than 30 mm Hg at any time point, and only 8% had even a transient rise over 25 mm Hg. The data trends also suggested that although IVD improved the outcomes compared to PDT alone, the addition of an anti-VEGF agent, especially within a 2-week window of the PDT/IVD treatment, provided the greatest visual benefit.

PDEX II TRIAL
The trends observed in that limited retrospective trial led us to devise the first randomized masked prospective trial comparing these two combination groups. The PDEX II trial is an institutional review board (IRB)-approved, multicenter, prospective, randomized, masked, noninferiority trial comparing the relative merits of group 1 (same day triple therapy using reduced-fluence verteporfin PDT, IVD, and ranibizumab followed by as-needed treatment) vs group 2 (monthly ranibizumab monotherapy for 12 consecutive months). The strict inclusion criteria include only treatment-na•ve patients with vision between 20/32 and 20/320. Although all lesion types are included, any lesions with pigment epithelial detachments larger than 50% of the total lesion are excluded to minimize the effect of retinal pigment epithelium (RPE) tears on treatment outcomes. Retreatments in group 1 are given if there is evidence of subretinal hemorrhage, subretinal, intraretinal or sub-RPE fluid by clinical exam, optical coherence tomography (OCT), or fluorescein angiogram. Retreatment is initially with ranibizumab, but after three treatments, the patient is again eligible for triple therapy. Early Treatment Diabetic Retinopathy Study (ETDRS) refractions are performed on the initial visit, and then at the 3-, 6-, 9-, and 12-month visits. OCTs are performed monthly, and angiograms are performed every 3 months.

The primary outcome measures were best corrected visual acuity (BCVA) at 6- and 12-month visits. The secondary outcome measures included treatment frequency and imaging data suggestive of ongoing lesion activity. The first patient was enrolled in August 2006, and the last patient completed his 12-month visit in December 2008. In all, 60 patients were enrolled, and 51 completed their 12-month visit.

Safety and efficacy data are now being analyzed and prepared for manuscript and will not be discussed in this article. Representative images, however, are provided for this article (Figures 1-6).

LUCEDEX CLINICAL TRIAL
We are further investigating the role of dexamethasone in AMD therapy in the LuceDex trial, which enrolled the first patient in January 2008. It is another IRB-approved, randomized, prospective clinical trial comparing Group 1 (ranibizumab plus dexamethasone) vs Group 2 (ranibizumab alone). Each group receives monthly therapy for four consecutive injections followed by as-needed therapy. Once again we are employing only ETDRS refracted visual acuity, as well as monthly OCT and quarterly angiogram. Retreatment in each group is based on any evidence of lesion activity as determined by clinical examination or imaging information. Group 1 patients continue to receive ranibizumab plus dexamethasone and group 2 will receive ranibizumab alone. Primary outcome measures are visual acuity at 6 and 12 months. Secondary outcomes will assess the need for additional treatments and imaging parameters of ongoing lesion activity.

SUMMARY
Combination therapy protocols afford the advantage of tailoring treatments based on an individual's presenting findings, ongoing response to intervention, and expectations. Data gleaned from the PDEX I trial suggested that IVD was a safe and effective adjunct in the treatment of wet AMD. PDEX II will, for the first time, compare combination therapy using PDT, dexamethasone, and ranibizumab to what is currently considered the gold standard of therapy: 12 consecutive monthly ranibizumab injections. It may help provide guidelines regarding the optimal form of therapy in regard to visual acuity, treatment frequency, and the relative risks for vision loss and gain with each form of therapy. We are hopeful for publication of this work in the first quarter of 2009. The larger-scale studies that are currently under way, including the RADICAL (Reduced Fluence Visudyne Anti-VEGF-Dexamethasone In Combination for AMD Lesions trial; see article in this issue of Retina Today, page 16) and the MONT BLANC and DENALI studies, will provide much greater insight into the relative risks and rewards of each of these treatment regimens.

Subhransu K. Ray, MD, PhD, is an Associate Clinical Professor of Ophthalmology at University of California San Francisco, Medical Center, and California Pacific Medical Center and he practices at Bay Area Retina Associates in Oakland, CA. Dr. Ray reports that he has received unrestricted grants from QLT for the PDEX I and II trials, unrestricted grants from Genentech for the LuceDex trial, and is a consultant for ongoing studies for Genentech, QLT, and Novartis. He can be reached at +1 510 832 6554; or via e-mail at retina01@gmail.com.