16.5.3 Triple Therapy for Exudative AMD

In order to further address the multifactorial pathogenesis of exudative AMD, several investigators have examined the combination of corticosteroids, VPDT, and anti-VEGF agents (Table 16.2). This regimen has been referred to by the descriptive term “Triple Therapy” [133]. One of the goals of triple therapy is to improve vision to a level comparable to anti-VEGF monthly monotherapy while reducing the number of treatments in patients with CNV due to AMD.

One of the first published reports on triple therapy was a prospective, noncomparative, interventional case series of 104 patients [133]. In contrast to the previous studies with reduced-fluence, VPDT was administered in a reduced-duration fashion (42 J/cm2, accomplished by light delivery time of 70 s). Approximately 16 h after VPDT, dexamethasone (800 mg) and bevacizumab (1.5 mg) were injected intravitreally. Dexamethasone was selected over IVTA since dexamethasone could be injected as a solution and thus was more rapidly cleared from the vitreous than IVTA suspensions (thereby possibly reducing unwanted corticosteroid side effects) [133]. Patients attended follow-up visits every 6 weeks, and fluorescein angiography was performed every 3 months or earlier if OCT showed significant retinal edema. All 104 patients received one triple therapy cycle (five patients received a second triple treatment due to remaining CNV activity). The triple therapy was supplemented in 18 patients (17.3%) with an additional intravitreal injection of bevacizumab. After a mean follow-up period of 40 weeks (range, 22–60 weeks), the mean increase in visual acuity was +1.8 lines, and the mean decrease in

retinal thickness was 182 mm. No serious adverse events were observed. Thus, the study concluded that in most patients with CNV due to AMD, triple therapy resulted in significant and sustained visual acuity improvement after only one cycle of treatment. In addition, the therapy was found to be safe and convenient for patients, all at a potentially lower cost compared with therapies that must be administered more frequently [133].

Another study investigating triple therapy examined consecutive patients with subfoveal CNV secondary to AMD [134]. Patients were treated with standard-fluence VPDT using a standard protocol (600 mW/cm2 for 83 s to deliver 50 J/cm2) immediately followed by 1.25 mg of bevacizumab and 4 mg of IVTA. Then, 1.25 mg of bevacizumab was given at 3 months for residual leakage. Thirty-six eyes of 33 patients, with mean follow-up of 14.7 months were analyzed. At 6 months, 61.1% (22/36) showed stable or improved vision, and 27.8% (10/36) gained ³3 lines. Twenty-eight eyes (77.8%) achieved CNV resolution after this single session of triple therapy. One eye lost more than six lines due to retinal pigment epithelium tear, three eyes showed a significant cataract requiring surgery, and two showed persistent raised IOP at 6 months. In this study, the short-term results of single session triple therapy suggested that it may be a useful treatment option for neovascular AMD based on its low retreatment rates, sustainable CNV eradication results, and visual gain achievements [134]. Other small studies have also concluded that triple therapy may allow maintenance of visual acuity while reducing the number of necessary treatments [135–137].

For a more definitive answer, the RADICAL (Reduced Fluence Visudyne Anti-VEGF-Dexame- thasone In Combination for AMD Lesions) Study was a phase II, multicenter, randomized, single-masked study that compared the efficacy of reduced-fluence VPDT and ranibizumab combination therapy with or without dexamethasone, with ranibizumab monotherapy in 162 treatment-naive subjects with exudative AMD [138]. The unpublished 1 year results indicate that triple therapy consisting of half-fluence VPDT with ranibizumab and dexamethasone resulted in a mean visual acuity improvement of +6.8 letters compared with +6.5 letters in the ranibizumab monotherapy group. In addition, triple therapy resulted in a mean of 3 retreatment visits compared with 5.4 retreatment visits in the ranibizumab monotherapy group [135]. The full results of the RADICAL Study are eagerly awaited, as the study will provide valuable information regarding whether or not combination therapy reduces retreatment rates compared with ranibizumab monotherapy while maintaining similar visual acuity outcomes with an acceptable safety profile.

16.5.4Combination Therapy with Radiation

Another potential combination therapy for CNV is the use of ionizing radiation to induce vascular endothelial cell apoptosis [139] and reduce fibroblast proliferation [140] combined with agents that inhibit VEGF, a factor that promotes angiogenesis as well as vascular permeability [37]. Anti-VEGF agents lead to rapid reduction of intraretinal and subretinal fluid, but require repeated injections with no well-defined treatment end [37]; meanwhile, radiation has a potentially more durable effect on neovascular membranes [86, 87]. Thus, this combination seems promising [141, 142].

To test this theory, a small, prospective, nonrandomized study enrolled 34 patients with subfoveal CNV due to AMD to undergo pars plana vitrectomy and delivery of 24 Gy of Sr-90 epimacular brachytherapy (NeoVista, Fremont, CA). Some received an injection of bevacizumab 10 days prior to surgery (group 1), and the others at the time of surgery (group 2). All patients received a second treatment with bevacizumab 1 month after the vitrectomy and radiation treatment. Unfortunately, 10 of 34 participants did not meet inclusion criteria (including age, previous treatment, lesion

location/size/activity), and compliance with the timing of the first injection was poor, such that only the combined safety and efficacy data has been reported [89].

At month 12, the mean change in best-corrected visual acuity was +8.9 letters, with a zenith of +15.3 letters at the 3-month visit, 91% had lost less than 15 letters, 68% had stable or improved vision, and 38% gained 15 letters or more. Although no instances of radiation toxicity were seen, 6 of 24 phakic patients (25%) developed cataracts and 21% had continued CNV leakage, with most recurrences taking place after the 6-month follow-up visit. Other adverse events attributed to the procedure included subretinal hemorrhage (n = 1), retinal tear (n = 1), subretinal fibrosis (n = 2), and epiretinal membrane (n = 1) [143]. The trial is ongoing, with 3-year safety data expected in the future. An expanded phase III trial using combination therapy of Sr-90 epimacular brachytherapy and intravitreal ranibizumab in treatment of naïve patients called the CABERNET (CNV secondary to AMD treated with beta radiation epiretinal therapy) trial is fully enrolled with results expected in early 2011.

The MERITAGE I (Macular epiretinal brachytherapy in treated age-related macular degeneration patients) was a prospective, pilot study to evaluate the role of the combination of Sr-90 epimacular brachytherapy and intravitreal ranibizumab in patients who failed previous anti-VEGF therapy. Sixteen patients with persistent retinal fluid due to subfoveal CNV were enrolled with the specific goal of maintaining visual acuity while reducing the treatment burden. Patients were required to undergo a loading phase of three consecutive monthly anti-VEGF injections, followed by a maintenance phase with a minimum of 5 anti-VEGF injections the year prior to enrollment or three injections in the 6 months prior to enrollment. All participants underwent vitrectomy with epiretinal brachytherapy of 24 Gy Sr-90. Rigorous retreatment criteria with anti-VEGF agents included new or increased subretinal hemorrhage or CNV on fluorescein angiogram, an increase of central retinal thickness of 50 mm or greater on OCT, or a loss of 5 ETDRS letters without activity [143].

When comparing the 6 months before combination therapy to the 6 months following treatment, there was a 50% reduction in the number of anti-VEGF injections. Notably, three patients (19%) with chronic disease of greater than 2-year duration accounted for 37% of all postoperative injections. There was a mean increase of +1.2 ETDRS letters in all patients and +3.0 letters in