PONE-D-21-38928A meta-analysis of the value of circulating tumor cells in monitoring postoperative recurrence and metastasis of colorectal cancerPLOS ONE

Dear Dr. WU,

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.

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ACADEMIC EDITOR:  Please respond to the reviewers' comments. ==============================

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Please respond to the reviewers' comments.

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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: No

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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: This meta-analysis by Wu et al examines the utility of CTC to predict recurrence or metastases of stage I-III CRC following surgery. Thirteen studies with 1788 patients were included in the analysis. CTC detected by membrane arrays and at least one week post-operatively had the best sensitivity, pooled PLR, pooled NLR, and pooled DOR for predicting recurrence and metastases. The emerging role of liquid biopsies in oncology clinical trials and management of patients makes the topic clinically relevant.

Major Comments:

1) Why was disease recurrence and metastases combined? Was this because of how the 13 included studies were designed? Since local disease recurrence is theoretically curable, while only a subset of metastatic disease is, it would be better if CTC predicting recurrence was separated from CTC predicting metastases.

2) Though I was able to find the PRISMA checklist, I did not find Figure 1: Search flowchart. Please include in revision.

3) Since there are multiple ongoing studies utilizing ctDNA to predict disease recurrence in resected CRC, it would benefit the discussion to compare/contrast CTC and ctDNA in this space.

4) How did the authors qualitatively conclude that peripheral blood CTC has a moderate monitoring value for predicting CRC recurrence and metastases following surgery? How would they incorporate CTC detection into their clinical practice?

Minor Comments:

1) What is meant by B-ultrasound?

2) Can the authors discuss why CTC were assayed around 7 days post-op? Theoretically, cancer cells embolized during surgery could still be present. In contrast, ctDNA is typically assayed 3-6 weeks post-op.

3) Some misspelled words, such as "literatures."

4) On pg 19, no mention of EpCAM as a marker of CTC was included in detection methods.

5) Please clarify the sentence on page 20, "a low number of CTCs often had a good response rate." Low CTC could represent lower stage disease pre-treatment, a less aggressive biology, etc. and not only a better treatment response.

Reviewer #2: Thank you for your work, yet there are some flaws to be addressed:

- the paper needs to be revised by a native English speaker

- Figure 1 is totally blurred and therefore it should be improved

- In the paper there are several misprints, please improve the manuscript

- the authors did not succeed in include a clinical impact of this research. Have you considered the implementation of molecular tumor board in resected setting? Please read this paper that could help you. PMID: 34896250

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-38928R1A meta-analysis of the value of circulating tumor cells in monitoring postoperative recurrence and metastasis of colorectal cancerPLOS ONE

Dear Dr. WU,

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.

ACADEMIC EDITOR: Please address reviewer's comments. In particular, please edit the written English.

Please submit your revised manuscript by Sep 02 2022 11:59PM. 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jason S. Gold

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Please address the reviewer's comments. In particular, please edit the written English.

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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: (No Response)

Reviewer #2: (No Response)

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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: Yes

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

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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

**********

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: The authors have addressed many of my prior critiques. Please revise by incorporating responses to the comments below.

Major comments:

1) Please include your response to my prior critique about separating recurrence and metastases in the discussion section. This point is important for readers to understand. Locally recurrent disease is still potentially curable while metastatic disease is not.

2) I appreciate the added comments regarding ctDNA. The most recent NCCN guidelines include this discussion regarding ctDNA

A prospective, multicenter study of 130 patients with stage I–III colon cancer detected ctDNA by multiplex, PCR-based next-generation sequencing (NGS).306 Thirty days after surgery, patients with positive ctDNA assays were seven times morelikely to experience disease relapse than patients who were ctDNAnegative (HR, 7.2; 95% CI, 2.7–19.0; P < .001). Likewise, after adjuvant chemotherapy, patients with ctDNA-positive assays were 17 times more likely to have disease relapse (HR, 17.5; 95% CI, 5.4–56.5; P < .001). Another prospective study of 150 patients with localized colon cancerdetected dtDNA with NGS following surgery.307 In this study, detection of ctDNA was also associated with poorer DFS (HR, 17.56).

It would be helpful to include these studies in the discussion and more extensively discuss the advantages/disadvantages of ctDNA vs CTC as ctDNA is being rapidly incorporated into clinical trials while CTC is less so. The point of this meta-analysis is to convince readers that CTC should also be considered as a rational and practical liquid biopsy.

3) The response to my prior critique that "CTC combined with CEA, CA125, CA19-9 and other tumor markers has higher sensitivity and specificity" should be included in the discussion. Again, to emphasize that there are alternatives to ctDNA.

4) Please include a statement somewhere in the discussion that shows that CTC obtained one week post-surgery does not represent hematogenous spread during the procedure itself. I'm still skeptical that one week post-op is the best time to sample CTC which represent metastatic potential.

Minor comment:

1) The manuscript needs further editing of written English. For example in the first paragraph of the discussion, I believe "pathogenesis" is meant when "pathogens" is used. Another example is on page 18 where "litter" precedes "relevant literature." I do not understand that meaning.

Reviewer #2: thank you for your valuable work.

The authors have addressed all the reviewers' comments.

The paper is well-written and interesting to the general audience.

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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.

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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

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[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.

A meta-analysis of the value of circulating tumor cells in monitoring postoperative recurrence and metastasis of colorectal cancer

PONE-D-21-38928R2

Dear Dr. WU,

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.

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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,

Jason S. Gold

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have appropriately responded to all the reviewers' questions and comments.

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

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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: 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: Prior critiques have been addressed appropriately by the authors. After editorial review for grammar and spelling, would be appropriate for publication.

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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

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