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. 2020 Aug 11;15(8):e0237330. doi: 10.1371/journal.pone.0237330

Response to photodynamic therapy combined with intravitreal aflibercept for polypoidal choroidal vasculopathy depending on fellow-eye condition:2-year results

Mio Matsubara 1, Yoichi Sakurada 1,*, Atsushi Sugiyama 1, Yoshiko Fukuda 1, Ravi Parikh 2,3, Kenji Kashiwagi 1
Editor: Manuel Alberto de Almeida e Sousa Falcão4
PMCID: PMC7418965  PMID: 32780752

Abstract

We investigated whether response to photodynamic therapy (PDT) with intravitreal aflibercept injection (IAI) for polypoidal choroidal vasculopathy (PCV) differs depending on fellow eye condition. A retrospective review was conducted for consecutive 60 eyes with PCV treated with PDT combined with IAI as well as 2-years of follow-up data. Fellow eyes were divided into 4 groups; Group 0: no drusen, Group 1; pachydrusen, Group 2; soft drusen, Group 3: PCV/fibrovascular scarring. Best-corrected visual acuity improved at 24-months irrespective of groups and there were no significant differences in visual improvement among treated eyes among the 4 groups. Within 2-years, 35 (58.3%) required the retreatment. The need for retreatment including additional injection and the combination therapy was significantly less in Group 1(12.5%) compared to the others (P = 0.0038) and mean number of additional IAI was also less in Group 1 compared to the others (P = 0.017). The retreatment-free period from the initial combination therapy was longest in Group 1 (23.6±1.1 months) (P = 0.0055, Group 0: 19.1±6.9, Group 2: 12.8±7.9, Group 3: 11.5±9.9). The need for retreatment was significantly different according to fellow-eye condition. Among PCV patients, pachydrusen in fellow eyes appear to be a predictive characteristic for a decreased treatment burden at 2 years.

Introduction

Polypoidal choroidal vasculopathy (PCV) is widely considered to be a unique subtype of exudative age-related macular degeneration (AMD) characterized by aneurysmal dilations with branching vascular network on indocyanine green angiography (ICGA). [1, 2] To date, PCV has been considered to be a variant of type1 choroidal neovascularization secondary to neovascular AMD and they share clinical and genetic background. [3–7] Its prevalence accounts for a half of advanced AMD on Japanese clinic studies, although some debate that PCV is a distinct entity. [8, 9]

Photodynamic therapy (PDT) combined with intravitreal anti-vascular endothelial growth factor (VEGF) injection are a first-line treatment option for PCV along with intravitreal anti-VEGF injection monotherapy in the real-world. [10–14] PDT induces occlusion of polypoidal lesions by vaso-constrictive effect on choroid; however, it causes ischemia in the choroid and RPE, which may result in VEGF upregulation. Anti-VEGF agents reduce the up-regulated VEGF, and thus decreasing subretinal and sub-RPE exudation. Therefore, combination therapy involving PDT and intravitreal injection of anti-VEGF agents might be an ideal therapy for PCV in terms of visual improvement and occlusion of polypoidal lesion. [15, 16]

Pachydrusen are a new clinical entity characterized by isolated or scattered yellow-whitish drusenoid deposits as seen in the posterior pole of the retina over areas of a thickened choroid. [17, 18] Recent studies demonstrated that morphology under pachydrusen showed increased Haller’s layer with attenuation of choriocapillaris. [19, 20] Pachydrusen are not specific to AMD and they are often seen in pachychoroid diseases such as central serous chorioretinopathy. [20] Several studies reported that pachydrusen were more prevalent in eyes with PCV compared to those with other exudative AMD. [21–23] Recently we reported clinical and genetic characteristics of pachydrusen in patients with exudative AMD. [23] However, there have been no reports investigating the treatment outcomes in eyes with PCV and pachydrusen.

In the present study, we classified eyes with PCV into 4 groups depending on untreated fellow-eye condition; Group 0; no drusen, Group 1; pachydrusen, Group 2; soft drusen, and Group 3; PCV/fibrovascular scarring and investigated 2-year results of the combination therapy for PCV and compared 2-year results among the 4 groups.

Methods

A retrospective medical chart review was conducted for consecutive 60 patients with PCV who were initially treated with PDT combined with intravitreal aflibercept injection (IAI) between January 2013 and August 2017 and completed 2-years follow-up. This retrospective study was approved by the institutional review board of University of Yamanashi and followed the tenets of declaration of Helsinki. Written informed consent was obtained from each patient before the treatment.

Prior to the treatment, all study patients received comprehensive examination including best-corrected visual acuity measurement using Landolt chart, slit-lamp examination with 78 diopter lens, color fundus photography, fluorescein and indocyanine green angiography(FA/ICGA) (HRA-2, Heidelberg Engineering, Heidelberg, Germany), optical coherence tomography(OCT) using Spectralis (ver5.4 HRA+OCT) and/or DRI-OCT1 Atlantis(Topcon Corp, Tokyo, Japan). All OCT images were obtained by a horizontal or vertical line through the fovea. In patients with extrafoveal lesions, we performed OCT scans corresponding to the lesion in addition to scans of the fovea. Late phase images of FA/ICGA were obtained 10 minutes after the dye injection. Using OCT sans, soft drusen were identified RPE elevations while pachydrusen were sub-retinal piment epithelial deposits. Central retinal thickness (CRT) was measured as the vertical distance between inner surface of neurosensory retina and retinal pigment epithelium beneath the fovea. Subfoveal choroidal thickness was measured as the vertical distance between Bruch’s membrane and choroidoscleral border at the fovea.

PCV was diagnosed as we previously described. [9] All PCV cases showed solitary or multiple aneurysmal dilations (polypoidal lesions) with or without branching vascular networks on ICGA and irregular retinal pigment epithelium (RPE) elevation with serous/hemorrhagic detachment of neurosensory retina and/or RPE on OCT.

Choroidal vascular hyperpermeability (CVH) was defined as multifocal hyperfluorescent area with blurred margins within the choroid that increased the intensity in the late phase ICGA as we previously described. [9]

Treatment

Intravitreal injection of aflibercept (2.0mg/0.05ml) (Bayer AG, Leverkusen, Germany) was administrated for all study eyes 1 week before PDT. PDT was performed according to a standard protocol: verteporfin (Visudyne, Novartis) was administrated intravenously(6mg/mm2) for 10 minutes. Fifteen minutes after the verteporfin injection, a pulse of 689-nm- wavelength light was delivered using a diode laser unit (Visulas PDT system 690S, Carl Zeiss) for 83 seconds with an intensity of 600mW/cm2. Greatest linear dimension (GLD) was defined as covering all areas including branching vascular networks and polypoidal lesions on ICGA. Spot size was defined as 1000μm in addition to GLD.

Follow-up and retreatment

After the initial combination therapy all study patients were followed every 3 months until recurrence. Recurrence was defined as exudative changes including subretinal fluid or hemorrhage as seen on OCT or subretinal/sub-RPE hemorrhage seen on ophthalmoscopy. When recurrence was seen, additional FA/ICGA was performed. Additional combination therapy was administrated when a polypoidal lesion with or without branching vascular networks was seen on ICGA. Additional IAI was administrated when branching vascular networks without polypoidal lesions were seen on ICGA. After first recurrence all patients were followed-up every month.

Classification of groups

Depending on untreated fellow eye conditions, patients were subdivided into 4 groups: Group 0 (no drusen), Group 1 (pachydrusen), Group 2 (soft drusen), Group 3 (PCV/scarring). SD-OCT and late phase ICGA was used to differentiate pachydrusen from soft drusen. Soft drusen exhibited hypofluorescent on late phase ICGA, [24, 25] on the other hand pachydrusen exhibited hyperfluorescent on late phase ICGA. [17, 23] Presence or absence of drusen was judged in the 45°color fundus photography of the untreated fellow eye. Group classification was independently performed by 2 graders (M.M, and Y.S). Discordant diagnosis was resolved through open arbitration. A representative case with pachydrusen was shown in Fig 1 and a representative case with soft drusen was shown in Fig 2.

Fig 1. Fellow eye with pachydrusen in unilateral polypoidal choroidal vasculopathy.

Fig 1

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A 69-year-old female with polypoidal choroidal vasculopathy. (A) Drusen were scattered around the macula on the fundus photography in the right eye and orange-red lesions were located on the macula in the left eye. Late phase indocyanine angiography demonstrated hyperfluorescence corresponding to a white line on color photography in the right eye and polypoidal lesions on macula in the left eye. (B) (Left) A horizontal scan demonstrated a drusenoid deposit(pachydrusen) corresponding to a white line in the right eye. (Right) A horizontal scan though the fovea demonstrated serous retinal detachment with double layer sign.

Fig 2. Fellow eye with soft drusen in unilateral polypoidal choroidal vasculopathy.

Fig 2

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A 78-year-old female with polypoidal choroidal vasculopathy. (A) Drusen were scattered around the macula on the fundus photography in both eyes. (B) (Left) The late phase indocyanine green angiography (ICGA) showed that polypoidal lesion on the macula in the right eye. (Right) The late phase angiography revealed hypofluorescent spots corresponding to the drusen. (C) (Left) A horizontal scan through the fovea demonstrated subretinal fluid and subretinal hyperreflective materials on optical coherence tomography (OCT). (Right) A horizontal scan corresponding to a white line on the ICGA showed the bump of retinal pigment epithelium (a black arrow) on OCT.

Statistical analysis

Statistical analysis was performed using DR. SPSS. Differences of continuous variable and categorical variables were analyzed by Mann-Whitney U test and chi-square test, respectively. Differences of values between before and after treatment were analyzed by Wilcoxon signed rank test. Log-rank test was used to compared retreatment-free period among the 4 groups. P-value less than 0.05 was considered statistically significant.

Results

Table 1 shows demographic characteristics of patients with PCV in each group. Group 2(fellow eyes with soft drusen) is significantly older compared with other groups (Group 0: p = 1.4×10−4, Group 1: p = 0.001, Group 3: p = 0.019). Gender distribution was not significantly different among the 4 groups, while baseline BCVA was slightly better in Group 1 than Group 2 (p = 0.047). Baseline GLD was slightly larger in Group 2 than Group 1(p = 0.047). Baseline CRT was significantly greater in Group 1 compared with Group 0(p = 0.004) and Group 3 (p = 1.3×10−3) and baseline GLD was significantly greater in Group 2 than Group 3 (p = 0.029). Baseline subfoveal choroidal thickness (SCT) was greatest in Group 1 among the 4 groups; however, a difference in SCT was seen between Group 1 and Group 2 (p = 0.047).

Table 1. Demographic characteristics of patients with polypoidal choroidal vasculopathy.

all (n = 60) Group 0(no drusen) (n = 20) Group1(pachydrusen) (n = 8) Group 2 (soft drusen) (n = 26) Group3 (PCV/scar) (n = 6)
sex(male) 41(68.3%) 12(60%) 6(75%) 18(69.2%) 5(83.3%)
age 72.8±8.4 67.9±7.8 69.3±4.6 78.2±6.9 70.5±5.7
logMAR BCVA 0.44±0.28 0.45±0.25 0.30±0.11 0.52±0.29 0.28±0.31
CRT 382.7±106.0 350.3±97.4 474.8±72.4 399.7±101.5 293.8±57.0
SCT 269.2±94.0 269.0±108.5 317.6±45.1 254.2±86.4 270.2±92.4
GLD 1700.8±763 1775±783 1288±741 1777±733 1675±587
CVH on the affected eye 18(30%) 10(50%) 7(87.5%) 0 1(16.7%)
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Log MAR: logarithm of the minimum angle of resolution

CRT: central retinal thickness, SCT: subfoveal choroidal thickness, GLD: greatest linear dimension, CVH: choroidal vascular hyperpermeability

In all 60 study eyes, mean BCVA significantly improved from 0.44±0.28 at baseline to 0.22±0.20 at 6-month, 0.21±0.20 at 12-month, 0.18±0.20 at 18-month, and 0.17±0.20 at 24-month (p = 3.1×10−9, 2.5×10−9, 5.7×10−10 and 9.3×10−11, respectively). In each group, mean BCVA significantly improved at 24-month (Group 0: p = 1.3×10−4, Group 1: p = 5.0×10−2, Group 2: p = 9.5×10−6, Group 3: p = 4.2×10−2). Fig 3(A) shows changes of BCVA in each group. After adjusting age, gender, and baseline BCVA, there was not a statistically significant difference in BCVA improvement at 24-month among the 4 groups.

Fig 3. Changes of best-correct visual acuity, central retinal thickness, and subfoveal choroidal thickness among the 4 groups.

Fig 3

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(A) Changes of best-corrected visual acuity among the 4 groups. Baseline visual acuity significantly improved from 0.45±0.26 at baseline to 0.22±0.24, 0.21±0.20, 0.16±0.18 and 0.14±0.17 at 6-month, 12-month, 18-month and 24-month (p = 2.7×10−4,1.8×10−4, 1.8×10−4, and 1.3×10−4, respectively) in Group 0. Baseline visual acuity improved from 0.30±0.12 at baseline to 0.09±0.09, 0.05±0.08, 0.10±0.10, 0.08±0.15 at 6-month, 12-month, 18-month and 24-month (p = 1.2×10−2, 1.2×10−2, 2.5×10−2, and 5.0×10−2, respectively) in Group 1. Baseline visual acuity significantly improved from 0.52±0.29 to 0.25±0.18, 0.28±0.22, 0.24±0.22, 0.23±0.22 at 6-month, 12-month, 18-month and 24-month (p = 1.8×10−5, 3.1×10−4, 1.4×10−4, and 9.5×10−6, respectively) in Group 2. Baseline visual acuity significantly improved from 0.28±0.34 to 0.23±0.28, 0.12±0.0.14, 0.07±0.20, 0.10±0.23 at 6-month, 12-month, 18-month and 24-month (p = 0.71, 0.14, 2.6×10−2 and 4.2×10−2, respectively) in Group 3. (B) Changes of central retinal thickness among the 4 groups. Mean central retinal thickness(CRT) significantly decreased from 350±100 μm at baseline to 177±33μm at 6-month, 178±31μm at 12-month, and 196±62μm at 24-month (p = 8.9×10−5, 8.9×10−5 and 2.5×10−4, respectively) in Group 0, mean CRT also significantly decreased from 475±77 μm at baseline to 205±23μm at 6-month, 197±24μm at 12-month, and 192±33μm at 24-month (p = 1.2×10−2, 1.2×10−2 and 1.2×10−2, respectively) in Group 1, mean CRT significantly decreased from 400±104 μm at baseline to 207±60μm at 6-month, 221±75μm at 12-month, and 194±47μm at 24-month (p = 8.3×10−6, 3.3×10−5 and 9.3×10−6, respectively) in Group 2, and mean CRT decreased from 294±62 μm at baseline to 250±104μm at 6-month, 197±44μm at 12-month, and 238±74μm at 24-month (p = 0.25, 2.8×10−2 and 5.8×10−2, respectively) in Group 3. There were no significant differences in CRT at 24-month among the 4 groups (p = 0.32, analysis of variance). (C) Changes of subfoveal choroidal thickness among the 4 groups. Mean subfoveal choroidal thickness(SCT) significantly decreased from 269±111 μm at baseline to 237±101 μm at 6-month, 238±104 μm at 12-month, and 234±98 μm at 24-month (p = 2.5×10−4, 7.2×10−4 and 1.2×10−4, respectively) in Group 0, mean SCT also significantly decreased from 318±48 μm at baseline to 253±36 μm at 6-month, 260±53 μm at 12-month, and 268±40 μm at 24-month (p = 1.7×10−2, 1.2×10−2 and 1.2×10−2, respectively) in Group 1, mean SCT significantly decreased from 254±88 μm at baseline to 222±83 μm at 6-month, 220±87 μm at 12-month, and 208±81 μm at 24-month (p = 3.5×10−5, 9.9×10−6 and 8.3×10−6, respectively) in Group 2, and mean SCT decreased from 270±101 μm at baseline to 250±101 μm at 6-month, 248±92 μm at 12-month, and 238±92 μm at 24-month (p = 2.8×10−2, 8.0×10−2 and 2.5×10−2, respectively) in Group 3. There were no significant differences in SCT at 24-month among the 4 groups (p = 0.32, analysis of variance).

During the 24-month study period, 35(58.3%) eyes required retreatment. The number of retreated eyes was lower in Group 1(12.5%) compared with other groups (p = 0.0038, chi-square test, Group 0: 50%, Group 2: 76.9%, Group 3: 66.7%). Fig 4 shows Kaplan-Meier estimator associated with retreatment-free period among the 4 groups. Retreatment-free period was the longest in Group 1 compared to the other groups(P = 0.0055,Man-Whitney U test) and significant differences in the retreatment-free period were seen between Group 1 and Group 2 (p = 0.0023, log-rank test) and between Group 1 and Group 3 (p = 0.0046, log-rank test). The mean number of additional combination therapy was 0.20, 0, 0.34, 0.33 in Group 0, Group 1, Group 2, and Group 3, respectively, which was not significantly different among the 4 groups (p = 0.43, analysis of variance). Mean number of additional intravitreal injections of aflibercept was 0.85±1.35, 0.125±0.35, 2.46±2.58, 2.33±2.34 in Group 0, Group 1, Group 2, and Group 3, respectively. Eyes in Group 1 required less additional IAI compared to other groups (P = 0.017, chi-square test). A statistically significant difference was seen between Group 1 and Group 2 (p = 0.009, Mann-Whitney U test) and between Group 0 and Group 2 (p = 0.015, Mann-Whitney U test).

Fig 4. Kaplan-Meier estimator showing retreatment-free period after the initial combination therapy.

Fig 4

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Mean retreatment-free period after the combination therapy was 19.1±6.9 (95%CI:15.8–22.3), 23.6±1.1 (95%CI:22.7–24.0), 12.8±7.9 (95%CI:9.6–16.0), 11.5±9.9 (95% CI:1.1–21.9) in Group 0, Group 1, Group 2, Group 3, respectively. Although it did not reach a statistical difference in retreatment-free period between Group 0 and Group 1(p = 0.072, log-rank test), there were significant differences in retreatment-free period between Group 1 and Group 2 (p = 0.0023,log-rank test), and between Group 1 and Group 3 (p = 0.0046, log-rank test).

In all 60 study eyes, mean CRT significantly decreased from 269±94 μm at baseline to 234±86μm at 6-month, 234±89μm at 12-months, and 228±85μm at 24-months (p = 3.4×10−11, 7.6×10−11 and 4.8×10−11, respectively) and Fig 3(B) shows changes of central retinal thickness among the 4 groups. Fig 3(C) shows changes of subfoveal choroidal thickness among the 4 groups.

Discussion

Drusen are extracellular materials located between Bruch’s membrane and the retinal pigment epithelium. Although they are a manifestation of the normal aging process when their size is less than 63 μm, they are generally considered early signs of AMD when they exceed 63 μm in size. The risk for progression to advanced AMD varies depending on size, types and distribution pattern of drusen, and fellow eye condition. [26–29] Therefore, it is important for physicians to differentiate drusen types and understand characteristics of each drusen type. However, there have been a few studies in the literature examining treatment outcomes in eyes with pachydrusen as they are a relatively recently described clinical entity. Our study demonstrated that among eyes with PCV, fellow eyes with pachydrusen were predictive of decreased recurrence and treatment burden.

In the present study, we classified patients with PCV into 4 groups (Group 0: no drusen, Group 1: pachydrusen, Group 2; soft drusen, Group 3; PCV/ fibrovascular scarring) based upon the untreated fellow-eye and investigated whether there are significant differences in response to the combination therapy for PCV among the 4 groups. Mean retreatment-free period was significantly longer in Group 1(fellow eye with pachydrusen) (Group 0: 19.1±6.9, Group 1: 23.6±1.1, Group 2: 12.8±7.9, Group 3: 11.5±9.9 months, p = 0.001, analysis of variance). Therefore, the additional number of retreatments was also decreased in Group 1.

There are several reasons to explain the present results. Firstly, it has been reported that eyes with thickened subfoveal choroidal thickness lead to a favorable course including visual improvement and chance of recurrence after the combination therapy for PCV. [30] In the present study, subfoveal choroidal thickness was significantly thicker in Group 1 compared to the other 4 groups, a finding which was consistent with previous reports. [21–23] Second, it has been reported that choroidal vascular hyperpermeability (CVH) is associated with the need for less additional anti-VEGF injections at 12 months among PCV eyes receiving combination PDT and anti-VEGF therapy. [31] CVH was first reported in eyes with CSC as patchy area of ICGA hyperfluorescence seen best in mid- and late-phase study. [32] CVH has been considered angiographic evidence of a disturbance of choroidal vascular circulation. It has been recently reported that pachyvessels traversed the area of CVH on mid and late phase ICGA, suggesting that a thickened outer choroid is associated with development of CVH. [33] In the present study, CVH was present in18 eyes (30%), which is similar to the figure in previous reports [31, 34] and CVH is most frequently seen in Group 1. Third, several studies have reported that older age is a risk factor for recurrence/retreatment in treatment for exudative AMD, including anti-VEGF monotherapy or the combination therapy. [35–37] Eyes from Group 1 eyes are youngest among the cohort. In a recent report, exudative AMD patients with pachydrusen were younger than those with soft drusen or pseudodrusen. Pachydrusen might be early onset compared with soft drusen and pseudodrusen. At 2 years, mean BCVA significantly improved from baseline (0.44±0.28) to their final visit at month 24 (0.17±0.20) in all 60 study eyes (p = 9.3×10−11). As reported previously, [10, 14, 37] combination therapy of PDT and IAI results in favorable outcomes at 2 years. Although we previously reported that visual improvement differs depending on fellow eye condition when treating with intravitreal aflibercept monotherapy for neovascular AMD, [38] there were not any significant differences in visual improvement among the 4 groups in this study.

The pachychoroid phenotype was characterized by the presence of a pachyvessel, focal or diffuse choroidal thickening on OCT and CVH on ICGA. Further, the absence or paucity of soft drusen is also a feature of pachychoroid. Of note none of the study eyes with soft drusen had CVH, further supporting the distinction of the pachychoroid phenotype. Most eyes with pachydrusen also have pachychoroid features including CVH as is in the case in the present study. Considering the close link between pachychoroid and pachydrusen, authors feel that eyes with pachydrusen and PCV lend credence to the idea that a choroidal mechanism is mediating the exudation. PDT is effective for pachychoroid diseases including CSC and PCV with pachychoroid features by normalizing the thickening choroid; on the other hand, eyes with soft drusen and exudation are considered drusen mediated exudation; Soft drusen may also induce inflammation in the retina, which explain why eyes with soft drusen appear to have increased recurrence of exudation due to the theory of an inflammatory mediated mechanism of exudation. Thus, the authors feel that two pathways may lead to exudation, a choroidal mediated and a drusen mediated one. These differing mechanisms for exudation may explain the different rates of recurrence.

Our study demonstrates the importance of assessing the clinical characteristics among untreated fellow eyes in treatment naïve PCV patients as fellow eye characteristics are predictors of recurrence, recurrence-free period, and number of additional retreatments.

There were several limitations in this study. The major limitation of the present study is a retrospective nature of analysis and small sample size, especially Group1 and Group 3. A large -scale prospective study would be needed to confirm this tentative conclusion. To the best of our knowledge, this is the first report that demonstrated patients with pachydrusen in fellow eyes were good responders to the combination therapy and may have a lower treatment burden for PCV. Further study is needed to determine whether patients with pachydrusen also have similar responses to other treatment modalities including anti-VEGF monotherapy.

In summary, untreated fellow eye characteristics may predict recurrence, the recurrence-free period after the combination therapy for PCV and subsequent treatment burden.

Supporting information

S1 Data

(XLS)

Click here for additional data file. (26.5KB, xls)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 23791972 (YS). The funder provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Manhattan Retina and Eye Consultants has provided a salary for R.P. and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

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Decision Letter 0

Manuel Alberto de Almeida e Sousa Falcão

5 Mar 2020

PONE-D-20-00729

Response to photodynamic therapy combined with intravitreal aflibercept for polypoidal choroidal vasculopathy depending on fellow-eye condition:2-year results

PLOS ONE

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Reviewer #1: I read with interest the present paper which explores the differences between treatment response in PCV patients according to the type of drusen found in the fellow eye. It is a original ideia and interesting to explore in the search of biomarkers of disease prognosis and response to treatment.

However, there are several issues that must be addressed before accepting the manuscript for publication.

First, the short title has a minor error in "depending"

Introduction:

The authors start by stating that "PCV is a unique subtype of exudative age-related macular degeneration (AMD) ", this, however, is still a debated statement. Controversy persists, especially as PCV can be found in other settings and pathologic associations.

The introduction is somewhat globally inconsistent and better rephrasing and English review is necessary before publication.

Combination treatment versus anti-VEGF monotherapy approach is still not consensual and is not the point of the present study, but assumptions of superiority of one over the other cannot be made as expressed in the second paragraph. Other bibliography sources are to be added to support the information provided if this point is presented here.

Pachydrusen are presented as a distinct clinical entity, but reference and linkage to pachychoroid spectrum should be more clearly explored. Should these pachydrusen be completely assumed to be part of AMD, or they can be present in other settings? The group refers to a previous study on clinical and genetic characteristics of pachydrusen in patients with exudative AMD, where they acknowledge that patients with pachydrusen have genetic and clinical characteristics distinct from those of soft drusen and pseudodrusen of typical AMD, however the presence of both pachydrusen, pachychoroid and PCV in the setting of other diseases is not further explored.

Methods:

Again, English is to be improved, for example in the line 85 " slit-lamp examination with or without 78 diopter lens intraocular measurement".

Only one vertical and one horizontal line in OCT analysis are enough? How was the CRT values obtained? And choroidal thickness?

Only late-phase ICGA was used to discriminate between soft and pachydrusen but other features must be considered, only one reference for this ICGA based definition is not sufficient.

Since PCV is stated here to be considered as a variant of neovascular AMD, was monthly loading dose performed or only one combination treatment was performed with observation after 3 months? As this is not standard for PCV treatment or typical nAMD treatment, was follow-up of only once every 3 months considered sufficient?

Was the t-test possible to use in this sample? Groups are quite small - group 1 has only 8 subjects and is the main focus of this work.

Results:

Line 124: The group's enumeration in methods is wrong: 1, 2, 3, and 3 again. Different from the Results - Table: from 0 to 4, the results are therefore not understandable in the subsequent sections when comparisons between groups are made.

Group 0 - CNV with no drusen in the fellow eye. Is this group to be considered AMD? Or is CNV due to other causes? Such asymmetry between eyes would not be expected. Can these 4 groups be truly comparable? It seems the authors are mixing different causes of PCV, and therefore different results are expected regarding treatment.

Hyperpermeability of the choroid is substantially superior in the group with pachydrusen - again pathophysiology should be further explored in the discussion, before discussing different responses to treatment.

Discussion:

The work is much interesting from a clinical perspective, as biomarkers of treatment and prognostic are necessary to improve outcomes in CNV treatment, but the authors should investigate and elaborate more on the difference of phenotypes and if these could represent in fact variants of the same disease process or distinct clinical entities with PCV as the final result. Comparing treatment outcomes is not sufficient per se. Instead of only focusing in pachydrusen, the complete pathophysiologic picture and pachychoroid spectrum versus typical AMD and then response to treatment should be considered and discussed.

Reviewer #2: Dear Authors,

The paper reports some interesting results in a very hot topic in AMD treatment, the underestimated PCV. The authors presents some findings that are very important to observe regarding the fellow eye conditions and how the affected eye responds to the proposed therapy. The combined therapy PDT + aflibercept for PCV appears to be a good choice at a very interesting rationale, however the availability of verteporfin in some countries is limited. There is a trend for anti-VEGF mono therapy for most of those case, and some papers shows very similar results.

Regarding the figures, the authors illustrate two examples of patients in group 2 and 3, showing the differences of pachydrusen and soft drusen. The other figures illustrate the main results as described in the methods.

It is important to remember that this is a retrospective study, with uneven number of patients on each group, specially in group 1 and 3, with only 8 and 6 patient respectively, almost 1/3 of the patients of the other groups, this might affect the comparative results. The most interesting of the paper was to observe that patients with pachydrusen in the FE had the longest re-treatment free period and less additional IV injections, that might reflect a better and effective response to PDT as pointed to the authors.

Overall the paper is well written, some english corrections should be made, and in my opinion the authors should enrich their discussion. Of course is not possible to make definitive conclusion with a retrospective studies but may suggest some insights for future papers.

All the best

**********

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PLoS One. 2020 Aug 11;15(8):e0237330. doi: 10.1371/journal.pone.0237330.r002

Author response to Decision Letter 0

11 May 2020

Dear Academic Editor:

We thank you, and the reviewers for timely and constructive feedback on our manuscript. We appreciate the opportunity to respond.

Reviewer #1: I read with interest the present paper which explores the differences between treatment response in PCV patients according to the type of drusen found in the fellow eye. It is a original ideia and interesting to explore in the search of biomarkers of disease prognosis and response to treatment.

However, there are several issues that must be addressed before accepting the manuscript for publication.

Reply: Thank you for your timely and positive feedback on our manuscript.

First, the short title has a minor error in "depending"

Reply: Thank you for your pointing. We corrected the term from “depnding” to “depending”.

Introduction:

The authors start by stating that "PCV is a unique subtype of exudative age-related macular degeneration (AMD) ", this, however, is still a debated statement. Controversy persists, especially as PCV can be found in other settings and pathologic associations. The introduction is somewhat globally inconsistent and better rephrasing and English review is necessary before publication.

Reply: We agree and have emphasized that although some feel PCV is a subtype of AMD, there is debate as to whether PCV is a distinct entity. Please see additions to line 44, 50-51 to reflect these changes. The manuscript was reviewed and edited by one (R.P) of the authors, a native speaking US retinal specialist with prior publications and research experience to ensure improved clarity and phrasing in English.

Combination treatment versus anti-VEGF monotherapy approach is still not consensual and is not the point of the present study, but assumptions of superiority of one over the other cannot be made as expressed in the second paragraph. Other bibliography sources are to be added to support the information provided if this point is presented here.

Reply: We agree and have added citations from clinical trials such as EVEREST 1 and 2 demonstrating superiority of both anatomic and visual outcomes of combination therapy over PRN anti-vegf monotherapy.

Pachydrusen are presented as a distinct clinical entity, but reference and linkage to pachychoroid spectrum should be more clearly explored. Should these pachydrusen be completely assumed to be part of AMD, or they can be present in other settings? The group refers to a previous study on clinical and genetic characteristics of pachydrusen in patients with exudative AMD, where they acknowledge that patients with pachydrusen have genetic and clinical characteristics distinct from those of soft drusen and pseudodrusen of typical AMD, however the presence of both pachydrusen, pachychoroid and PCV in the setting of other diseases is not further explored.

Reply: Thank you for your comments. Pachydrusen are often seen in eyes with pachychoroid diseases including central serous chorioretinopathy, pachychoroid neovasculopathy, and polypoidal choroidal vasculopathy. Therefore, these manifestations are not specific to AMD. We added the following sentences“ Pachydrusen are not specific to AMD and they are often seen in pachychoroid diseases such as central serous chorioretinopathy”.

Methods:

Again, English is to be improved, for example in the line 85 " slit-lamp examination with or without 78 diopter lens intraocular measurement".

Reply: Thank you for your pointing. The term “intraocular measurement” was removed. The manuscript was reviewed and edited by one (R.P) of the authors (U.S retinal specialist).

Only one vertical and one horizontal line in OCT analysis are enough? How was the CRT values obtained? And choroidal thickness?

Reply: We are happy to clarify these things. Please see lines 103-108. We performed a horizontal and vertical OCT scan through the fovea. In patients with extrafoveal lesions, we performed OCT scans corresponding to the lesion in addition to scans of the fovea. This scan pattern might be insufficient; however, we cannot judge whether this scan pattern has influence on the present results.

CRT was measured as the vertical distance between inner surface of neurosensory retina and retinal pigment epithelium beneath the fovea. Subfoveal choroidal thickness was measured as the vertical distance between Bruch’s membrane and choroidoscleral border at the fovea.

Only late-phase ICGA was used to discriminate between soft and pachydrusen but other features must be considered, only one reference for this ICGA based definition is not sufficient.

Reply: Please see lines 95-97 and we have added how we defined soft drusen and pachydrusen on OCT imaging as well. OCT scans demonstrate that soft drusen are RPE bump while pachydrusen are drusenoid deposits. In this retrospective study, we did not perform volume-scan OCT covering posterior pole for all study eyes. Therefore, it is difficult to differentiate all drusen in the posterior pole. We cited only reference [24]; however, a previous report demonstrated that soft drusen exhibited hypofluorescent. (Arnold JJ et al. Indocyanine green angiography of drusen. Am J Ophthalmol. 1997). We cited this article as reference [25].

Since PCV is stated here to be considered as a variant of neovascular AMD, was monthly loading dose performed or only one combination treatment was performed with observation after 3 months? As this is not standard for PCV treatment or typical nAMD treatment, was follow-up of only once every 3 months considered sufficient?

Reply: In Japan and other nations outside of the US, often PRN treatment is necessary as monthly dosing is not always feasible. In our study, an initial anti-VEGF was given to address acute exudation and PDT was done for longer term therapy of aneurysmal lesions. Patients were followed every 3-month intervals until recurrence. This approach involving PDT and anti-VEGF agents was first reported by Sato et al in 2010 (Am J Ophthalmol). In this report, a follow-up interval was 3-month was used and our current standard of care. Following their report, we determined the follow-up period until appearance of recurrent exudation. We considered that our follow-up period (3-month) was adequate until recurrence based on prior studies and treatment patterns in Japan.

Was the t-test possible to use in this sample? Groups are quite small - group 1 has only 8 subjects and is the main focus of this work.

Reply: Instead of a t-test, differences of values between before and after treatment were analyzed by Wilcoxon signed rank test. Therefore, all p-values were tested by Wilcoxon signed rank test was changed.

Results:

Line 124: The group's enumeration in methods is wrong: 1, 2, 3, and 3 again.

Reply: Thank you for bringing this to our attention. We corrected the numbering from Group 0 to Group 3.

Different from the Results - Table: from 0 to 4, the results are therefore not understandable in the subsequent sections when comparisons between groups are made.

Reply: We apologize for any confusions. The groups are label 0-3 for a total of 4 groups. The tables are correct to the best of our knowledge.

Group 0 - CNV with no drusen in the fellow eye. Is this group to be considered AMD? Or is CNV due to other causes? Such asymmetry between eyes would not be expected. Can these 4 groups be truly comparable? It seems the authors are mixing different causes of PCV, and therefore different results are expected regarding treatment.

Reply: Thank you for your comments. We wish to clarify that minimal or a complete lack of drusen are typically the case in PCV as well as other pachychoroid phenotypes such as CSC (Maruko et al, Am J Ophthalmol, 2007). Further, we also wish to highlight in the text both proposed mechanisms of exudation in neovascular retinal disease which are choroid mediated (ie pachychoroid) or inflammatory (ie from drusen).

Please see lines 341-358 which discusses phenotypical differences in PCV and traditional AMD as well as proposed mechanisms of exudation.

.

Hyperpermeability of the choroid is substantially superior in the group with pachydrusen - again pathophysiology should be further explored in the discussion, before discussing different responses to treatment.

Replay: Thank you for valuable comments. We agree and will add a discussion on the above.

Please see lines 319-325 including the added citations [32] and [33].

Discussion:

The work is much interesting from a clinical perspective, as biomarkers of treatment and prognostic are necessary to improve outcomes in CNV treatment, but the authors should investigate and elaborate more on the difference of phenotypes and if these could represent in fact variants of the same disease process or distinct clinical entities with PCV as the final result. Comparing treatment outcomes is not sufficient per se. Instead of only focusing in pachydrusen, the complete pathophysiologic picture and pachychoroid spectrum versus typical AMD and then response to treatment should be considered and discussed.

Reply: Thank you for your thoughtful comments. We agree and have added the above. Please see lines 341-358.

Reviewer #2: Dear Authors,

The paper reports some interesting results in a very hot topic in AMD treatment, the underestimated PCV. The authors present some findings that are very important to observe regarding the fellow eye conditions and how the affected eye responds to the proposed therapy. The combined therapy PDT + aflibercept for PCV appears to be a good choice at a very interesting rationale, however the availability of verteporfin in some countries is limited. There is a trend for anti-VEGF mono therapy for most of those case, and some papers shows very similar results.

Regarding the figures, the authors illustrate two examples of patients in group 2 and 3, showing the differences of pachydrusen and soft drusen. The other figures illustrate the main results as described in the methods.

It is important to remember that this is a retrospective study, with uneven number of patients on each group, especially in group 1 and 3, with only 8 and 6 patient respectively, almost 1/3 of the patients of the other groups, this might affect the comparative results. The most interesting of the paper was to observe that patients with pachydrusen in the FE had the longest re-treatment free period and less additional IV injections, that might reflect a better and effective response to PDT as pointed to the authors.

Overall the paper is well written, some English corrections should be made, and in my opinion the authors should enrich their discussion. Of course, is not possible to make definitive conclusion with retrospective studies but may suggest some insights for future papers.

Reply: Thank you for your positive comments and constructive criticism.

1. PDT is still commonly performed for eyes with PCV in Asia despite a complicated procedure. Due to costs, in most of Asia anti-VEGF is PRN and thus PDT is often used to reduce treatment burden as it is not practical for most patients to receive continuous anti-VEGF if no active exudation. Clinical trial data such as the EVEREST II and FUJISAN studies have shown the decreased treatment burden of combination therapy compared to anti-VEGGF monotherapy.

2. As the reviewer pointed, we acknowledged that weak point of the current study is retrospective nature of analysis and small number of Group 1 and Group 3. We added the several sentences to improve the manuscript in the discussion.

3. The manuscript has been edited by one of the authors (R.P) a retinal specialist in US.

Thank you again for reviewing our manuscript.

Attachment

Submitted filename: Response to reviewers revision.docx

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Decision Letter 1

Manuel Alberto de Almeida e Sousa Falcão

24 Jul 2020

Response to photodynamic therapy combined with intravitreal aflibercept for polypoidal choroidal vasculopathy depending on fellow-eye condition:2-year results

PONE-D-20-00729R1

Dear Dr. Sakurada,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Manuel Alberto de Almeida e Sousa Falcão, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors made required changes in the final paper and all comments that were made was addressed by the authors

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Reviewer #1: No

Reviewer #2: Yes: Fernando Marcondes Penha

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Data

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    Attachment

    Submitted filename: Response to reviewers revision.docx

    Click here for additional data file. (24KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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