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

Mio Matsubara; Yoichi Sakurada; Atsushi Sugiyama; Yoshiko Fukuda; Ravi Parikh; Kenji Kashiwagi

doi:10.1371/journal.pone.0237330

Peer Review History

Original SubmissionJanuary 9, 2020
5 Mar 2020 Decision Letter - Manuel Alberto de Almeida e Sousa Falcão, Editor 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 Dear Dr Sakurada, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. We would appreciate receiving your revised manuscript by Apr 19 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. 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 ****** 4. 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: No Reviewer #2: Yes ****** 5. 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: 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 ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
11 May 2020 Author Response 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. Attachments Attachment Submitted filename: Response to reviewers revision.docx https://doi.org/10.1371/journal.pone.0237330.r002
24 Jul 2020 Decision Letter - Manuel Alberto de Almeida e Sousa Falcão, Editor 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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 ****** 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 ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes:** Fernando Marcondes Penha https://doi.org/10.1371/journal.pone.0237330.r003

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