Effects of photodynamic therapy plus intravitreal aflibercept with subtenon triamcinolone injections for aflibercept-resistant polypoidal choroidal vasculopathy
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We would like to address several challenges that have arisen from the study by Sakai et al. , which are specifically summarized below.
Missing data from the article by Sakai et al. 
The PCV duration before the entry into the study
The duration of the aflibercept treatment prior to the start of triple therapy
The anatomical types of macular edema (diffuse/subretinal fluid/cystic changes within neurosensory retina/mixed type) at index date and at month 12
The proportion of patients with complete dry macula at the end of the study
The anatomical lesions of the PCV (serous and hemorrhagic detachments of the RPE and neurosensory retina, exudative changes, aneurismal polypoidal lesions with overlying atrophy of the pigment epithelium, abnormal branch vascular networks, vitreous hemorrhage, subretinal fibrosis, pigment epithelial hyperplasia, and atrophic degeneration) at baseline and at the end of the follow-up
The proportion of patients with scar formation and development of geographic atrophy at the end of the study
The prevalence of vitreoretinal interface abnormalities (e.g., vitreomacular adhesion/traction and epiretinal membranes) at enrollment and at the end of the follow-up period
The qualitative status of the external limiting membrane band, the ellipsoid zone, and the interdigitation zone at the index date and the magnitude of the changes (disruption/absence) during the follow-up as potential prognosticators of BCVA and CMT
The qualitative status of the retinal pigment epithelial band and grading of the RPE changes (pigment migration within the neurosensory retina, RPE porosity, micro-rips or blowouts in the RPE, focal RPE atrophy, RPE thickening, presence of reticular pseudodrusen).
Subfoveal choroidal thickness at the study enrollment and at month 12
Fluorescein angiographic findings at presentation and at month 12 including hyperfluorescence resembling occult CNV lesions in early or mid-phase of angiogram having lacy/stippled appearance, late hyperfluorescence only, progressive leakage, and fibrovascular PED
ICGA findings at the index date and at month 12 including location of lesions (sub, juxta, and extrafoveal), number of polypoidal lesions per patient, and inner choroidal vascular abnormalities (hyperpermeability, focal dilation, constriction, and tortuosity of vessels) comprising a network of branching choroidal vessels with terminal, polyp-like aneurismal dilatations
The study was retrospectively conducted with a relatively small sample size in aflibercept (Eylea, Regeneron, Tarrytown, NY, USA)-resistant patients with polypoidal choroidal vasculopathy (PCV).
Initially, the 13 patients with PCV should have been classified into two angiographic subtypes, namely, subtype 1, polypoidal choroidal neovascularization (CNV) sharing a common pathogenic background with neovascular age-related macular degeneration (AMD) and subtype 2, idiopathic PCV, based on the presence or absence of both feeder and draining vessels on indocyanine green angiography . Importantly, there is a difference in early treatment response with aflibercept between the two subtypes of PCV. Thus, the subtype 1 polypoidal CNV showed better visual improvement, with higher percentage of polyp regression comparable to that of AMD, than the subtype 2 idiopathic PCV. The different treatment effects may be attributable to their different pathophysiology and genetic backgrounds [3, 4].
The assessment of the effectiveness of photodynamic therapy (PDT) combined with injections of intravitreal aflibercept (IVA) and subtenon triamcinolone acetonide (STTA) can not be made because nothing was stated with regards to the existence of a washout period between the last injection with aflibercept dosed before the outset of the study and the index date (e.g., the date of conversion to triple therapy). A real washout period is essential between the two periods of treatment in terms of aliased effects. Thus, the impact of the significant carryover effects of the aflibercept treatment may be confounded in this study with direct treatment effects of the triple therapy, because these effects could not be estimated separately; carryover effects may bias the interpretation of data analysis [5, 6].
The decrease of the therapeutic benefit from prolonged use of aflibercept might have been attributed in this series to the development of the tachyphylaxis and/or tolerance. The authors did not use the usual routes to restore the lack of efficiency of treatment with aflibercept prior to switching to triple therapy. Thus, the tachyphylaxis might have been overcome by switching to similar drugs with different molecular structures, e.g., bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) or ranibizumab (Lucentis, Genentech), and the tolerance would have required an increased dosage or shorter dosing time intervals to achieve the desire effect . We wondered why the IVA injection was also used in association with PDT and STTA injection because there was a resistance to aflibercept treatment which had been highlighted prior to the index date.
Despite the significant changes in visual acuity, central retinal thickness, and pigment epithelial detachment (PED) height, the 12-month outcomes of this study were unsatisfactory. Specifically, 30.8% of the patients maintained PED, 30.8% of the patients continued to have intraretinal or subretinal fluid, 15.4% had submacular hemorrhage, and the proportion of adverse events (15.38%) was quite high. Likewise, 84.7% of the patients required additional anti-vascular endothelial growth factor (VEGF) agents, despite complete remission of polypoidal lesions. The final suboptimal results of this series might be explained by the longer chronicity of disease, the insufficient treatment administered (the mean numbers of PDT, IVA, and STTA treatments over 12 months were 1.0, 3.46, and 1.0, respectively), the multiple injections with IVA given prior to the index date, and the two adverse effects of aflibercept. Importantly, unlike bevacizumab, which has a protective effect against occlusion of choriocapillaris induced by PDT , and ranibizumab, which does not impair the choroidal thickness , aflibercept treatment may result in a significant subfoveal choroidal thickness loss by suppressing the choroidal vascular hyperpermeability and vasoconstriction . Thus, choroidal vascular impairment may affect the integrity of the retinal pigment epithelium and outer retina, favoring development of the fovea-involving geographic atrophy, because the choroid is the sole source of metabolic exchange for the fovea. In addition, through the fragment crystallizable (Fc) domain, aflibercept can bind to the Fc receptor of both choriocapillaris endothelial cells and red blood cells, leading to complement-mediated cell death .
Altogether, regardless of the treatment approach chosen, e.g., the PDT alone, the anti-VEGF monotherapy, the combination of PDT with anti-VEGF treatment, or the triple therapy, the efficacy of treatment depends primarily on the promptness of the therapy after PCV onset. Patients should be thoroughly followed to initially highlight and prevent subretinal/sub-RPE fluid and hemorrhage.
Both authors (D.C and M.C) were involved in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.
The authors have full control over the primary data and they agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data if requested.
Compliance with ethical standards
Conflict of interest
All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No financial disclosures.
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
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