PONE-D-20-24681

Modified Gemcitabine, S-1, and Leucovorin Combination for Patients with Newly Diagnosed Advanced or Metastatic Pancreatic Adenocarcinoma: A Multi-center Retrospective Study in Taiwan

PLOS ONE

Dear Dr. Li-Yuan Bai,

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Erika Cecchin

Academic Editor

PLOS ONE

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

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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: This study aimed to retrospectively evaluate the feasibility of a modified chemotherapeutic regimen using the combination of gemcitabine plus the oral fluoropyrimidine S-1, as first-line treatment of locally advanced or metastatic pancreatic adenocarcinoma in Taiwan before the reimbursement of nab-paclitaxel. Among the 44 evaluable patients. partial response rate and disease control rate were 29.5% and 68.2%, respectively; progression-free survival and overall survival were 6.94 and 11.53 months, respectively. The most common grade 3 or higher toxicities were anemia (18.3%) and neutropenia (6.1%). These results suggest that the investigating therapeutic regimen could be feasible and relatively safe. However, some limitations in this study should be considered, including its retrospective nature and the limited sample size.

The present manuscript is well-written and clear regarding its endpoints; however, it should be subjected to some minor changes, as it follows:

-In the title please modify Advanced in Locally Advanced.

-In the paragraph "Introduction": on line 77 please correct trial to trials; on line 82 please specify that the considerable

toxicities are related to FOLFIRINOX; on line 89 however should be substituted with despite of modified schedule; on line 113

please specify that the reference [8] is referred to gastric and not pancreatic cancer.

-In the paragraph “Discussion” authors should better explain the reasons why gemcitabine was given at a 20% lower dose

(800 mg instead of 1000 mg/m2) and with a modified schedule (on day 1 every 2 weeks instead of days 1 and 8 every 3

weeks). Indeed similar modifications of dosage and schedule could have affected safety and toxicity results; authors should

mention and argue the point.

Reviewer #2: This is a retrospective study of a chemotherapy regimen GSL for patients with locally advanced and/or metastatic pancreas cancer. There are only 49 patients in the study. The toxicity was manageable so the chemotherapy was reasonably well tolerated. However, the efficacy was minimal as the median survival was 10 months and the median progression-free survival was 8 months. The regimen has minimal efficacy.

Reviewer #3: The manuscript entitled ‘Modified Gemcitabine, S-1, and Leucovorin Combination for Patients with Newly Diagnosed Advanced or Metastatic Pancreatic Adenocarcinoma: A Multi-center Retrospective Study in Taiwan’ was aimed at evaluating efficacy and toxicity of first-line gemcitabine administered at a fixed-dose rate in combination with the oral fluoropyrimidine S-1 and folinic acid in late stage pancreatic cancer patients.

As the authors well highlight in the manuscript, more active treatments are currently available also in Taiwan, however this study has some value and results showed a substantial activity of the chemotherapeutic combination.

Unfortunately, the retrospective nature of this study represents an unfavorable aspect. Thus, in order to maximally exploit this study and to provide the reader with more relevant information, the following aspects (see below) have to be satisfied.

Main comments

Results are limited to the description of survival parameters, objective response, toxicity.

In order to better characterize the response (efficacy/toxicity) of this setting of patients in respect to the study combination, a proper statistical analysis (univariate and multivariate analysis) of relationships between efficacy (survival parameters - PFS and OS; objective response) or toxicity and clinical/pathological characteristics included in Table 1 should be performed.

The statistical analysis should also include as variables to be considered the administered cycles and dose reductions (i.e. by subdividing patients according to at least two groups) and second line treatments. Please, add in table 1, accordingly, the mean number of administered cycles (and range), dose reductions and second line treatments.

English language should be revised by a mother tongue person.

Minor comments

Please, include in Table 3 also the absolute numbers of patients and not only percentages.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Modified Gemcitabine, S-1, and Leucovorin Combination for Patients with Newly Diagnosed Locally Advanced or Metastatic Pancreatic Adenocarcinoma: A Multi-center Retrospective Study in Taiwan

PONE-D-20-24681R1

Dear Dr. Li-Yuan Bai,

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,

Erika Cecchin

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The Authors addressed the criticisms raised by the Reviewers and better addressed their study limitations in the paper discussion.

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

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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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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: (No Response)

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: (No Response)

Reviewer #2: 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: (No Response)

Reviewer #2: I think that the authors have carefully considered the criticisms of each reviewer and revised the manuscript accordingly. It is now acceptable 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: Yes: Michela Guardascione

Reviewer #2: No