가톨릭대학교 의과대학 안과 및 시과학 교실 R3 장동진 / Pf.이원기 Efficacy of Intravitreal Bevacizumab Combined With Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Am J Ophthalmol 2010;150:48-54 e1. 가톨릭대학교 의과대학 안과 및 시과학 교실 R3 장동진 / Pf.이원기

Introduction Polypoidal choroidal vasculopathy (PCV) complex of branching vascular networks terminating in aneurysmal or polypoidal lesions. higher in Asian accounts for almost half of eyes presumed to have exudative age-related macular degeneration (AMD) in Japan

Introduction Photodynamic therapy (PDT) with verteporfin (Visudyne) subfoveal choroidal neovascularization (CNV) associated with AMD effective for treating PCV unexpected subretinal hemorrhages after PDT Bevacizumab (Avastin) For treating CNV secondary to AMD the efficacy for PCV seems limited reduced exudative fluid but did not affect the original abnormal vasculatures  subsequent recurrence of fluid in most eyes.

Introduction Combination? PDT - occlusion of polypoidal vascular lesions anti-VEGF drugs - resolution of the associated fluid but some limitations Combination?

Methods 146 Japanese patients Diagnosed based on indocyanine green angiography (ICGA). Symptomatic, treatment-naïve, subfoveal PCV Retrospective, comparative, interventional case series PDT 1.25mg bevacizumab 1 day before PDT 1, 3, 6, 9, 12 month Comprehensive ocular exam. (including BCVA, Fundus exam, color fundus photography, OCT FAG, ICG baseline and every 3months Additional intermediate visits at 4- to 6-week intervals Additional treatments Abnormal vascular lesion  PDT Exudative fluid on OCT  Bevacizumab inj.(combined tx group only)

Methods “Resolution” of PCV lesions after the initial treatment disappearance of symptomatic vasculatures on ICGA at 3 months with complete resolution of exudative fluid on OCT “Recurrence” reappearance of abnormal vasculature on ICGA with exudative fluid on OCT.

Results

Results * : P<0.05 $ $ $ $ % % $ %

Results Improved or maintained BCVA Improved BCVA 61/61 81/85 61/61 81/85 55/61 75/85 100% 94.1% 90.2% 88.2% 14.8% 3.5% 23.0% 18.8% Improved or maintained BCVA Improved BCVA 62.3% 54.1%

Results Factors associated with the long-term BCVA multivariate analyses baseline BCVA (P < 0.0001) the GLD (P = 0.0015) PED (P = 0.0022) treatment (P = 0.048) BCVA at 12 months better baseline VA smaller lesion size absence of PED combined therapy

Results Monotherapy Combination Therapy p Resolution of lesions at 3 months 75.3% (64/85) 78.7% (48/61) 0.63 Recurrence 40.6% (26/64) 43.8% (21/48) 0.74 Additional treatments during the 1-year follow-up 0.66 PDT 0.43 PDT, 0.92 bevacizumab additional injections Pearson chi-square test

Results Adverse events within a month Monotherapy Combination Therapy a subretinal or subpigment epithelial hemorrhage, or both >1mm 15 eyes (17.7%) 3 eyes (4.9%) 0.022* Hemorrhages seriously affected vision 5 eyes 1 eye RPE tear 1eye$ * : fisher exact test $ : did not affect vision

Discussion the prevalence of PCV PDT with verteporfin high in presumed exudative AMD in Asian PDT with verteporfin superior results for treating PCV compared with CNV secondary to AMD In the era of anti-VEGF therapy intravitreal bevacizumab positive anatomic results such as resolution of fluid certain amount of bevacizumab may act directly on the abnormal vasculature in the subretinal pigment epithelial spaces. limited efficacy of bevacizumab monotherapy when treating the abnormal vasculature of PCV, 2 possible reasons Insufficient amount of bevacizumab may reach the subretinal pigment epithelial spaces because of its larger molecular size VEGF-independent nature of PCV

Discussion Current study an additional positive effect of an intravitreal bevacizumab was observed in the visual outcomes through 1 year. During the early treatment period, the efficacy of bevacizumab for improving BCVA was apparent. maximum improvement in the BCVA at 3 months, which was attributed primarily to rapid resolution of the exudative fluid and fibrin induced by bevacizumab, as we observed previously. The leakage from abnormal vessels was treated effectively through the reduction of VEGF. Moreover, bevacizumab may prevent transient induction of VEGF after PDT and subsequent reaction of vessels.

Discussion a significantly lower rate of subretinal or subpigment epithelial hemorrhages, or both, associated with PDT in the combined treatment group. 17.7% vs 4.9% The development of subretinal hemorrhages after PDT a characteristic adverse event after PDT used to treat PCV physicians want to avoid. suppression of hemorrhages decreased vascular permeability suppression of hemorrhages.  encourage ophthalmologists to choose the combined therapy.

Discussion For the long-term VA the impact of the combined therapy - decreased lesion recurrences and atrophic tissue changes related to persistent lesions Resolution of the original PCV vasculature a similar rate between the treatments the recurrence rates also were similar Bevacizumab monotherapy did not cause regression of the abnormal PCV vasculature lesions may be attributed mainly to PDT alone Factors associated with a better 12-month VA combined therapy better baseline VA smaller lesion size absence of PED

Discussion longer follow-up periods additional sessions of PDT - for the recurrences  increase of risks induced by PDT (subretinal hemorrhages or ischemic damage of normal choroidal tissue) PDT combined with an anti-VEGF drug can reduce those side effects of PDT injection of an anti-VEGF drug without PDT is an option  the appropriate combination of an anti-VEGF drug and PDT is important to maintain better VA for the long term.

Discussion PEARL Trial  ranibizumab monotherapy 6-month interim results of monthly injections of ranibizumab The results showed that ranibizumab monotherapy improved the mean VA at 6months by a mean of 7.2 letters and that 2 patients (17%) gained more than 15 letters. That seemed almost the same as the visual results in our combined therapy group at 12 months. the polypoidal lesions seen on ICGA decreased in 4 eyes (33%) at 6 months the smaller molecular size of ranibizumab compared with bevacizumab monthly continuous injections may enable the drug to penetrate into the subretinal pigment epithelial space more efficiently However, difficulties in achieving complete resolution  ranibizumab monotherapy - potential for continuous risk of recurrences.

Discussion The current study was limited EVEREST Study Retrospective and not a randomized, comparative trial. However, the absence of bias in the choice of the initial treatment a relatively large number of eyes that had not received any previous treatments EVEREST Study prospective randomized clinical trial 6-month results PDT combined with intravitreal ranibizumab PDT monotherapy Ranibizumab helpful to know which treatment should be chosen as the initial therapy although the differences of efficacy between ranibizumab and bevacizumab remained to be clarified.