January 10, 2011
January 10, 2011
AMD is generally categorized as nonneovascular (dry) or neovascular (wet). Clinical findings of non-neovascular AMD include drusen, pigmentary changes, and atrophy of the retinal pigment epithelium with resultant gradual visual decline. Neovascular AMD occurs when choroidal neovascularization (CNV) penetrates through compromised areas of Bruch’s membrane and into the potential space between the retina and retinal pigment epithelium. Neovascularization can present with subretinal and intra-retinal edema, exudation, hemorrhage, and eventually a fibrovascular scar resulting in profound loss of central visual acuity. The vast majority of AMD related visual loss is caused by the neovascular form.2 With the aging US population, clinicians can expect to see an exponential increase in neovascular AMD over the next twenty years; in fact, it is estimated that one million individuals will develop neovascular AMD in the next five years in the US alone.3
Prior to 2000, patients with neovascular AMD had limited treatment options for subfoveal CNV. The Macular Photocoagulation Study (MPS) Group had proposed thermal laser for the treatment of subfoveal lesions.4 Although thermal laser was shown to reduce the risk of severe vision loss (≥6 lines from baseline), damage to central vision from the treatment itself was immediate, permanent, and difficult for patients to comprehend.This led to a search for alternative treatments such as photodynamic therapy (PDT), submacular surgery, and anti-angiogenesis drugs. PDT with verteporfin was the first of these new modalities to be shown to be effective in randomized controlled clinical trials and was approved by the US Food and Drug Administration (FDA) in 2000.
Verteporfin is a benzoporphyrin derivative that is administered via intravenous infusion over a ten-minute period at a concentration of 6mg/m2 of body surface area.Verteporfin is rapidly distributed throughout the body, bound to low-density lipoproteins (LDLs). Since neovascular tissue is rich in LDL receptors, verteporfin- LDL complexes preferentially accumulate in choroidal neovascular membranes.5,6 Fifteen minutes after administration, verteporfin is then activated in vivo with the application of 689nm non-thermal laser at an intensity of 600mW/cm2 for 83 seconds directly over the choroidal neovascular complex.Activation results in the formation of cytotoxic, free radicals that cause selective vasoconstriction, platelet aggregation, and fibrin clot formation in choroidal neovascular tissue resulting in vessel closure.5,6
The clinical efficacy of PDT with verteporfin for AMD has been evaluated in four large, randomized, double-blind, placebo-controlled studies. The treatment of AMD with photodynamic therapy (TAP) study showed a significant reduction in the risk of vision loss with PDT with verteporfin in patients with classic or classic plus occult subfoveal CNV. After 24 months, 53% of PDT recipients achieved the primary endpoint (<15 letters vision loss) versus 38% of those receiving placebo (p<0.001). Subgroup analysis suggested predominantly classic lesions (≥50% of lesion area) benefited the most; after two years, 59% of PDT treated patients lost less than 15 letters versus 31% of those receiving placebo in this subgroup.The mean number of PDT treatments in the first year overall was 3.4 and 2.2 in the second year.7,8
The verteporfin in photodynamic therapy (VIP) study evaluated the effects of treatment with PDT with verteporfin in mainly occult lesions. At 24 months, 46% of PDT treated eyes versus 33% of placebo were less likely to lose 15 letters of visual acuity (p=0.023). Patients were also less likely to suffer severe vision loss (≥6 lines) in the verteporfin treated group (29% vs. 47%, p=0.001). Further subgroup analysis revealed that the greatest benefit was seen in patients with lesion size ≤4 disc areas (regardless of visual acuity) or visual acuity worse than 20/50 (regardless of lesion size).9,10
Analysis of the TAP and VIP studies has suggested that lesion size is a more significant predictor of the treatment benefit than lesion composition or visual acuity.11 Minimally classic and occult lesions that were four disc areas or smaller were found to have similar visual acuity outcomes to those reported for predominantly classic lesions that were less than four disc areas. However, for larger lesions, only classic lesions demonstrated a treatment benefit from PDT.
The Visudyne® in minimally classic (VIM) trial compared standard versus reduced light fluence in PDT for patients with minimally classic subfoveal CNV. Standard fluence was 50J/cm2 in previous studies while reduced fluence in the VIM study was 25J/cm2.The 24-month data from the VIM study showed that 74% of patients receiving reduced fluence lost less than 15 letters versus 47% of those receiving standard fluence (p=0.03).12 The Visudyne® in occult (VIO) study was designed to evaluate PDT in the treatment of occult lesions with no classic component. Early analysis of the two-year data from this study revealed that PDT treatment did not meet the primary end-point in this subgroup.
In addition to neovascular vessel closure, the free radicals and inflammatory response following PDT may induce localized vascular endothelial derived growth factor (VEGF) production, and damage the choriocapillaris and retinal pigment epithelium.13
The anti-inflammatory properties of corticosteroids are well known and intra-ocular triamcinolone acetonide has recently been found to be an encouraging adjunct to PDT in patients with CNV secondary AMD.14It is possible that the favorable effects of triamcinolone are due to the steroid’s intrinsic anti-angiogenic properties and the downregulation of inflammatory pathways which are inherent to neovascular complexes.15-18
Triamcinolone may also be beneficial by limiting cytokine-induced edema and VEGF production that ensues in retinal tissue adjacent to PDT treated areas.13,19 Spaide et al. reported a small non-comparative case series that showed a reduction in loss of visual acuity with combination therapy and a reduction in the number of PDT treatments over 12 months.The 26 eyes in the study included 13 treatment-naïve CNV patients and 13 patients with previous PDT treatment.A 2.5 line mean improvement in visual acuity was observed in the newly treated group; while the previously treated group improved a mean of 0.44 lines.14Potential complications of intra-vitreal triamcinolone include sterile and infectious endophthalmitis, increased susceptibility to infection, elevated intra-ocular pressure, and retinal detachment.20-23
Alternative treatments to PDT have now focused primarily on intra-vitreal injections of anti-angiogenic therapy focusing on the VEGF molecule. Of these, ranibizumab, a recombinant humanized antibody to VEGF, has shown the most promise in randomized controlled trials.When compared directly with PDT with verteporfin (ANCHOR phase III trial at 12 months), 94% and 96% of patients, treated with ranibizumab 0.3mg and 0.5mg respectively, achieved the primary efficacy endpoint of maintaining or improving visual acuity versus 64% of those treated with PDT (p<0.0001).24
Patients receiving intra-vitreal anti-VEGF treatment are often on regular dosing schedules of every 4–6 weeks. It is unclear what particular dosing schedule is optimal or if repeated injections are necessary for complete and persistent resolution of CNV. Frequent injections place patients at a small but repeated risk of endophthalmitis and also place a significant burden on the healthcare system due to repeated follow up visits. PDT may thus still play an important role in the form of combination therapy, by reducing the need for multiple retreatments.
The on-going FOCUS phase I/II trial compares PDT versus PDT plus ranibizumab. Preliminary one year data showed that patients treated with PDT plus ranibizumab were less likely to lose ≥15 letters (90% v 68%; p=0.0003) than those receiving PDT alone.25
The treatment of neovascular AMD continues to be a therapeutic challenge. The development of PDT with verteporfin was a major step in treating subfoveal lesions without the use of thermal laser. Newer treatments such as intra-vitreal anti-VEGF treatment now have an integral role in treating neovascular AMD,but have drawbacks of frequent dosing schedules, infection risk, and high healthcare costs. Further studies are needed to determine if PDT in combination with these agents will play an increasing role in the future treatments of CNV.