Interobserver variability in interim PET assessment in Hodgkin lymphoma—reasons and solutions

Thomas W. Georgi; Lars Kurch; Dirk Hasenclever; Victoria S. Warbey; Lucy Pike; John Radford; Osama Sabri; Regine Kluge; Sally F. Barrington

doi:10.1371/journal.pone.0283694

Peer Review History

Original SubmissionDecember 9, 2022
8 Jan 2023 Decision Letter - Domenico Albano, Editor PONE-D-22-33844Interobserver variability in interim PET assessment in Hodgkin lymphoma - Reasons and solutionsPLOS ONE Dear Dr. Georgi, 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. Please submit your revised manuscript by Feb 22, 2023. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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: Yes 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: Dear authors, this is a really interesting work focusing on an interest issue of nuclear medicine as you underline in the introduction and in the discussion. The english language and the syntax are good. I have some minor issues to underline: - why not perform the qDS also in the case of major discrepancies? - in the conclusione you stated that semiquantitative assessment can solve disagreement, however in your study this is true only in a small amount of the cases; please correct. - a minor point is that the acronym SUV is used without a definition. Reviewer #2: This manuscript describes the results of a blinded iPET scan review conducted by two experienced nuclear physician of scans collected from the Rapid randomized trial for early stage HL. Authors describe the results of the two readers and report on the reasons for major and minor discrepancies. They also describe adoption of qPET as a meaningful method to solve some of the discrepancies. In the discussion they provide some suggestion to reduce discrepancies. Overall this is simple descriptive study that allows to define some practical suggestion that, however, would require validation or at least an expert consensus. From a clinical point of view this study adds little to what is currently known and does not really help to identify a final key message. Authors should try to answer the main question that for a clinician is...what is the clinical consequence of observed discrepancies? Which are pactical suggestions to move the field forward? Are suggestions able to reduce the effect of discrepancies for the final clinical decision? One practical suggestion is to add a table with a summary of practical suggestion identified to reduce discrepancies. One relevant aspect here is that baseline PET scans were missing. How do authors believe availability of baseline scan would have helped to reduce discrepancies? The main conclusion with this paper is about the utility of qPET to solve some discrepancies. To be pragmatic does this mean that qPET should be used from the beginning instead of the conventional visual approach recommended for the DS definition? ****** 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.] 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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0283694.r001
Revision 1
15 Feb 2023 Author Response Point-by-point reply to the reviewers’ comments Reviewer #1: Why not perform the qDS also in the case of major discrepancies? We performed the qDS also in the patients with a major discrepancy. A concordant qDS was not achieved in any of the patients with a major discrepancy. We added this information in the result part of the manuscript (line 170-171) and in a table (S1 Table) in the supplementary material. In the conclusion you stated that semiquantitative assessment can solve disagreement, however in your study this is true only in a small amount of the cases; please correct. You are right, only a minor number of discrepancies 35/192 (18%) can be solved by semiquantitative assessment. The majority of discrepancies are detection- or interpretation-based and can not be solved by additional quantification since lesions overlooked or not considered to be lymphoma are not quantified. This fact is given in the second paragraph of the conclusion (line 267-268). However, we think that our statement in the last paragraph of the conclusion is correct (line 272-273) and evaluation-based discrepancies can be solved by additional quantification, if both readers measured the same lesion. Evaluation-based discrepancies occur if both readers agree on the lymphoma residuals, yet disagree which of them is the ´hottest´ lesion or which is the visual DS of the hottest lesion. The use of a quantitative method provides a specific value for each lesion. These values determine the order of the lesions and, thus, the ´hottest´ lesion regardless of the reader. Moreover, quantified lesions can be classified into a qDS according to validated cut-off values. A minor point is that the acronym SUV is used without a definition. The acronym SUV is written out now (line 100). Thank you for this remark. Reviewer #2: Practical suggestion, however, would require validation or at least an expert consensus. The discordant iPET results were discussed between the two readers (LK, TG) and three further authors of our manuscript (SB, RK, VW) in order to find causes for interobserver discrepancies. Our group consists of five nuclear physicians with long-year experience in the iPET assessment in lymphoma patients, e.g. reference reading of all PET scans in the EuroNet-PHL-C1 and -C2 trial with pediatric patients with Hodgkin lymphoma (RK, LK, TG) and in the RAPID trial with adult Hodgkin lymphoma patients (SB, VW). Therefore, our practical suggestions can be seen as an expert consensus. This fact has not yet been clearly stated in the manuscript. We added this information in the method part (line 110-112) and in the discussion part (line 187-188) of the manuscript. What is the clinical consequence of observed discrepancies? The iPET assessment plays an important part in the determination of further lymphoma treatment. Pediatric patients with Hodgkin lymphoma with a negative iPET result were not irradiated anymore in the EuroNet-PHL trials. In adult patients, the iPET result is used to determine the number of subsequent chemotherapy cycles. Thus, interobserver discrepancies can have significant clinical consequences. On the one hand, undertreatment of patients increases the risk of recurrence. On the other hand, an increased treatment intensity that is not indicated unjustifiably increases the risk of therapy-associated late effects, especially in children. The current threshold between a positive and negative iPET result is between DS 3 and 4. In 40 (21%) of all 192 discrepancies in our study, both readers disagreed as to whether the iPET was positive or negative. This would have led to different further treatment intensities. We added these informations in the introduction (line 54-56) and discussion (line 241-244 and 247-249) part of the manuscript. Are suggestions able to reduce the effect of discrepancies for the final clinical decision? Yes, our suggestions are able to reduce discrepancies for the final clinical decision. As mentioned above, In 40 patients, both readers disagreed as to whether the iPET was positive or negative. Six of these 40 discrepancies were resolved by additional quantification. Some of the other discrepancies might be also solved by our suggested improvements. We added this information in the discussion part (line 249-251) of the manuscript. According to your remark, we added a table with practical suggestions to reduce interobserver discrepancies (table 4). In return, we have dispensed with Figure 1. How do authors believe availability of baseline scan would have helped to reduce discrepancies? First, the likelihood of missing a lymphoma lesion in the iPET scan is significantly reduced because the reader is looking for every lesion visible in the baseline PET scan. Second, the differentiation between malignant and inflammatory tracer uptake is much easier. Increased tracer uptake in initially involved lymph nodes is most probably malignant. Whereas increased uptake in initially not involved lymph nodes is more likely to be inflammatory if the lymphoma is generally responding well to treatment. Thus, baseline PET scan is suitable to reduce both, detection- and interpretation-based discrepancies. Does this mean that qPET should be used from the beginning instead of the conventional visual approach recommended for the DS definition? No, our suggestion would be the use of a quantitative method additionally to the visual assessment. This would decrease evaluation-based discrepancies. 35/192 (18%) visual discrepancies in our study achieved a concordant qDS. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0283694.r002
14 Mar 2023 Decision Letter - Domenico Albano, Editor Interobserver variability in interim PET assessment in Hodgkin lymphoma - Reasons and solutions PONE-D-22-33844R1 Dear Dr. Thomas W Georgi, 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, Domenico Albano Academic Editor PLOS ON 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 ******** 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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) ****** 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 ******** https://doi.org/10.1371/journal.pone.0283694.r003
Formally Accepted
17 Mar 2023 Acceptance Letter - Domenico Albano, Editor PONE-D-22-33844R1 Interobserver variability in interim PET assessment in Hodgkin lymphoma - Reasons and solutions Dear Dr. Georgi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Domenico Albano Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0283694.r004

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