Core Messages

›Exudative age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age in the Western world.

›The hallmark of exudative AMD is choroidal neovascularization (CNV).

›CNV is a multifactorial process involving inflammatory, vascular, and angiogenic components.

›Commercially available treatments for exudative AMD primarily target a solitary aspect of this multifactorial disease.

›Combining various treatment modalities for exudative AMD targets multiple components of the CNV pathway and has the potential for similar, and perhaps enhanced, efficacy while reducing treatment frequency.

16.1 Introduction

The most common cause of severe vision loss in age-related macular degeneration (AMD) is the development of choroidal neovascularization (CNV), a condition termed exudative (also known as wet or neovascular)

M. Barakat (*) • N. Steinle • P.K. Kaiser

Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

e-mail: mark.barakat@gmail.com; steinln@ccf.org; pkkaiser@aol.com

AMD. Exudative AMD is the leading cause of blindness in people over 50 years of age in the Western world [1–3]. Unfortunately, the worldwide prevalence of exudative AMD is predicted to increase as life expectancy continues to improve [4]. Fortunately, there have been many recent advances in the management of exudative AMD, including the advent of medical therapies to combat CNV, which has improved the ability to fight this devastating disease.

CNV secondary to AMD is responsible for 75% of the severe vision loss attributable to AMD [5]. The pathogenesis of CNV has been the subject of widespread research and debate. CNV is thought to be attributable to various processes including cumulative oxidative stress associated with the ageing process, inflammation of the choriocapillaris, imbalance between proand antiangiogenic chemokines, ischemia, and pathologic increased permeability of the choriocapillaris [6–10]. The pathogenic processes that lead to development, maintenance, and growth of CNV offer several potential targets for treatment. These treatments can be broadly divided into those that target either the inflammatory, vascular, or angiogenic components of CNV. In order to further enhance the treatment effects seen with monotherapy, the combination of therapies targeting multiple components of CNV offers the potential for even greater efficacy through additive or synergistic effects. Successful combination therapy may even reduce treatment frequency. A move toward combination therapy in the treatment of AMD would mirror successful combination treatment regimens currently utilized in other areas of medicine, including oncology [11–15], human immunodeficiency virus [16, 17], and hypertension [18, 19].

Therapies

Cortiocosteroids, including triamcinolone and dexamethasone, were some of the first pharmacologic treatments evaluated for the treatment of CNV. In addition to their anti-inflammatory effects, corticosteroids have anti-fibrotic, anti-permeability, and antiangiogenic properties [20, 21]. The beneficial effects of steroids include stabilization of the blood–retinal barrier, resorption of exudation, and downregulation of inflammatory stimuli. Corticosteroids are also potent inhibitors of neovascularization by direct and indirect angiostatic effects, and have been shown to impede the neovascular cascade by directly suppressing levels of vascular endothelial growth factor (VEGF) [22, 23]. In part, due to safety concerns, and with the advent of newer, more effective therapies, corticosteroids are now rarely used as monotherapy in exudative AMD [20]. However, the biological effects warrant further investigation, particularly in combination with other treatment modalities.

Verteporfin (Visudyne, Novartis, Basel, Switzerland) photodynamic therapy (VPDT) has a totally different mechanism of action. It is an angioocclusive therapy that is based on accumulation of the drug in the CNV followed by photoactivation of the drug with laser light [24]. This photoactivation of verteporfin generates reactive oxygen species that cause localized endothelial cell changes and vascular occlusion within the CNV while minimizing damage to the overlying retina [25, 26]. Although the primary mechanism of action of VPDT involves occlusion of the new vessels, the treatment is also likely to have secondary effects. For example, it has been shown that VPDT is pro-inflammatory, alters cytokine release, and modifies angiogenic signals including inducing increased expression of VEGF, VEGFR-3, and PEDF [27, 28]. Verteporfin therapy is approved to treat patients with subfoveal lesions composed of predominantly classic CNV (regardless of lesion size) and for those with small lesions (£4 disc areas) containing occult with no classic or minimally classic CNV and having evidence of recent disease progression [29–32].

Antiangiogenic monotherapy is another modality in the fight against exudative AMD that has been shown to inhibit cell proliferation, reduce formation and growth of new blood vessels, and minimize vascular leakage [4]. In addition, data indicates that blockade of

sels if these vessels are targeted before pericyte recruitment and vascular maturation [33].

Currently available antiangiogenic agents include pegaptanib (Macugen, Eyetech, New York, NY), ranibizumab (Lucentis, Genentech, South San Francisco, CA), and bevacizumab (Avastin, Genentech, South San Francisco, CA). Pegaptanib is a pegylated aptamer that selectively binds only to the VEGF165 isoform, but not to any other VEGF isoforms, and has been shown to reduce the risk of vision loss due to CNV in patients with AMD [34, 35].

Ranibizumab is an affinity matured, humanized Fab fragment of a mouse monoclonal antibody to VEGF that binds to all isoforms of VEGF (“pan-VEGF blockade”), inhibiting vascular permeability and angiogenesis [36]. Intravitreal ranibizumab (IVR) has been shown in pivotal phase 3 trials to stabilize or improve vision in over 90% of patients and significantly improve vision in over 30% of patients while maintaining a good safety profile, and was approved by the FDA for the treatment of exudative AMD in June 2006 [37–39].

Bevacizumab is a humanized monoclonal antibody to VEGF that, like ranibizumab, binds to all isoforms of VEGF and has been FDA approved for the treatment of colorectal cancer, breast cancer, lung cancer, and renal cell cancer [40, 41]. Although there is no formulation specifically developed for ocular use, several uncontrolled case series have reported vision improvements similar to IVR when it is used off-label as an intravitreal injection in exudative AMD [42–46]. Multiple other antiangiogenic agents are currently under evaluation for the treatment of CNV due to exudative AMD [47–52].

The susceptibility of proliferating endothelial cells to radiotherapy has been reported in several studies [53, 54]. Since CNV lesions are composed of rapidly proliferating pathologic endothelial cells, radiation therapy has been investigated as a treatment for exudative AMD due to the known radiosensitivity of these rapidly proliferating vascular endothelial cells [55]. The potential exists to selectively harm the radiosensitive proliferating endothelial cells while minimizing damage to the intrinsic retinal vasculature [56]. Radiation also has the benefit of relatively fewer treatments over the treatments described above, which can present a significant advantage for patients with transportation difficulties, such as the elderly, the disabled, or those living in rural areas [57].

Several different techniques can be used in the delivery of radiation therapy including:

–External beam radiotherapy (also known as teletherapy).

–Proton beam irradiation.

–Plaque brachytherapy.

–Epiretinal radiation therapy.

Radiation has potentially damaging effects on the

retina, optic nerve, lens, and lacrimal system [58–60]. Furthermore, elderly patients with possible vascular compromise, especially in the retinal and optic nerve circulation, might be more susceptible to radiation damage [59]. Minimizing collateral damage to normal ocular structures will be a key focal point in the demonstration of radiation therapy as a safe and effective therapy for exudative AMD. Overall, external beam radiotherapy, proton beam irradiation, and plaque brachytherapy have shown limited success in clinical testing [57, 61–87]. However, the role for these radiation modalities remains to be defined as a possible adjuvant therapy, or as an alternative for patients who decline or are not appropriate for currently superior monotherapies (e.g., anti-VEGF therapies).

Historically, external beam radiotherapy has not been successful due to poor targeting resulting in a greater volume of retinal tissue being irradiated than anticipated and a high rate of complications. The IRay device (Oraya Therapeutics, Newark, CA) is a robotically controlled, noninvasive, orthovoltage (low-voltage) X-ray irradiation therapeutic platform that delivers three 5.3 Gy beams through the inferior pars plana at the 5:00, 6:00, 7:00 o’clock meridians and overlap at the macula to deliver precisely 16 Gy to a 4 mm spot size on the macula. This targeted delivery of external beam radiation avoids high radiation levels to the surrounding structures including lens, optic nerve, and brain.

Another approach to the delivery of radiation to the macula is the use of an intraocular epiretinal probe (NeoVista, Fremont, CA) for targeted delivery. In contrast to external beam radiation and plaque brachytherapy, this approach has the potential to reach therapeutic doses at the macula with even less radiation exposure to surrounding tissues. An intraocular strontium-90 (Sr-90) applicator that delivers either 15 or 24 Gy of beta radiation has shown vision stabilization in over 80% of patients in phase II testing at 1 year [88]. Adverse events in early clinical trials were chiefly limited to those due to the vitrectomy needed to insert the probe, with no radiation toxicity seen during years 1 or 2 [88, 89]. However, both safety and efficacy results are still preliminary in nature and the pivotal phase 3 results are pending.

A number of other treatments for subfoveal CNV due to exudative AMD have been tried, with limited success. These alternatives include laser photocoagulation [90–92], submacular surgery [93, 94], macular translocation [95], macular transplantation [96], and other antiangiogenic drug therapies such as interferon alpha [97, 98].

16.3Current Limitation of Therapy in the Treatment of Exudative AMD

Despite significant advancements made in the understanding and treatment of exudative AMD over the past decade, the need for therapeutic improvement exists. For example, of all the treatments investigated to date, the intravitreal anti-VEGF therapies have been the most clinically successful. However, treatment with anti-VEGF monotherapy does not improve vision in all patients, and it appears that frequent retreatments are necessary to maintain efficacy [37, 38, 99]. Given the frequency of injections, it is important to note that each intravitreal treatment carries a risk of endophthalmitis, uveitis, cataract formation, retinal tear, and retinal detachment, not to mention physical, emotional, and financial stress [37, 38, 99]. The current treatment regimens with intravitreal antiVEGF injection therapies have no defined endpoint; thus, it is unknown how long these therapies must be continued.

Furthermore, the enduring effect on vision is unknown once therapy is halted. Moreover, VEGF is an important neuroprotective molecule within the eye, and is not exclusively expressed by the pathological neovascular tissues. Thus, reducing the number of antiVEGF injections could potentially lower the risk of disrupting the normal physiological processes mediated by VEGF [100–103]. Finally, it is also difficult to predict long-term patient compliance given the high frequency of intravitreal injections in the current anti-VEGF treatment regimens [104].

16.4Rationale for Combination Therapy in the Treatment of Exudative AMD

Evidence suggests that anti-VEGF agents become less effective as neovascularization matures, especially as the vessels become enveloped by pericytes. These