The advent of anti-VEGF therapies has revolutionized treatment for exudative AMD. The efficacy of ranibizumab has been clearly demonstrated through multiple randomized clinical trials. However, the relatively short interval between treatments and the lack of permanent closure of the neovascular membrane have led many to explore the possibility of combination therapy with verteporfin.
Several years ago, we reported on profound choroidal hypoperfusion associated with combination full fluence visudyne and triamcinolone therapy. This led us to embrace the results of the VIM study showing a trend toward better visual outcomes in patients undergoing reduced fluence (50%) photodynamic therapy. Results of our first 25 patients treated with reduced fluence PDT + triamcinolone showed no evidence of profound choroidal hypoperfusion. With follow-up of approximately 1 year, 25% of these patients gained >3 lines of vision though 50% had recurrence of the subretinal membrane within 6 months of treatment. Our experience over the last 3 years has convinced me that reduced fluence photodynamic therapy does not detrimentally affect the potential improvement in visual acuity with ranibizumab therapy.
With the availability of ranibizumab and bevacizumab, combination therapy initially took a back seat to monotherapy. Certainly, monthly monotherapy with ranibizumab does deliver excellent efficacy, it is difficult to continue this treatment regimen indefinitely. In addition, monotherapy using either PIER or PRONTO requires a significant treatment burden. While randomized clinical trials are underway to determine if combination therapy (double or triple therapy) increases treatment interval or results in more permanent closure of the subretinal membrane, I would like to focus on two clinical situations for which I believe verteporfin therapy is uniquely relevant.
Patients with large peripapillary membranes with subretinal fluid tracking under the fovea are often not amenable to standard thermal laser photocoagulation. In my experience, these membranes often will not adequately respond to monotherapy with pan-VEGF blockade. A patient with a large peripapillary membrane and 20/400 vision had 3 injections of pegaptanib, 2 injections of a bevacizumab and 2 injections of ranibizumab without visual improvement or resolution of the subfoveal fluid (Figures 1-3).
Figure 1: Color photograph, fluoresecein angiogram and OCT of patient with peripapillary membrane following treatment with Pegaptanib, bevacizumab and ranibizumab.
Figure 2: Color photograph, fluoresecein angiogram and OCT of patient with peripapillary membrane following treatment with Pegaptanib, bevacizumab and ranibizumab.
Figure 3: Color photograph, fluoresecein angiogram and OCT of patient with peripapillary membrane following treatment with Pegaptanib, bevacizumab and ranibizumab.
The patient then underwent a single combination therapy of reduced fluence PDT and ranibizumab with resultant marked resolution of fluid and improvement of vision to 20/80 (Figure 4). This treatment benefit lasted approximately 1 year and she recently developed a small recurrence of hemorrhage and fluid requiring re-treatment with combination therapy.
Figure 4: OCT following combination reduced fluence PDT and ranibizumab.
Patients with retinal angiomatous proliferation can be difficult to manage. Photodynamic therapy is used with caution in these patients especially in the presence of a retinal pigment epithelial detachment as RPE rips can develop. In several patients, I have used a pan-VEGF blockade initially for several months to flatten the RPE detachment associated with retinal angiomatous proliferation (Figures 5-7 before anti-VEGF therapy, Figures 8-9 after 3 injections of bevacizumab).
Figure 5: Color photograph, fluorescein angiogram and OCT of patient with retinal angiomatous proliferation before therapy.
Figure 6: Color photograph, fluorescein angiogram and OCT of patient with retinal angiomatous proliferation before therapy.
Figure 7: Color photograph, fluorescein angiogram and OCT of patient with retinal angiomatous proliferation before therapy.
Figure 8: Color photograph and OCT following 3 monthly injections of bevacizumab. Color photograph shows marked reduction in hard yellow exudates. OCT shows complete resolution of subretinal fluid and RPE detachment.
Figure 9: Color photograph and OCT following 3 monthly injections of bevacizumab. Color photograph shows marked reduction in hard yellow exudates. OCT shows complete resolution of subretinal fluid and RPE detachment.
With careful follow-up, at the first sign of re-activation based upon recurrent fluid on OCT-do not allow RPE detachment to reform (Figure 10-11), I perform reduced fluence PDT in combination with bevacizumab. This has resulted in prolonged closure of the blood vessel (1 year) and stabilization of vision (Figure 12).
Figure 10: Fluorescein angiogram and OCT 6 weeks after last
bevacizumab injection showing recurrent membrane and fluid on OCT.
Figure 11: Fluorescein angiogram and OCT 6 weeks after last
bevacizumab injection showing recurrent membrane and fluid on OCT.
Figure 12: OCT following combination therapy showing complete resolution of fluid.
The rapid evolution of care for AMD will certainly continue. Only through randomized controlled studies will optimal treatment regimens be elucidated. However, open exchange of ideas through modalities such as ophthalmologyweb.com will be invaluable in the development of ideas that can be tested in a more rigorous manner.
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