RF-PDT, reduced-fluence photodynamic therapy; SF-PDT, standard-fluence photodynamic therapy; DM, dexamethasone; TA, triamcinolone acetonide; IVB, bevacizumab; IVR, ranibizumab; ST, sub-Tenon; OCT, central foveal thickness optical coherence tomography from baseline to the final follow-up unless otherwise specified; IOP, intraocular pressure; VEGF, vascular endothelial growth factor; Reduced Fluence Visudyne Anti-VEGF-Dexamethasone in Combination for AMD Lesions trial, RADICAL trial.

Dexamethasone, Bevacizumab, and PDT

Augustin and Schmidt-Erfurth (25) performed a prospective noncomparative interventional case series of triple therapy in 104 treatment-naive patients with neovascular AMD. This study employed reduced-fluence PDT (70 vs. 83 seconds), with same-day single-port 25-gauge limited vitrectomy (removal of 0.5 mL) and injection of 0.8 mg dexamethasone and 1.5 mg of bevacizumab. Patients were followed at 6-week intervals, with a mean follow-up of 40 weeks. Eighteen eyes (17%) received a single additional intravitreal injection of bevacizumab for persistent macular fluid on OCT without detectable angiographic leakage, and in an additional five cases (5%), a second cycle of triple therapy was used to treat recurrent angiographic CNV activity. Mean visual acuity improved significantly from 20/126 to 20/85 (P < 0.01), and 39.4% of the patients gained three or more lines of vision, while mean retinal thickness decreased from 464 to 281 μm (P < 0.01). No patients demonstrated significant intraocular pressure (IOP) elevation.

Forte et al. (63) performed retrospective case series comparing triple therapy in 61 eyes of 56 treatment-naive patients to anti-VEGF monotherapy in 40 eyes of 40 treatment-naive patients (63). The investigators utilized standard-fluence PDT followed by same-day intravitreal injections of 0.4 mg dexamethasone and either 1.25 mg bevacizumab (26 eyes) or 0.5 mg ranibizumab (35 eyes). Patients were followed at 1- to 2-month intervals with a mean follow-up of 14.1 months in the triple therapy group. A mean of 0.92 retreatments with triple therapy were given over 12 months at the managing physician’s discretion. At 12 months, the triple therapy group demonstrated improvement in mean visual acuity from baseline of 20/174 to 20/120 (P = 0.02), and likewise, mean retinal thickness improved from 323 to 212 μm (P < 0.01). Compared to the anti-VEGF monotherapy group, the triple therapy group required significantly fewer total number of treatments during follow-up (1.92 vs. 3.12), significantly fewer monthly treatments (0.13 vs. 0.19), and demonstrated a longer interval prior to first retreatment (5.4 vs. 3.6 months).

Ehmann and Garcia (64) reported a retrospective interventional case series in 32 eyes of 30 treatment-naive patients. The authors studied reduced-fluence PDT (25 J/cm²) followed by an intravitreal injection of 0.8 mg dexamethasone the same day, with subsequent intravitreal injections of 1.25 mg bevacizumab at 1 and 7 weeks after PDT. All patients were followed for 12 months. At 13 weeks after initial PDT and dexamethasone, repeat OCT and fluorescein angiography were performed to assess CNV activity. The mean number of treatment cycles was 1.4, with 22 (69%) eyes requiring only one cycle of treatment. Mean visual acuity improved from 20/110 at baseline to 20/68 at 12 months (P < 0.01), with associated foveal thickness decreased from 328 to 216 μm (P < 0.01). No patients demonstrated a significant IOP elevation.

Bakri et al. (62) compiled a retrospective case series of 31 patients treated with triple therapy for AMD, of which 18 patients (58%) had received anti-VEGF therapy prior to enrollment (mean 3.6 injections). This study examined reduced-fluence PDT (25 J/cm²) followed by same-day intravitreal injections of 0.2 mg dexamethasone and 1.25 mg bevacizumab. Patients were followed at 1- to 2-month intervals with a mean follow-up of 13.7 months. Retreatment was given in all patients based on physician-dependent retreatment criteria. A mean of 1.7 bevacizumab injections and 0.2 repeat triple therapy treatments per patient were given in the first 6 months, and a mean of 2.3 bevacizumab injections and 0.3 repeat triple therapy treatments were given throughout follow-up. In all patients, change in mean visual acuity from baseline (20/80) to final follow-up (20/60) was not statistically significant (P = 0.69). Subgroup analysis of treatment-naive eyes and previously treated eyes likewise revealed no significant improvement in visual acuity. For all patients, there was a borderline improvement in mean retinal thickness (293 μm at baseline to 245 μm at final follow-up, P = 0.053). No patients demonstrated significant IOP elevation.

Triamcinolone, Bevacizumab, and PDT

Ahmadieh et al. (65) performed a prospective interventional case series in 17 treatment-naive eyes. They studied standard-fluence PDT followed by intravitreal injections of 2 mg triamcinolone and 1.25 mg bevacizumab 48 hours after PDT. Patients were followed at 6-week intervals for a mean follow-up of 50.4 weeks. CNV activity on angiography required retreatment with intravitreal bevacizumab. Seven eyes (41%) did not require retreatment, while 10 eyes (59%) were retreated, and most eyes required two additional bevacizumab injections. Mean visual acuity in the triple therapy group improved from 20/110 at baseline to 20/51 (P < 0.01) after 24 weeks, and similarly, mean retinal thickness improved from 395 at baseline to 221 μm (P = 0.05) at the same time points. IOP elevation was noted in one patient, but the IOP was controlled with topical medications.

Yip et al. (66) performed a prospective interventional case series in 36 eyes, 15 (42%) of which had undergone prior PDT. The investigators utilized standard-fluence PDT followed by same-day intravitreal injections of 4 mg triamcinolone and 1.25 mg bevacizumab. Follow-up was 1 week, 6 weeks, 3 months, and then every 3 months after treatment for a mean follow-up of 14.7 months. Retreatment with bevacizumab was required if fluorescein angiography demonstrated CNV activity at 3 months, and eight eyes (22%) required repeat injections. Mean visual acuity demonstrated no significant improvement from 20/332 at baseline to 20/303 (P = 0.60) at 6 months. Foveal thickness on OCT was not followed. Multiple complications were reported including one RPE rip, significant cataract requiring surgery in three eyes, and IOP elevations in three eyes that were controlled with eyedrops.

Kovacs et al. (67) collected a retrospective case series of triple therapy in 26 treatment-naive patients. This group studied reduced-fluence PDT (25 J/cm²) followed by an intravitreal injection of 1.25 mg bevacizumab and a sub-Tenon’s injection of 40 mg triamcinolone at the same visit. Patients were followed at variable intervals for a mean of 56.7 weeks, and retreatment with intravitreal bevacizumab was at the physician’s discretion. By the end of the study, 13 of 26 eyes (50%) needed retreatment; 11/18 eyes (61.1%) required retreatment by 12 months. Mean visual acuity demonstrated no significant improvement from 20/243 at baseline to 20/218 (P = 0.21) at 6 months. In one patient, an increase in IOP after treatment was controlled with topical medications.

Dexamethasone, Ranibizumab, and PDT

The RADICAL study was a single-masked, randomized, multicenter phase II trial that compared the efficacy of reduced-fluence PDT and ranibizumab combination therapy, with or without dexamethasone, with ranibizumab monotherapy in 131 treatment-naive patients with neovascular AMD. The trial comprised four study groups, comparing half-fluence PDT with ranibizumab, half-fluence PDT with ranibizumab and dexamethasone, and quarter-fluence PDT with ranibizumab and dexamethasone to ranibizumab monotherapy. Doses of 0.5 mg ranibizumab and 0.5 mg dexamethasone are used for all treatment groups. Patients were followed monthly for the first year and quarterly or more frequently at the physician’s discretion for the 2nd year. At 12 months, triple therapy with half-fluence PDT, ranibizumab, and dexamethasone demonstrated a visual improvement of +6.8 letters compared with +6.5 letters in the ranibizumab monotherapy group. After 24 months, triple therapy required a mean of 4.2 retreatments compared to 8.9 retreatments in the ranibizumab monotherapy group. The outcomes of the RADICAL trial were presented at the 2010 American Society of Retinal Specialist’s meeting, but a final published report in the peer-reviewed literature is pending (68).

Radiation + Anti-VEGF

Brachytherapy and external beam therapy are the two radiation delivery methods that have been utilized for treatment of neovascular AMD. Brachytherapy requires a radiation source placed close to the macula. During epimacular brachytherapy, a probe is inserted through the pars plana and held over the macula for a short period of time for radiation delivery. Alternatively, plaque brachytherapy utilizes a radioactive plaque sewn onto the sclera adjacent to the macula for radiation delivery. External beam radiotherapy utilizes radiation from a source outside the body directed at the lesion of concern. Delivery systems for external beam radiotherapy vary from hospital-based to office-based systems.

The Cochrane collaboration reviewed 13 randomized controlled trials that investigated external beam radiation monotherapy in 1,154 eyes with neovascular AMD. The radiation dose in the studies varied from 7.5 to 25 grays (Gy). The primary outcome of this review was loss of visual acuity defined as the dichotomous variable “more than six lines of vision loss,” and secondary outcomes included change in visual acuity from baseline as a continuous variable. This review noted a 40% relative risk reduction of more than six lines of vision loss at 12 months; however, this finding was not maintained at 24 months. Importantly, this review also noted no significant adverse events with 2 Gy radiation fractions up to a total dose of 20 Gy, though some ocular complications were noted at a dose of 25 Gy. The authors concluded that meta-analysis did not support the use of external beam radiation monotherapy for neovascular AMD (34). Similarly, results were reported from a randomized, controlled, 36-month trial of Strontium plaque brachytherapy for 88 eyes with neovascular AMD. This study investigated two different dosages of radiation, with a maximum dosage of 15 Gy. The primary trial outcome was change in visual acuity, and no significant difference between observation and plaque radiation was reported after 12 months of follow-up (69).

Though current evidence does not support external beam or plaque radiation as monotherapy for neovascular AMD, combination therapy with VEGF blockade and two innovative methods of radiation delivery is currently being investigated. Epimacular brachytherapy (Epi-Rad, Neovista, Fremont, CA) is one such method of radiation delivery that uses a probe surgically placed through the pars plana and held over the area of neovascularization. Another is an office-based external beam device (IRay, Oraya Therapeutics, Inc., Newark, CA).

Epimacular brachytherapy requires a pars plana vitrectomy, placement of a proprietary epimacular radiation applicator adjacent to the CNV, and delivery of 24 Gy of beta radiation over approximately 4 minutes. The radiation applicator houses the Strontium-90 isotope in a shielded container, and the isotope can be deployed to the minimally shielded applicator tip intraoperatively (70). Avila et al. (71) investigated the effects of radiation applicator treatment in combination with two bevacizumab treatments in 34 eyes. Intravitreal bevacizumab was dosed either 10 days prior to radiation treatment or immediately after the radiation treatment. Outcomes were reported at 12 months, and 36-month follow-up is planned. After 12 months, the mean change from baseline was a gain of +8.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, with 38% of patients demonstrating a ≥15 letter gain in vision. Likewise, the mean baseline thickness at the foveal center was 322 μm and improved to 250 μm at 12 months. Maximal vision gain and reduction in foveal center thickness from baseline were noted at 3 and 6 months, respectively. No cases of radiation retinopathy or radiation optic neuropathy were reported.

The noteworthy findings reported by Avila et al. are undergoing current investigation in other larger trials combining vitrectomy, epimacular brachytherapy, and intravitreal ranibizumab in comparison to ranibizumab monotherapy for treatment-naive patients with neovascular AMD. These studies include the CABERNET and MERITAGE trials based in the United States and the United Kingdom, respectively. The MERLOT study is also investigating the efficacy of Epi-Rad for patients requiring persistent anti-VEGF treatments.

The CABERNET trial 24-month results were presented at the Angiogenesis 2012 meeting (72). In the vitrectomy + epimacular brachytherapy + ranibizumab combination therapy group, ranibizumab was administered at baseline, 1 month, and then as needed during monthly follow-up visits. In the monotherapy group, ranibizumab was administered during each of the first three monthly visits and then as needed during remaining monthly visits. The epimacular brachytherapy combination therapy group demonstrated a mean loss of −2.5 letters at 24 months compared to a +4.4 letter gain for the ranibizumab monotherapy group. Patients in the combination therapy group received an average of 6 injections over 24 months, while the ranibizumab monotherapy group received 11 injections over the same duration. The epimacular brachytherapy combination therapy group failed to meet the 10% noninferiority margin compared to ranibizumab monotherapy. Of the 310 patients undergoing epimacular brachytherapy combination therapy, there were 10 patients with signs of possible early radiation retinopathy by 24 months and no patients with definitive proliferative radiation retinopathy. The preliminary results of the CABERNET trial do not currently support a role for epimacular brachytherapy combination therapy as a first-line treatment of neovascular AMD.

The IRay is an office-based, stereotactic, robotic, radiotherapy platform designed to deliver low-energy x-ray radiation through the pars plana to the macula. The device features eye tracking to accurately direct radiation and cease radiation delivery in the event of excess eye movement. After standard A-scan ultrasound, radiation is delivered at three separate locations through the inferior pars plana to overlap on the macula. Exposure to adjacent structures is minimized by a lid speculum, and appropriate radiation angulation prevents radiation to the lens (73). In a preliminary prospective study of 19 patients undergoing ranibizumab injections and 24-Gy macular radiation via the office-based external beam system, a mean change in visual acuity of +6.4 letters from baseline at 6 months was noted. After the initial two required injections, a mean of 0.4 ranibizumab injections were administered to each patient over 6 months (74). In another small prospective study of 26 patients undergoing ranibizumab injections and 16-Gy macular radiation via the office-based external beam system, a mean change in visual acuity of +9.5 letters from baseline after 6 months was noted. After the initial two required injections, a mean of 0.5 ranibizumab injections were administered to each patient over 6 months (75). No radiation-related adverse events were reported in either preliminary study. Combination therapy using the office-based external beam system in conjunction with ranibizumab is currently undergoing phase II study as part of the Investigation of Nontransplant-Eligible Patients Who Are Inotrope Dependent (INTREPID) trial in Europe as well as another trial in Mexico.

Anti-PDGF + Anti-VEGF

Combining PDGF and VEGF inhibition has replicated animal model CNV regression (44) in human subjects. E10030 (Ophthotech, Princeton, NJ) is an PDGF blocking aptamer that has completed phase I testing in 22 patients with results presented at ARVO 2009 (76). Treatment-naive patients were given separate sequential injections of 0.5 mg ranibizumab and E10030 as one of four different doses on a monthly basis. At the 12-week primary endpoint, the mean change in visual acuity was +15.7 letters, and 60% of patients gained 15 letters from baseline overall. Over the same time frame, the mean center point retinal thickness decreased from 395 μm at baseline to 229 μm, and 85% of lesions demonstrated CNV regression on fluorescein angiography. No adverse events were reported in this initial series. Of note, 12-week follow-up was reported for only 15 patients at the ARVO 2009 meeting. Combination therapy with E10030 and ranibizumab is currently undergoing phase II study.

Conclusion

Monthly intravitreal injections with ranibizumab remain the gold standard for treatment of neovascular AMD, although 1-year results from the CATT trial suggest that PRN treatment with monthly follow-up, and OCT-guided dosing can produce comparable visual outcomes with a mean of approximately seven and eight injections of ranibizumab and bevacizumab, respectively (9). Results from the VIEW-1 and VIEW-2 trials demonstrate equivalence between monthly ranibizumab and injection of aflibercept every 2 months after three initial monthly injections; however, it remains to be seen how aflibercept will be used clinically and how often patients will require follow-up. Frequent injections and even frequent clinic visits without injections are burdensome to patients, so the need remains for other therapeutic innovation. Additionally, some patients with neovascular AMD have persistent decreased visual acuity or persistent signs of active exudation despite prolonged serial anti-VEGF therapy. These patients may benefit from a combination therapy approach to either improve efficacy or decrease treatment burden. Neovascular AMD is a multifactorial process involving angiogenic stimulus, inflammation, and mesenchymal cell alteration. Selective inhibition at multiple points of this cascade offers potential theoretical benefits over VEGF blockade alone.

Several studies reviewed above, including unpublished results from the RADICAL trial, suggest a potential role for triple therapy to reduce treatment burden for selected cases of neovascular AMD. However, decreasing treatment frequency may sacrifice some of the visual acuity benefit seen with monthly anti-VEGF therapy. Further investigations will be needed to delineate optimal PDT fluence, choice and dose of steroid, and anti-VEGF dosing and follow-up interval. The preliminary results of the DENALI and CABERNET trials do not support a role for combination PDT + anti-VEGF or epimacular radiation brachytherapy + anti-VEGF in patients with new-onset neovascular AMD. Combination therapy with one or more therapeutic modalities such as PDT, steroid, radiation, and PDGF inhibition in conjunction with VEGF inhibition remains an incompletely evaluated, but potentially useful, alternative approach to anti-VEGF monotherapy in selected patients with neovascular AMD. Anti-VEGF therapy combined with anti-PDGF treatment offers the potential for CNV regression and the possibility of enhanced visual improvement over anti-VEGF treatment alone. Larger, phase II studies are currently underway to evaluate this combination therapy approach.

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