Intravitreal Anti-VEGF Plus PDT Combination Therapy for Neovascular AMD: A Clinical Perspective
Vascular endothelial growth factor (VEGF), the major stimulus for growth of choroidal neovascularization (CNV), is now the main target of monoclonal antibodies in the treatment of neovascular age-related macular degeneration (AMD). For the first time in the history of neovascular AMD therapy, an average improvement in visual acuity may be achieved using these agents. Cost-utility analysis has shown that one such agent, ranibizumab, almost doubles the improvement in quality of life of AMD patients compared with photodynamic therapy with verteporfin (PDT).1-6
Anti-VEGF agents such as ranibizumab (Lucentis) and bevacizumab (Avastin) often require intravitreal injections in four- to six-week intervals, with repeated exposure to such injection-related risks as endophthalmitis, and frequent follow-up visits.7-12 Although patients with neovascular AMD are receiving better treatment than ever before, they must make significant sacrifices in time. Also, the expense to third-party payers is substantial. As a result, PDT has been revisited as a complementary treatment to anti-VEGF therapy. Anti-VEGF therapy decreases angiogenesis and vascular permeability, resulting in suppression of CNV. PDT may cause relatively immediate closure of CNV. By adding PDT to an anti-VEGF regimen, permanent inhibition of CNV may be possible, with a reduction in the number of required injections. This concept of synergy has been the topic of several published papers and has led to the organization of large, multi-centered randomized controlled trials, such as the DENALI trial.
We previously reported our experience with intravitreal bevacizumab (give dose) combined with PDT at the Barnes Retina Institute, and others have since reported their experience using this combination.13-16 In our retrospective review, treatment-naive patients received bevacizumab followed by PDT within a one to two week interval. Treatment with the same combination was repeated based upon persistent subretinal fluid (by optical coherence tomography) or leakage on fluorescein angiography. Of the 40 eyes, 26 (65%) required only a single initial treatment of combination therapy to maintain lesion inactivity for at least six months. Thirteen eyes (33%) received only a single retreatment, and four of these eyes had subfoveal fibrosis. Only one eye (2%) underwent two retreatments with combination therapy. The mean time to retreatment was 110 days. Thirty-three eyes (83%) had stabilization of visual acuity, and 29 eyes (73%) had an improvement in visual acuity. Thirteen (33%) gained three or more lines of visual acuity. Across all lesion subtypes, the mean improvement in visual acuity was 1.73 lines. There were 23 eyes with at least 12-month follow-up, and a remarkable 74% of this group achieved stabilization of their visual acuity with only a single combination treatment. There were no ocular or systemic complications noted in this series. This suggests a benefit of combining intravitreal anti-VEGF with PDT.
David Misch, MD, of Florida presented his experience with intravitreal bevacizumab combined with PDT (the injection and PDT were separated by about a week with most patients receiving the injection before PDT) at the 2006 Annual Meeting of the American Society of Retina Specialists. He followed 63 treatment-naive eyes for a mean of 229 days and found 88% experienced visual acuity stabilization with combination therapy. More than one-third of the eyes experienced a gain of three or more lines in visual acuity. Only 35% underwent retreatment. In his second cohort of 44 eyes that had undergone previous therapies, 74% achieved stabilization with a mean follow-up of 335 days. Twenty-eight percent gained three or more lines of visual acuity, and 41% underwent retreatment.
Another group recently reported its initial results of PDT combined with intravitreal bevacizumab in 165 eyes.17 Fifty-five were randomized to PDT alone, 55 to 1.25 mg intravitreal bevacizumab alone and 55 to combination therapy consisting of intravitreal bevacizumab injection followed by PDT. Visual acuity improvement was observed in both the bevacizumab-alone and combination therapy groups. Those in the PDT-alone group experienced a slight worsening of visual acuity. Significant reductions of central foveal thickness measured by optical coherence tomography were observed in all three groups. The follow-up was three months, and only 23 of the 46 eyes with a visual acuity improvement at one month sustained this improvement at the final follow-up. However, most interesting is the fact that of these 23 eyes, 22 (96%) received treatment with bevacizumab combined with PDT, suggesting that PDT may help to sustain the visual acuity improvement that is achieved with bevacizumab. Likewise, in another study, 64% of 11 patients who previously failed treatment with PDT alone required only a single additional combination treatment in six months.13 None of the eyes progressed after combination therapy of intravitreal bevacizumab and PDT.
Other clinicians have added a third agent such as a steroid to their combination therapy regimen. One group treated 17 patients with PDT combined with both intravitreal bevacizumab and intravitreal triamcinolone.14 The mean central macular thickness was reduced from 395 to 221 µm at 24 weeks of follow-up. Repeat injections of intravitreal bevacizumab alone were performed if fluorescein angiography continued to suggest CNV activity. During an average follow-up period of about four months, almost 60% underwent only a single retreatment consisting of bevacizumab alone to maintain initial visual gains and central macular thickness reductions.
Another study evaluated reduced-fluence PDT in combination with intravitreal dexamethasone and bevacizumab for CNV secondary to AMD.18 Of 104 patients receiving triple therapy, only five (5%) underwent a second session of triple treatment during the mean follow-up time of 10 months. The triple therapy was complemented in 18 patients (17%) by an additional intravitreal injection of bevacizumab. The mean increase in visual acuity was 1.8 lines with a mean decrease in retinal thickness of 182 µm. The authors concluded that significant and sustained visual acuity improvement was possible after only one cycle of treatment.
These reports suggest a possible benefit to combining PDT with intravitreal bevacizumab. The number of treatments required to stabilize eyes or, in some patients, improve visual acuity, may be reduced compared to using anti-VEGF injections alone. The need for repeated injections with anti-VEGF monotherapy suggests that the neovascular complexes are not extinguished, but may lay dormant so long as the neovascular drive from VEGF is quelled. It may be that PDT is necessary to disrupt the architectural components of CNV (accessory support cells) that do not respond to VEGF inhibition or may cause immediate closure of the abnormal vessels.
There are, however, many unanswered questions including: the optimal timing of each therapy in relation to one another; the optimal timing for retreatment; how to retreat (combination versus monotherapy); and the possible addition of other agents. The fluence at which PDT should be administered when combined with anti-VEGF agents has also been questioned. The VIM (Verteporfin In Minimally Classic CNV) study showed a trend favoring reduced-fluence PDT for minimally classic CNV. We currently treat all cases with reduced fluence using criteria from the VIM trial (standard fluence: 50 Joules / 600 mW per cm2; reduced fluence: 25 Joules / 300 mW per cm2) in an attempt to minimize collateral damage. Further, it is not yet known if the final visual outcome is improved when PDT is added compared to when intravitreal agents alone are employed. These questions can only be answered through a randomized controlled trial. It is important to note that large studies of anti-VEGF agents (MARINA and ANCHOR) exclude eyes with subretinal fibrosis. Many of the studies reviewed here include these eyes, which may limit final visual outcomes, and this must be considered when reviewing these small case series.
Fortunately, the interest in improving patients’ vision as well as a desire to use a treatment that may involve fewer intravitreal injections and is less intrusive into patients’ lives have led to the development of randomized controlled trials to help answer these remaining questions.
Neovascular AMD is a chronic disease capable of causing devastating vision loss. Although therapy with anti-VEGF agents is the gold standard, many intravitreal injections are often needed. Complementing anti-VEGF therapy with other agents such as PDT may decrease the social and economic burden to patients. Further study is needed to determine at which stage CNV becomes less responsive to VEGF inhibition, and at what critical threshold VEGF sparks de novo or recurrent neovascularization. Ongoing randomized controlled
trials will provide many answers to the possible benefit of combining therapies for neovascular AMD.
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About our author(s):
Gaurav Shah, MD
Associate Professor of Ophthalmology
Barnes Retina Institute
St Louis, MO