PONE-D-20-03800

Bone metastasis and skeletal-related events in patients with solid cancer: a Korean nationwide health insurance database study

PLOS ONE

Dear Dr Hong,

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: The manuscript requires a revision according to the recommendations from the reviewers. One reviewer mentioned that the article is not easy-to-read. To ensure the quality of English and the readability of the article, please provide proof of English editing service by native English speakers when resubmitting the revision. 

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Kind regards,

Jason Chia-Hsun Hsieh, M.D. Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The manuscript requires a revision according to the recommendations from the reviewers. One reviewer mentioned that the article is not easy-to-read. To ensure the quality of English and the readability of the article, please provide proof of English editing service by native English speakers when resubmitting the revision.

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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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

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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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: 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: The enclosed manuscript by Hong et al. is an analysis of bone metastases and skeletal related events in Korea using a national database. The authors find an incidence of bone metastases and SREs in an Asian population similar to what has been published from other parts of then world. The authors look at survival after bone mets and SREs and provide useful information on the natural history of bone metastases. The incidence of bone metastases in stomach and liver cancer is useful as these diseases occur frequently in this population.

I believe this article adds to the worldwide information on the scope of the problem of bone metastases.

I suggest acceptance of this manuscript with no revision needed

Reviewer #2: This study is a good dataset may contribute to the better identification of bone health in patients with solid cancers. However, I have some concerns on the methodology.

Specific Comments

1. Which ICD-code of bone surgery SRE in this study ?

2. The literature showed that once a patient experiences an SRE, the risk of subsequent SRE is increase. I wonder if this study had the data on the cumulative number of SREs in each patient ?

3. Pathologic fracture is strongly associated with an increased risk of death. How about the differences of overal survival between BM patients with fracture SRE and those without fracture SRE, and those without SRE.

4. In the discussion part, please correct "1,845 bone metastasis patients" into "1,849".

Reviewer #3: The definition of SRE (Skeletal-related events) about radiation is slightly different for each paper. (severe bone pain requiring radiation vs. just radiation to bone)

In some cases, radiation therapy is administered for asymptomatic bone metastases in patients to reduce the risk of skeletal-related events. Therefore, it must be noted and the authors should concern and describe about this.

Reviewer #4: This is well written and organized paper. The authors addressed the bone metastasis and SRE in patients with diverse solid cancers in Korea.

Minor points

1. In material and methods section. I can’t easily understand the following sentences. Please explain. “We excluded paticipants who were aged less than 20 years~ at least 2 years to assess for bone metastases and SREs” What does washout mean?

2. Please add Kaplan-Meier survival curves for OS, and survival after bone metastasis if possible. (You can add just 2 figures, one for OS including all cancer types, and the other for survival after bone metastasis)

Reviewer #5: This study showed the epidemiology of bone metastases and skeletal-related events (SREs) in Korea using claims data from the National Health Insurance Service National Sample Cohort. However, the study presented only numerical value. Statistic data was not connected to QOL or medical cost, although authors mentioned in discussion and conclusion. I can’t discover a new and unique point from this study. Therefore, unfortunately, I think that this manuscript is not candidate for publication in PLOS ONE.

Major point

1. This study focused on 7 major cancer types (stomach, colorectal, liver, lung, breast, prostate, and other genitourinary cancers). The reference about Korea cancer incidence should be added.

2. Why did authors use the only C795 for bone metastases? The reason should be documented in discussion.

3. Authors defined pathologic fracture, spinal cord compression, bone radiation, and bone surgery as SREs. Why did authors exclude hypercalcemia from SREs? And what was the procedure cord for bone surgery? How did authors handle overlapping data from the different cords? I don’t understand this sentence “In addition, patients diagnosed in 2002 were excluded for washout and were followed up for at least 2 years to assess for bone metastases and SREs”.

4. In result, authors commented that bone mets increased with age and there was no difference in region or household. Statistical p value should be added. If authors did not use statistical analysis, the content should be corrected.

5. Discussion is ambiguous and extensive. This cloud the issue. Please clarify authors’ suggestion and present specified contents.

6. The manuscript is not easy to read and the English used really should be checked for grammar and spelling.

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Reviewer #1: No

Reviewer #2: Yes: Lan T. Ho-Pham

Reviewer #3: Yes: IK JAE LEE

Reviewer #4: Yes: Jun Eul Hwang

Reviewer #5: No

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Bone metastasis and skeletal-related events in patients with solid cancer: a Korean nationwide health insurance database study

PONE-D-20-03800R1

Dear Dr. Hong,

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,

Jason Chia-Hsun Hsieh, M.D. Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All the questions were answered adequately.

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

Reviewer #3: All comments have been addressed

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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: The authors have addressed questions posed by reviewers. I recommend acceptance of this revised version

Much improvement in English grammar

Reviewer #2: The authors have addressed all the issues raised sufficiently. This manuscript may be now acceptable for publication.

Reviewer #3: I reviewed the revised manuscript submitted by the authors.

The authors responded appropriately to what I pointed out.

Reviewer #4: (No Response)

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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

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No