PONE-D-20-35344

Accuracy of frozen section in intra-operative margin assessment in breast conserving surgery: systematic review and metanalysis

PLOS ONE

Dear Dr. garcia,

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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We look forward to receiving your revised manuscript.

Kind regards,

Lanjing Zhang, MD, MS

Academic Editor

PLOS ONE

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Additional Editor Comments:

This is a well-designed systematic review and meta-analysis. The findings are not very novel as one of the reviewers commented, while its method is overall acceptable. See the following concerns for your consideration.

Major points:

1. The search terms "lumpectomy" and "breast conserving surgery" are missing, but should be included.

2. Does frozen section also have high sensitivity? If so, please comment on it and add "sensitivity" in the concluding sentence.

3. Cross-sectional and cohort studies have different study design and scientific rigor/biases. It will be very important and interesting to conduct subgroup analyses based on study design (Cross-sectional and cohort studies in different groups).

4. Histology types of breast cancer may influence its outcome, and cancer distribution pattern. So it may also be necessary either discuss this point in light of/citing prior studies ((e.g. PMID: 28746732 and PMID: 30518616) or conduct subgroup analysis.

Minor points:

1. It will be helpful if the sensitivity and specificity of each study are shown.

2. Recommend to cite the papers that shows increasing use of lumpectomy/BCS in recent years (e.g. PMID: 24929768, PMID: 29423512 and PMID: 28586788)

3. Writing style issues: Just some examples.

Title: in breast ... may be replaced with for breast...

Abstract: metanalysis and exams may be replaced with meta-analysis and studies, respectively; CI should be spelled out, I2 may be replaced with I-squared or I-2;

Section 2.2: "we admitted" may be replaced with "we included"

Section 2.4: a "that" is needed before "were selected"

[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

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

Reviewer #1: I Don't Know

Reviewer #2: N/A

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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

**********

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

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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 manuscript demonstrated results of systematic review and metanalysis on accuracy of frozen section on margin evaluation in breast conserving surgery.

1. This topic is not cutting edge; it was extensively discussed on the literature more than 10 years ago on this breast pathology practice. Currently,

The frozen section for margin evaluation in partial mastectomy specimens is not commonly used in an intraoperative setting of pathology practice at least in hospitals located in the US due to some technical issues including but not limited to the following:

-It is well known that breast tissue is fatty and difficult to cut into a complete section for microscopic evaluation when

it is fresh (without fixed in formalin solution for certain period of time). This nature of fresh breast tissue makes

margin evaluation by frozen section often challenging. Nowadays, some surgeons use radiographic image on fresh

tissue specimen instead of frozen sections to decide if margins are clear and if a new margin (or which margin) needs

to be re-excised before completing a breast conserving surgery. This practice has been gone well over the years in

our institution.

-Also sometimes cutting frozen section on fresh breast tissue takes a longer time due to fatty nature of the specimen

compared to cutting non-fatty tissues; furthermore the frozen section practice prolongs operating time.

Although this study showed an accuracy of frozen section in intra-operative margin assessment in breast conserving surgery, now this practice has not been widely adopted at least in the US, probably, partly due to the reasons mentioned above. Therefore, not sure if this study had significant clinical utility at the current breast conserving surgery practice across the world.

2. A total of 19 studies (42 references) were analyzed; not sure if number of the studies is enough for this metanalysis.

3. English needs to be polished; there are some grammatical errors.

Reviewer #2: 1. Some hospitals routinely perform intraoperative margin assessment in breast conserving surgery, while others do not. Can you compare advantage and disadvantage of different techniques, including gross analysis, radiology, and cytology examination? How is local recurrence and reoperation rate individually? What scenarios do authors prefer to do frozen sections rather than other methods?

2. Is there any difference about false positive rate and false negative rate among different cancer type, such as IDC, ILC or mucinous carcinoma?

3. There is the large variability in false negative rate from 0% to 23%. What are reasons to cause this?

4. In Jorns and Ko studies, the number of patients with reoperation is larger than the number of patients with false negative rates. Except false negative margin, is there any other reason to let surgeons re-operate patients?

5. Is it possible to list turnaround time for results in the table considering that one of disadvantages of intraoperative assessment is to increase surgery time?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-20-35344R1

Accuracy of frozen section in intraoperative margin assessment for breast-conserving surgery: a systematic review and meta-analysis

PLOS ONE

Dear Dr. garcia,

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 specifically address the editor's comments which seemed not be done in the first round of revision. 

Please submit your revised manuscript by Apr 02 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Lanjing Zhang, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The revision has greatly improved the manuscript, but my concerns seemed not be addressed at all (See below). The abstract and text still have some writing style issues.

This is a well-designed systematic review and meta-analysis. The findings are not very novel as one of the reviewers commented, while its method is overall acceptable. See the following concerns for your consideration.

Major points:

1. The search terms "lumpectomy" and "breast conserving surgery" are missing, but should be included.

2. Does frozen section also have high sensitivity? If so, please comment on it and add "sensitivity" in the concluding sentence.

3. Cross-sectional and cohort studies have different study design and scientific rigor/biases. It will be very important and interesting to conduct subgroup analyses based on study design (Cross-sectional and cohort studies in different groups).

4. Histology types of breast cancer may influence its outcome, and cancer distribution pattern. So it may also be necessary either discuss this point in light of/citing prior studies ((e.g. PMID: 28746732 and PMID: 30518616) or conduct subgroup analysis.

Minor points:

1. It will be helpful if the sensitivity and specificity of each study are shown.

2. Recommend to cite the papers that shows increasing use of lumpectomy/BCS in recent years (e.g. PMID: 24929768, PMID: 29423512 and PMID: 28586788)

3. Writing style issues: Just some examples.

Title: in breast ... may be replaced with for breast...

Abstract: metanalysis and exams may be replaced with meta-analysis and studies, respectively; CI should be spelled out, I2 may be replaced with I-squared or I-2;

Section 2.2: "we admitted" may be replaced with "we included"

Section 2.4: a "that" is needed before "were selected"

I would also modify the abstract as:

Background and objectives: It is well established that tumor-free margins is an important factor

for reducing local recurrence and reoperation rates. This systematic review with meta-analysis of

frozen section intraoperative margin assessment aims to evaluate the accuracy, and reoperation

and survival rates, and to establish its importance in breast-conserving surgery. Methods: A thorough review

was conducted in all online publication-databases for the related literature up to March 2020. MeSH terms used: “Breast

Cancer”, “Segmental Mastectomy” and “Frozen Section”. We included the studies that evaluated accuracy of

frozen section, reoperation and survival rates. To ensure quality of the included articles, the

QUADAS-2 tool (adapted) was employed. The assessment of publication bias by graphical and

statistical methods was performed using the funnel plot and the Egger’s test. The review protocol

was registered in PROSPERO (CRD42019125682). Results: Nineteen studies were deemed

suitable, with a total of 6,769 cases. The reoperation rate on average was 5.9%. Sensitivity was 0.81,

with a Confidence Interval of 0.79–0.83, p=0.0000, I-2=95.1%, and specificity was 0.97, with a

Confidence Interval of 0.97–0.98, p=0.0000, I-2 =90.8%, for 17 studies and 5,615 cases. Accuracy

was 0.98. Twelve studies described local recurrence and the highest cumulative recurrence rate

in 3 years was 7.5%. The quality of the included studies based on the QUADAS-2 tool showed a

low risk of bias. There is no publication bias (p=0.32) and the funnel plot showed symmetry.

Conclusion: Frozen section is a reliable procedure with high accuracy, sensitivity and specificity

in intraoperative margin assessment of breast-conserving surgery. Therefore, this modality of

margin assessment could be useful in reducing reoperation rates.

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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 #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 #2: Yes

**********

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

Reviewer #2: N/A

**********

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 #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 #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 #2: (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 #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.

Accuracy of frozen section in intraoperative margin assessment for breast-conserving surgery: a systematic review and meta-analysis

PONE-D-20-35344R2

Dear Dr. garcia,

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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Kind regards,

Lanjing Zhang, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Sorry for missing your original rebuttal to the editor, but thank you for additional revision.

Please change "margins" in the first sentence of the abstract to "margin" during the copy editing.

Congratulations!

Reviewers' comments:

NA