PONE-D-20-22549

Treatment sequences of patients with colorectal cancer treated with ramucirumab in Japan: A retrospective observational study using an administrative database

PLOS ONE

Dear Dr. Tanizawa,

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,

Takeshi Nagasaka, M.D., Ph. D.

Academic Editor

PLOS ONE

Additional Editor Comments:

As the revisers’ comments, this study is too much focus on Ramucirumab, and did not evaluate aflibercept or bevacizumab with FOLFIRI as second line chemotherapy. Moreover, Yoshinori

Tanizawa, Zhihong Cai, and Yongzhe Piao are hired Eli Lilly company which sell RAMUCIRUMAB. The authors should be re-evaluating all of issues in this study for these regimens, and please discuss the results, objectively.

The MDV database has many biases, as the reviewer 2 mentioned. The authors make too emphasis about RAMUCIRUMAB.

However, If the authors re-edit this data not only for RAMUCIRUMAB but also other two anti-VEGF antibodies, this article will be worthful for giving information to clinicians in relation to considering 2nd line regimens.

Therefore, I decide this article as Major revision.

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"I have read the journal's policy and the authors of this manuscript have the following competing interests:

ES has received honoraria from Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd.

YK has received honoraria from Bayer Co., Ltd., Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Sanofi Co., Ltd., Eli Lilly Japan Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Merck Co., Ltd.

AM has received honoraria from Eli Lilly Japan Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.

HS has received research funding from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and honoraria from Bayer Co., Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., MSD Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Co., Ltd., and Yakult Honsha Co., Ltd.

YT, ZC, and YP are employees and/or minor shareholders of Eli Lilly Japan K.K."

We note that one or more of the authors have an affiliation to the commercial funders of this research study : Eli Lilly Japan K.K.

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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: Partly

Reviewer #2: No

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

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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 authors described the treatment sequences for advanced colorectal cancer (CRC) and the use of ramucirumab in Japan, and to explore factors associated with overall treatment continuation with antitumor drugs.

Factors significantly associated with shorter treatment continuation from second-line ramucirumab were low body mass index, not fully independent ADL, and previous irinotecan treatment. Factors significantly associated with longer treatment continuation were left-sided CRC, previous use of oral fluoropyrimidines or anti-EGFR antibody, longer duration of the previous therapy line (≥180 days), and use of qualitative tests for proteinuria and antihypertensives during second-line therapy.

The authors concluded that management of hypertension and testing for proteinuria are important for successful sequential therapy that includes antiangiogenic drugs.

I think that the meaningful table is only Table5. However, background is so mixed, and only univariate data were shown. I think that these analyses should be separated based on RAS status and sidedness at first, and multivariate analysis should be tried.

In conclusion, based on Table5, the authors mentioned that "management of hypertension and testing for proteinuria are important for successful sequential therapy that includes antiangiogenic drugs."

However, there are no information about the real information about hypertension and proteinuria in the database. I think that it is impossible to produce this conclusion. I think that the checkup of proteinuria and blood pressure is essential for the treatment of CRC using ramucirumab. The doctor who do not check these parameters may not be able to manage any complications of chemotherapy, leading to bias.

Reviewer #2: The manuscript is well written and shows a lot of real-world data of treatment sequence for CRC patients in Japan using a large administrative database. However, as authors mentioned in limitations session, the using database is not population based and may be far from general clinical data. For example, I recognized that the transition rate from 1st to 2nd line for CRC patients was almost 80%. On the other hand, this study showed the transition rate from 1st to 2nd line for presumed RAS-murtant CRC was 56.0% in Table 1. I think this MDV database lacks detailed clinical information.

Another point to mention, the authors suggest that management of hypertension and testing for proteinuria during treatment are important for successful continuation of sequential therapy that includes antiangiogenic drugs in conclusion session. Generally, patients who continue treatment for a long time have an increased risk of developing adverse events. So, it is difficult to say that management of hypertension and testing for proteinuria are important for successful continuation of treatment as conclusion. This conclusion could mislead the reader.

Reviewer #3: In this study, the authors, Shinozaki E et al, assessed the treatment sequences and use of ramucirumab in real-world data using MDV database to clarify the treatment sequences of patients with advanced CRC in Japan and to explore the clinical and treatment-related factors associated with treatment continuation with ramucirumab. Although this study includes several novel and interesting points, totally this paper is too much complicated and very difficult to read and understand. Several points need to be addressed for publication of “Plos One”.

My major concern is described below

1. Currently, one of the most relevant issues in CRC chemotherapy is the decision making of anti-VEGF drugs in second line treatment with FOLFIRI. However, this study is too much focus on Ramucirumab, and did not evaluate aflibercept or bevacizumab with FOLFIRI as second line chemotherapy. The authors should need to be re-evaluate all of issues in this study for these regimens, and please discuss the results. It is really helpful and clinically meaningful for clinicians.

2. This manuscript is too much complicated, and it is very difficult to read and understand due to assessment of several aspects using complicated and not perfect MDV database. Therefore, it is better to re-write to focus more clinically relevant points to easy to understand for readers.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-20-22549R1

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database

PLOS ONE

Dear Dr. Tanizawa Y,

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 Jan 31 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,

Takeshi Nagasaka, M.D., Ph. D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear Authors,

As the revisers’ comments, this study is now ready to acceptance.

However, there still some concerns.

P20, Abstract, the sentence is difficult to follow, ‘Patients who underwent adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for CRC in or after May 2016 were analysed until September 2019.’

This mean ‘this study enrolled CRC patients who underwent first-line chemotherapy, including the patients who received adjuvant therapy but presumably experienced early recurrence from May 2016 to September 2019’?

P27, Treatment sequences, the following sentences are very difficult to follow.

First-line or adjuvant therapy ended when patients added a new antitumor drug not included in the treatment regimen or when patients discontinued all antitumor drugs in the treatment regimen for 180 days or more, whichever occurred first.

Table 3.

Number of antiangiogenic drug prescriptions Median (IQR) 5 (3–9)

Please exclude mean (SD) 6.9 (6.1).

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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: All comments have been addressed

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

**********

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 described the treatment sequences for advanced colorectal cancer (CRC) and the use of ramucirumab in Japan, and to explore factors associated with overall treatment continuation with antitumor drugs.

The manuscript has been properly revised. I'm satisfied with this revised manuscript.

Reviewer #2: (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

[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.

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database

PONE-D-20-22549R2

Dear Dr.Tanizawa,

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,

Takeshi Nagasaka, M.D., Ph. D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

You addressed all concerns.

This article is enough to giving acceptance.

Reviewers' comments: