Age-related macular degeneration (AMD) is the most frequent cause of blindness among individuals aged 55 years or older in developed countries, and thus AMD is a major health problem worldwide (1). This impact of AMD is expected to grow in magnitude in the upcoming decade owing to progressive increases in both life expectancy and the proportion of elderly persons. In the United States alone, it is estimated that the number of persons having late AMD will increase to 2.95 million by 2020 (1). The choroidal neovascular (CNV) lesions of AMD lead to the vast majority of severe visual loss from this ocular disease (2). In a meta-analysis of 53 studies of eyes with untreated neovascular AMD, the mean vision loss was three lines after 1 year and four lines after 2 years of follow-up. In this same work, after 3 years after CNV onset, 75.7% of patients demonstrated 20/200 or worse vision and 41.9% of patients lost more than six lines of vision from baseline (3).

The exact pathophysiology of CNV is complex and not completely understood. In eyes with AMD, oxidative stress and inflammation at the level of the retinal pigment epithelium (RPE) and Bruch’s membrane may imbalance the homeostatic equilibrium and lead to up-regulation of angiogenic and inflammatory factors (4). These factors in turn may lead to promotion of a CNV membrane composed of inflammatory, vascular, and nonvascular components such as glial cell, fibroblasts, and a remodeled extracellular matrix (5).

Targeted modulation of the proangiogenic cascade in neovascular AMD through inhibition of vascular endothelial growth factor (VEGF) has been one of the triumphs of modern medicine. Off-label monthly intravitreal injection of bevacizumab (Avastin, Roche, Basel, Switzerland), a full-length humanized monoclonal antibody targeted against VEGF-A, demonstrated the ability to improve visual acuity in eyes with neovascular AMD (6,7,8,9). The landmark MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) studies demonstrated the ability of monthly injections of ranibizumab (Lucentis, Roche, Basel, Switzerland), a monoclonal antibody fragment, to improve visual acuity in eyes with neovascular AMD after 2 years of serial treatment (10,11). One-year results from the Comparison of AMD Treatments Trial (CATT) showed that monthly treatment with bevacizumab was not inferior to ranibizumab monthly treatment at 1 year and that pro re nata (PRN) injection of ranibizumab and bevacizumab using strict retreatment criteria was not inferior to monthly treatment (9). More recently, in November 2011, intravitreal aflibercept (Eylea, Regeneron Pharmaceuticals, Tarrytown, NY) was FDA approved for the treatment of neovascular AMD based
on results from the phase III studies VIEW-1 and VIEW-2 (VEGF Trap: Investigation of Efficacy and Safety in Wet AMD). These trials showed aflibercept to be equivalent to monthly ranibizumab injections in treatment of neovascular AMD with aflibercept dosed either monthly or every 2 months (after three monthly loading doses) (12,13). The results of the VIEW-1 and VIEW-2 studies are not yet published.

Ranibizumab and bevacizumab have been revolutionary advances in the treatment of neovascular AMD; however, the burden of repeated monthly clinic visits and injections remains significant. Investigators attempted to decrease the number of injections by using various individualized protocols. Using optical coherence tomography (OCT) and strict retreatment criteria, monthly follow-up in conjunction with PRN dosing of intravitreal ranibizumab has demonstrated visual acuity results comparable to monthly ranibizumab dosing (9,14,15). However, monthly follow-up with PRN dosing schedules does not address the burden of frequent clinic visits on patients and caregivers (16,17).

The newly FDA-approved aflibercept may also theoretically decrease the need for monthly injections, as data from phase III trials suggest that injections of aflibercept every 8 weeks after three monthly loaded doses resulted in comparable visual acuity and anatomic results to monthly injections with ranibizumab. However, clinical experience with this newly approved medication is thus far limited, and patients receiving aflibercept will still continue to require close follow-up and frequent treatments.

In addition to the burden of frequent clinic visits and serial intravitreal injections, VEGF blockade does not directly address the inflammatory and mesenchymal remodeling components of CNV development (18). Though inhibition of VEGF may also have some effect on these alternate mechanisms of CNV formation, concomitant treatment of neovascular AMD with a variety of therapeutic modalities theoretically offers the potential to decrease treatment burden and improve outcomes (5). Combination therapy with one or more treatment modalities such as photodynamic therapy (PDT), intraocular corticosteroid, radiation therapy, or anti-platelet-derived growth factor (PDGF) therapy, in conjunction with VEGF inhibition, is an example of an approach that may more broadly target both vascular and extravascular pathways of CNV formation. This type of multifaceted approach has been successfully utilized by oncologists when treating cancer and thus may also be a reasonable conceptual approach when treating neovascular AMD (5).

Prior to development of anti-VEGF medications, PDT was the standard of care for treatment of some forms of neovascular AMD. In 2000, the FDA approved the use of PDT for treatment of predominantly classic CNV secondary to AMD. PDT reduced the rate of vision loss but did not offer vision gain for the vast majority of treated patients with neovascular AMD. The standard PDT protocol utilizes intravenous infusion of verteporfin (Visudyne, QLT, Menlo Park, CA) activated by subsequent administration of nonthermal low-energy red laser light over 83 seconds. Photoactivation of verteporfin with laser results in free radical formation within the CNV lesion, resulting in damage to the vascular endothelium and subsequent vessel occlusion (19,20). Compared to thermal laser, PDT is less destructive; however, PDT can still induce choroidal hypoperfusion (21). Free radical release may be the causative mechanism that leads to some damage to the choroid (21). Additionally, PDT has also been shown to up-regulate intraocular VEGF production from the choroidal endothelial cells (22). One method to limit the toxicity of PDT is to reduce the fluence by either decreasing the power of laser light (less than 50 J/cm²) or reducing overall treatment time (less than 83 seconds). Studies have demonstrated that reduced-fluence PDT has similar therapeutic efficacy for CNV but potentially reduces the amount of choroidal toxicity seen with standard-fluence PDT (20,23).

Intravitreal corticosteroids may be a way to minimize unwanted inflammation produced during PDT treatment for neovascular AMD. Combining corticosteroid and PDT has been shown to reduce the need for retreatment with PDT in several studies (24,25,26,27). In addition to their potent anti-inflammatory effects, corticosteroids have been shown to demonstrate antiproliferative, antiangiogenic, and antifibrotic effects (28,29). In particular, intraocular steroids can decrease intraocular VEGF levels while also reducing levels of several other inflammatory cytokines (18). Triamcinolone acetonide and dexamethasone are examples of two commonly used steroids for intraocular therapy. The half-life of intraocular triamcinolone is approximately 3 weeks with a clinical effect lasting months. In contrast, dexamethasone is more potent but has a shorter half-life of approximately 3 days (30). Compared to triamcinolone, dexamethasone is less lipophilic, which leads to decreased trabecular meshwork adhesion and potentially a more favorable side effect profile (31).

Radiation therapy may be another approach to address the multifactorial etiology of CNV. Radiation therapy can partly inhibit angiogenic, inflammatory, and fibrotic pathways (32,33,34). The antiangiogenic effect of radiation therapy on endothelial cells in particular has been well established (35,36). Aside from their atypical location, blood vessels within CNV membranes demonstrate uncontrolled growth, atypical orientation, and increased permeability, which may make them more susceptible to radiation. Radiation therapy has been shown to promote a return to more normal vascular morphology in vascular membranes (37). The anti-inflammatory properties of radiation may also limit the continuous inflammatory cycle of CNV initiation, growth, involution, and reactivation (38). In addition, the antifibrotic effects of radiation (39) may decrease the potential for metaplastic transformation from CNV to macular scar (38).

Prevention of CNV maturation through inhibition of PDGF may result in CNV regression and lead to improved visual and anatomical outcomes in patients with neovascular AMD. Immature CNV is comprised mainly of endothelial
cells that mature in part through PDGF-mediated recruitment of pericytes (40). The pericytes support survival and development (41) of endothelial cells through a variety of physical and chemical mechanisms including production of VEGF (42). Pericyte stabilization of CNV endothelial cells may result in some innate resistance to VEGF blockade (43), and thus, preventing this pericyte recruitment through PDGF inhibition might result in CNV instability and regression (40). For example, PDGF inhibition in one animal model resulted in complete prevention of pericyte recruitment (44). Another animal study demonstrated that inhibition of both PDGF and VEGF was more effective in causing CNV regression than was anti-VEGF monotherapy (44).

PDT promotes neovascular regression via a vaso-occlusive mechanism of action, and the combination of VEGF blockage with PDT has potential for additive or synergistic effects. In particular, combined therapy may allow for longer treatment-free intervals and decreased number of intravitreal injections over time (45). Several prospective studies have examined the utility of standard-fluence PDT + bevacizumab (46,47,48). These studies all have shown stability or modest improvement in visual acuity and reduced number of treatments for the PDT + bevacizumab groups. More recently, investigators retrospectively compared 139 eyes with bevacizumab-treated neovascular AMD to 236 eyes treated with PDT + bevacizumab. At 12 months, the monotherapy group demonstrated a +5.1-letter gain compared to +4.8 letters in the combination treatment group. No significant difference in number of injections between groups was noted (49).

For AMD patients with predominantly classic CNV, the RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety (FOCUS) study examined the efficacy of standard-fluence PDT with and without the addition of monthly intravitreal ranibizumab injections. In the FOCUS study, all patients underwent standard-fluence PDT but were randomized to receive ranibizumab or sham injection 7 days after. Intravitreal ranibizumab was administered monthly, and PDT was repeated only if persistent leakage was observed on fluorescein angiography performed on a quarterly basis. At 12 months, patients in the PDT + ranibizumab treatment group demonstrated a mean +4.9 letter gain compared to a −8.2 letter loss in the PDT + sham injection group (50). Similar results of mean +4.6 letter gain versus −7.8 letter loss were observed for the PDT + ranibizumab treatment group and the PDT + sham injection group after 24 months of follow-up, respectively (51). However, the FOCUS trial was not designed to ascertain the differential efficacy between PDT + ranibizumab and ranibizumab monotherapy.

The SUMMIT clinical trial program was conducted to better define the role of PDT in conjunction with anti-VEGF agents, as well as to better understand the role of reducedfluence PDT in the treatment of neovascular AMD. This clinical trial program included a North American study (DENALI), European study (MONT BLANC), and an Asian study (EVEREST). Both the DENALI and MONT BLANC trials were designed to show the noninferiority of PDT + ranibizumab to intravitreal ranibizumab monotherapy. Of note, ranibizumab was dosed monthly for 3 successive months then administered on a PRN basis. In addition, DENALI was designed to quantify the percentage of trial participants with treatment-free interval greater than 3 months, and MONT BLANC was designed to investigate superiority of standard-fluence PDT + ranibizumab to ranibizumab monotherapy (52).

The 12-month results of the DENALI trial showed that the standard-fluence PDT + ranibizumab group gained on average +5.3 letters from baseline, and patients in the reduced-fluence PDT + ranibizumab combination group gained on average +4.4 letters. However, patients in the monthly ranibizumab monotherapy group gained on average +8.1 letters at month 12, and thus, DENALI did not demonstrate noninferiority between the groups. Most patients in the PDT + ranibizumab combination groups (93% for standard fluence and 84% for reduced fluence) demonstrated a ranibizumab treatment-free interval of at least 3 months during the study. The 12-month results of MONT BLANC trial showed a mean change in baseline visual acuity at 12 months of +4.4 letters for the ranibizumab monotherapy group and +2.5 letters for the standard-fluence PDT +ranibizumab group, suggesting that combination therapy was not superior to monotherapy. A similar proportion of treatment-free intervals were observed for both the combination group (96%) and the monotherapy group (92%) (30). The EVEREST trial differs in that it is designed to compare standard-fluence PDT combined + ranibizumab and ranibizumab monotherapy in the treatment of polypoidal choroidal vasculopathy. Final published reports of these trials in the peer-reviewed literature are pending.

Combination therapies that target both the inflammatory and angiogenic components of the CNV cascade have been investigated as another approach to treat neovascular AMD. Two small series report short-term functional and anatomical benefit of bevacizumab and triamcinolone combination therapy (53

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